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Inherited neurodegenerative diseases 

Inherited neurodegenerative diseases

Chapter:
Inherited neurodegenerative diseases
Author(s):

Edwin H. Kolodny

and Swati Sathe

DOI:
10.1093/med/9780199204854.003.02417

Update:

Neurofibromatosis 1 and 2—expanded discussion.

Von Hippel-Lindau disease—revised recommendations for screening of affected or at risk individuals.

Frontotemporal dementia—new information on genetic causes; description of inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia (IBMPFD).

Infantile seizures—genetic causes for some cases of febrile seizure; discussion of severe myoclonic epilepsy of infancy.

Other conditions—enhanced discussions of hereditary diffuse leucoencephalopathy with spheroids and pigmentary orthochomatic leucodystrophy, autosomal dominant spinocerebellar ataxias.

A relevant case history from Neurological Case Histories: Case Histories in Acute Neurology and the Neurology of General Medicine has been added to this chapter.

Updated on 28 Nov 2012. The previous version of this content can be found here.
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Essentials

Many nervous system disorders have a genetic basis, but may be difficult to diagnose because of nonspecific signs, slow progression, and lack of any family history.

Neurodegenerative disorders present an enormous challenge because of the complexity of the nervous system, the broad clinical and genetic heterogeneity characteristic of these diseases, and the progressive and generally irreversible nature of their neuropathology. A mutated gene is generally at fault, resulting in decreased production of a structural or regulatory protein important for the development or normal functioning of a special part of the nervous system.

Clinical approach

A systematic approach to the inherited neurodegenerative diseases involves analysis of (1) principal presenting signs—in most cases these will relate to one neuroanatomical region or pathology specific to that disease, e.g. the brain cortex in dementias; (2) time of onset; (3) mechanism of inheritance—the family history is obviously a key component, and specific enquiry regarding parental consanguinity must always be made; (4) extraneural clues—e.g. specific signs involving the eyes, skin, connective tissues, or visceral organs; (5) metabolic derangements—in an appropriate clinical context investigation may reveal evidence of disorders of pathways involving amino acids, organic acids, lipids, carbohydrates, purines and pyrimidines, heavy metals, porphyrins, and vitamins; (6) relevant genetic tests.

Making the diagnosis—careful correlation of presenting signs with specific components of the nervous system will demystify most neurodegenerative diseases. Judicious use of neurophysiological, neuropsychological, neuroradiological, and neuropathological testing narrows the possibilities, but ultimately the diagnosis may depend upon a biochemical test or the demonstration of a DNA abnormality within a particular gene.

Management—because of their complexity, it is recommended that patients with a neurodegenerative condition receive consultation from a multidisciplinary team involving both clinical specialists (e.g.—as required—neurologist, ophthalmologist, orthopaedic surgeon, radiologist, physiotherapist) and laboratory scientists (e.g.—as required—cytogeneticists, pathologists, biochemists, and molecular geneticists).

Particular inherited neurodegenerative diseases

Neurocutaneous syndromes (phakomatoses)—e.g. neurofibromatosis (1 and 2), tuberous sclerosis, von Hippel–Lindau disease, Sturge–Weber syndrome. These involve defects in tumor suppressor genes that lead to distinctive skin lesions in combination with tumors of brain and other organs.

Defects in DNA repair—e.g. xeroderma pigmentosum, ataxia telangiectasia, Cockayne’s syndrome. Present with a wide range of abnormalities, including in many conditions a propensity to various cancers and skin abnormalities.

Dementia—this is a common feature of many neurodegenerative conditions and the result of abnormal protein aggregation within cortical neurons in Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and prion protein diseases.

Inherited epilepsy syndromes—these are often caused by defects in genes regulating voltage- or ligand-gated ion channels, but epilepsy is also a feature of several lysosomal storage diseases and many other inborn metabolic disorders.

Leucodystrophies—these are disorders which have a genetic basis, a progressive clinical course, primary involvement of white matter, and a demonstrable biochemical or molecular defect. The primary leukodystrophies can be classified into three subgroups: (1) classic dysmyelinative disorders—e.g. X-linked adrenoleukodystrophy, metachromatic leukodystrophy; (2) hypomyelinative with delayed or decreased myelin production—e.g. Pelizaeus–Merzbacher disease; and (3) vacuolating myelinopathies—e.g. Canavan’s disease. Secondary inherited leukodystrophies include (1) metabolic disorders—e.g. various mitochondrial and lysosomal storage diseases, amino and organic acidemias, some glycogen storage diseases; (2) vascular disorders—e.g. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).

Movement disorders—basal ganglia pathology is a principal feature of these conditions, which include Wilson’s disease, Huntington’s disease, and Parkinson’s disease. The hereditary ataxias, e.g. Friedreich’s ataxia, involve primarily the cerebellum and/or spinocerebellar tracts. In the hereditary spastic paraplegias the pyramidal tracts of the spinal cord are a major site of pathology, whereas motor neuron involvement is characteristic of the spinal muscular atrophies and amytrophic lateral sclerosis. Failure of motor function can arise due to primary diseases of muscle, as in the hereditary myopathies and muscular dystrophies.

Future prospects

The search for new therapeutic agents for rare inherited neurogenerative diseases is currently exploring a wide range of possible interventions, including small chaperone molecules that target misfolded proteins, immunization against aberrant protein aggregations, antisense oligonucleotides, interference RNA, neural stem cells that repair complex neural circuitries, and drugs with neuroprotective and anti-inflammatory effects.

The tables are a guide to the established disease genes but are not comprehensive as new discoveries in neurogenetics are occurring at a rapid pace. For further listings, the reader should consult the Human Gene Bank (http://www.hgmd.cf.ac.uk) and Gene Clinics (http://www.geneclinics.org).

Introduction

As a result of the rapid expansion of molecular genetics into clinical medicine, we are currently witnessing monumental advances in our understanding of inherited diseases of the nervous system. In assessing patients with neurodegenerative diseases, the clinician can become overwhelmed by the growing list of diagnostic possibilities and available tests. Therefore, a systematic approach is needed that will narrow the differential diagnosis, reduce the time needed to determine an exact cause, permit earlier therapeutic interventions, and remove uncertainty in counselling patients and their relatives about prognosis and risk to other family members.

The earliest clinical signs in most inherited diseases of the nervous system refer to one neuroanatomical region or pathology specific to that disease. It may be the brain cortex as in dementias, the underlying white matter as in many leucodystrophies, the pyramidal tract as in the hereditary spastic paraplegias, the extrapyramidal system affected in various movement disorders, or cerebellar–spinal pathways typical of the spinocerebellar degenerations. Primary affection of the peripheral nervous system may lead to spinal muscular atrophy, peripheral neuropathy, or a myopathy. Therefore, it behoves the clinician to take note of the earliest signs and symptoms and to extract from the examination an indication of the principal anatomical system(s) involved.

The age at which clinical signs and symptoms appear provides the second major criterion for reaching an accurate diagnosis. Admittedly, elucidation of the molecular defects in classic forms of neurogenetic disorders has permitted an expansion of the phenotypic spectrum to include both earlier onset of more severe variants as well as later, adult-onset forms of disease. Thus the practitioner experienced in geriatrics cannot ignore the possibility of a typical childhood-onset disorder first appearing in late adult life, nor can the paediatrician discount the likelihood of a classic adult-onset condition presenting in childhood.

A third guide to consider is the mode of inheritance. Family history is obviously a key component but may be lacking, especially in autosomal recessive disease. Knowledge of consanguinity can, however, be helpful in this regard. Other inheritance patterns especially common in neurological diseases include the repeat nucleotide expansion disorders and mitochondrial inheritance. The clinician interested in neurogenetics should also become familiar with other disease-causing genetic mechanisms such as the effects of genetic imprinting (parent-of-origin effect), uniparental disomy, chromosomal disorders, and the effects of spontaneously occurring major rearrangements within and between chromosomes. Modifier genes may also have a profound effect on penetrance, i.e. whether a disease-causing gene is expressed or remains silent.

Another means of classification of neurogenetic diseases utilizes extraneural clues such as the presence of specific signs involving the eyes, skin, connective tissues, or visceral organs, e.g. certain inborn errors of metabolism may present with corneal clouding or cataracts, abnormalities in skin pigmentation, or enlargement of the liver and/or spleen. Yet another method of classifying the inherited neurodegenerative diseases focuses on the metabolic derangements that occur in each (see Section 12). Thus, we refer to disorders of pathways involving amino acids, organic acids, lipids, carbohydrates, purines and pyrimidines, heavy metals, porphyrins, and vitamins. Often it is also possible to localize the abnormality to a particular subcellular element such as the mitochondria, lysosome, or peroxisome.

Although ultimately it will be helpful to obtain a specific DNA diagnosis, many tools are available to assist the clinician in obtaining the correct clinical diagnosis. These include various neuroimaging techniques, neurophysiology studies, microscopic studies of blood cells and tissue biopsies, and biochemical analyses of blood, urine, cerebrospinal fluid, and cultured skin cells. Judicious choices of confirmatory studies need thoughtful consideration of the history and clinical findings, and family history, often in consultation with a neurometabolic disease specialist.

Many inherited diseases of the nervous system present only after a prolonged presymptomatic period of several decades. This creates difficulties in attempting to reverse a pathological process that is advanced and already associated with significant cell loss, and in counselling and preventing further cases within the same family. Therefore, where there are therapies, prospects for newborn screening are being considered. In cases of severe morbidity within families of an as yet untreatable disease, prenatal diagnosis, often using preimplantation testing, may be considered. Use of this technology presupposes knowledge of a specific genetic marker for the disease in question.

Neurocutaneous syndromes (phacomatoses)

The phacomatoses are recognized by distinctive skin lesions that appear in childhood and the subsequent appearance of tumours in the brain and other organs. Several of these diseases involve defects in tumour-suppressor genes.

Neurofibromatosis 1

Neurofibromatosis 1 (NF1), also called von Recklinghausen’s disease, is the most common of the phacomatoses, with a prevalence of 1 in 3000. The first feature to appear are café-au-lait macules which may be present at birth or appear during the first few months of life. There must be six or more café-au-lait spots for abnormality to be considered. Axillary freckling occurs next, usually by school age, followed by Lisch’s nodules (melanotic hamartomas of the iris) gradually developing and then neurofibromas at puberty, which are made of Schwann cells, fibroblasts, and mast cells. These tumours may be cutaneous or subcutaneous, or extend into multiple nerves forming plexiform neurofibromas. About 40% of patients develop plexiform neurofibromas, which can in turn develop into malignant peripheral nerve sheath tumours, which have a poor overall survival rate. A small percentage of patients develop optic pathway gliomas, which do not appear to cause any ophthalmological symptoms. T2-weighted MR images of brain reveal high-intensity, nonenhancing lesions, most often found in the brainstem, thalamus, cerebellum, and basal ganglia. These tend to disappear by late adolescence or early adulthood. Scolisis occurs in 21% of patients and may be dystrophic or nondystrophic; the latter is characteristic of NF1, is rapidly progressive, and has a worse prognosis. Other skeletal changes associated with mesodermal dysplasia include posterior vertebral body scalloping; thinning of the pedicles, transverse processes, and lamina; foraminal enlargement; sphenoid wing dysplasia and cortical thinning; periosteal proliferation; sclerosis; and bowing of the long bones. Phaeochromocytoma, renal artery stenosis, and precocious puberty are also encountered. Learning disabilities, attention deficit disorder, intellectual impairment, seizure disorder, and psychiatric manifestations may appear in a small percentage of patients.

The neurofibromas are benign tumours derived from the nerve sheath and contain multiple cell types. Pilocytic astrocytomas also develop most commonly in the optic nerve, chiasma, and tract. The NF1 gene maps to chromosome 17q11.2 and codes for neurofibromin, a GTPase-activating protein that silences the proto-oncogene p21-ras and plays a role in sketetal development and growth. This autosomal dominant disorder is often inherited from a more mildly affected parent. Random somatic mutation of the one remaining functional NF1 gene is believed to be required for tumour formation.

Plexiform neurofibromas causing pressure symptoms may necessitate excision and others may merit removal for cosmetic reasons; they often recur. Rapid expansion of a tumour, the development of pain, and loss of neural function suggest malignant change, and this occurs most often during adolescence or in young adults. Early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy is indicated. Development of hypertension will require investigation for phaeochromocytoma, and spinal deformity may need orthopaedic attention. Follow-up annually in a multidisciplinary neurofibromatosis clinic is advisable.

Neurofibromatosis 2

Inherited neurodegenerative diseasesNeurofibromatosis 2 (NF2) is also autosomal dominant but is much less common than NF1 with a frequency of 1 in 30 000. The principal manifestation is bilateral vestibular schwannomas associated with multiple meningiomas, cranial nerve tumours, optic gliomas, and spinal tumours. A definite diagnosis requires the presence of bilateral vestibular schwannomas or development of a unilateral vestibular schwannoma by 30 years of age and a first-degree blood relative with NF2, or a unilateral vestibular schwannoma and at least two of the following conditions associated with NF2: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity/juvenile cortical cataract Adults present with unilateral hearing loss, often associated with tinnitus. The Wishart form, usually associated with a truncating mutation, presents earlier with faster progression of lesions leading to deafness, cataracts and focal neurological deficits. The milder or Gardner form presents later in life with relatively stable tumours over years.

Inherited neurodegenerative diseasesRecommended diagnostic testing includes brain MRI with attention to internal auditory canal and spinal MRI to assess for tumours. In cases of bilateral hearing loss, a cochlear implant may be beneficial. Surgical treatment remains a cornerstone of management for symptomatic and progressive vestibular schwannomas, meningiomas, and spinal tumours. Vascular endothelial growth factor inhibitors have shown promising results for in delaying surgery for vestibular schwannomas, and other targeted molecular therapies are investigational options.

The NF2 gene is located on the long arm of chromosome 22 and encodes merlin or schwannomin, a protein expressed in neurons, the lens of the eye, blood vessels, leptomeningeal cells, astrocytes, gonadal tissue, and Schwann cells. As in the case of neurofibromin, merlin mediates growth suppression and the development of NF2 requires a second hit to the remaining normal NF2 gene. The loss of NF2 expression is also seen in 30 to 70% of sporadic meningiomas and almost all sporadic schwannomas. Segmental neurofibromatosis affecting a restricted area of the body may be due to somatic mutations.

Tuberous sclerosis (Bourneville’s disease)

Inherited neurodegenerative diseasesThe clinical features of tuberous sclerosis (TS) are intellectual impairment, infantile spasms, epilepsy, and the occurrence of retinal hamartomas and characteristic skin lesions. The disorder is dominantly inherited with a birth incidence of 1:6000, but may be transmitted by individuals who are asymptomatic or show only minimal clinical evidence of the disease. Isolated cases are frequent, making up as many as 80 or 90% of index cases. Many probably represent new mutations; others are transmitted by gene carriers with trivial manifestations. Genetic heterogeneity has now been established, with separate loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). The TSC1 gene product hamartin and the TSC2-derived protein tuberin form a functional heterodimer that results in downstream inhibition of mTOR (mammalian target of rapamycin), a serine-threonine kinase implicated in the activation of translation regulators involved in the expression of many proteins in cell proliferation and growth. Tuberin also binds p27, which has been implicated in regulating cell cycle progression. Glutamatergic and GABAergic neurotransmission abnormalities have been demonstrated in the tubers, which may underlie epilepsy and intellectual disability seen in TS. Mutations have been identified in 85% of patients with TS, of whom 85% are TSC2. Those with TSC1 mutation have a less severe disease phenotype.

The earliest cutaneous lesions are irregular foliate areas of depigmentation over the trunk. These patches are readily identified when viewed under ultraviolet (UV) illumination using Woods’ lamp. Facial angiofibromas (‘adenoma sebaceum’) are a second type of skin lesion that develops over the cheeks in a ‘butterfly’ distribution and on the forehead with multiple small warty elevations. Finally, a ‘shagreen patch’ may be present over the lower back. This consists of an area of elevated roughened skin with a yellowish tinge, which has been likened to shark skin. An ungual or periungual fibroma is present after puberty and in adult life.

The cerebral changes give rise to intellectual impairment, which is evident in early life and may be static or involve a slowly progressive cognitive decline, often complicated by a behavioural disorder. Infantile spasms or epilepsy with recurrent generalized or focal seizures may occur in association with intellectual impairment or in individuals of normal intelligence. The cerebral lesions, which are demonstrable by CT or MRI, are typified by nodular or tuberous masses composed of proliferated glial cells and enlarged distorted neurons. They may become calcified, and are found scattered throughout the cerebral cortex; they also extend into the ventricles to produce an appearance that was considered to resemble ‘candle guttering’ when seen in pneumoencephalograms. Gliomas sometimes arise in these lesions.

Retinal tumours, termed phacomas, may be present, and cardiac rhabdomyomas occasionally arise as well as hamartomas of the lungs and kidneys. Polycystic disease of the kidneys may also be associated.

Treatment consists of control of the epilepsy and management of the intellectual impairment and behavioural disorder. Facial angiofibromas have been successfully treated by laser ablation, and angiomyolipomas by embolization. Surgery is indicated if brain tumour size increases or if seizure foci are localized within abnormal brain tissue.

Von Hippel–Lindau disease

Von Hippel–Lindau disease (VHL) is an autosomal dominant disorder with an estimated incidence of 1 in 35 000 characterized by central nervous system (CNS) and retinal haemangioblastomas, renal cell carcinoma, and phaeochromocytomas. Renal and pancreatic cysts, tumours of the pancreas, cyst adenomas of the epididymis and broad ligament, and endolymphatic sac tumours of the inner ear are also frequent. The disorder is caused by germline mutations in the VHL tumour suppressor gene (TSG), located on chromosome 3p25–26, and demonstrates marked phenotypic variability and age-dependent penetrance. Inactivation of its protein product pVHL leads to up-regulation of several growth factors, including vascular endothelial growth factor and erythropoietin.

The retinal lesions consist of angiomatous vascular malformations. The cerebellar lesion is a haemangioblastoma, often cystic, which may slowly expand and require surgical treatment. Such tumours may be associated with polycythaemia.

Inherited neurodegenerative diseasesVHL: screening for affected or at-risk individuals

  1. 1 Careful ophthalmic examinations every 12 months beginning in infancy or early childhood

  2. 2 MRI scans of the head (±spine) every 12 to 36 months beginning in adolescence to detect presence of CNS hemangioblastomas

  3. 3 MRI scans of the abdomen every 12 months from age 16 years for renal cell carcinoma

  4. 4 Yearly screening for phaeochromocytoma beginning in early childhood. 24-h urine studies to measure catecholamine metabolites and measurement of plasma normetanephrine levels; the latter is reported to be the most sensitive test for detecting phaeochromocytoma

Patients with VHL require imaging of the CNS and spinal cord, monitoring of blood pressure and catecholamine metabolites, and an annual eye examination. Surgical removal is required for symptomatic tumours.

Sturge–Weber syndrome

Sturge–Weber Syndrome (SWS, also known as encephalofacial angiomatosis) is a sporadic congenital condition; the classic manifestation is a capillary malformation of the skin, port-wine birthmark, also known as port-wine stain/nevus, in the V1 distribution of the face (forehead and/or eyelid). This may be associated with involvement of V2 and V3 distributions, cerebral venous malformations (leptomeningeal angiomatosis), and glaucoma with ocular capillary venous vascular malformations. Bilateral port-wine nevus is associated with a higher risk of brain involvement.

Epilepsy (75–80% of patients), intellectual impairment, migraine, stroke-like episodes, and focal neurological deficits are frequent. CT of the brain reveals calcifications in the involved leptomeningeal vessels. Stroke-like episodes marked by transient hemiparesis or visual field deficits, difficult to distinguish from postictal Todd’s paresis, are described in SWS. However, the stroke-like episodes are more prolonged than a postictal paresis and may last days, weeks, or months, or become permanent. It has been suggested that SWS patients may have regional cerebral hypoperfusion with brain areas at risk for sustained ischaemia.

Bannayan–Riley–Ruvalcaba syndrome

This rare autosomal dominant disorder is characterized by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay, and intellectual impairment. Germline mutations in the PTEN (phosphatase tensin homologue deleted on chromosome TEN) are found in two-thirds of individuals with Bannayan–Riley–Ruvalcaba syndrome. PTEN, a tumour suppressor gene, has been mapped to chromosome 10q23.3.

Vascular malformations, such as arteriolovenous shunts, arteriovenous anomalies, and arteriovenous fistulas, are described in a subset of BRRS patients.

Defects in DNA repair

As in the phacomatoses, the diseases involving defects in DNA repair cause skin abnormalities, neurological manifestations, and tumours although the tumours are outside the CNS.

Xeroderma pigmentosum

Xeroderma pigmentosum (XP), defined by extreme sensitivity to sunlight, resulting in sunburn, pigment changes in the skin, and a greatly elevated incidence of skin cancer, begins in childhood. Neurological manifestations occur in 20 to 30% of patients, awith ge at onset from 2 years, and include progressive mental deterioration, cerebral atrophy, sensorineural deafness, choreoathetosis, cerebellar ataxia, peripheral neuropathy, and growth retardation. Ocular signs are restricted to the anterior, UV-exposed structures of the eye (lids, cornea, and conjunctiva) and include photophobia, conjunctival erythema, keratitis, and tumours.

XP is a recessively inherited disorder with 100% penetrance with an estimated incidence of 1 in 100 000 to 1 in 1000 000. Eight different causative genes have been mapped, which are involved in either nucleotide excision repair or post-DNA replication translation synthesis. In the most severely affected form, the XP-A gene, mapped to chromosome 9q34.1, is defective. The protein product of this gene has a much higher affinity for UV-damaged DNA than undamaged DNA, indicating a role for this protein in damage recognition.

For treatment, total protection from sun exposure and UV-emitting lamps is employed along with topical retinoid derivatives.

Ataxia telangiectasia

This autosomal recessive disorder presents in early childhood with unsteady gait and truncal instability. Infants meet major milestones until age 1; however, by age 2 to 3 years, staggering gait (ataxia) appears. The children generally become wheelchair bound by age 10 to 15 years. Oculomotor apraxia (inability to follow an object) and dysarthria occur early but are difficult to evaluate in young children.

Gaze initiation failure, choreoathetosis, and recurrent infections develop, followed by ocular telangiectasias between age 4 and 7 years. Later, cutaneous telangiectasias appear on the face, hands, and feet, the hair becomes prematurely grey, and lymph nodes are atrophic. Sexual infantilism, hepatic dysfunction, and insulin-resistant diabetes develops in older patients. Speech becomes incomprehensible, mental functioning declines, and, by the teens, the child has lost the ability to walk. Cancer develops in 38%, mainly in the form of lymphoreticular tumours and acute T-cell leukaemias. Older patients develop epithelial tumours in various organs. There is also an increase in the incidence of cancer in heterozygotes, especially breast cancer in women. Death occurs in the second decade. Late-onset forms, with onset as late as third or fourth decade and milder phenotype, have been described.

Laboratory tests reveal an elevated serum α‎-fetoprotein, low levels of IgA and IgG2, poor responsiveness to common antigens, and an increased sensitivity of the patient’s chromosomes to irradiation. ATM, the defective gene, located on chromosome 11q22–23, is a large protein kinase that serves as a regulator of the cell cycle checkpoint in response to breaks in double-stranded DNA.

On neuropathological examination there is a degeneration of the Purkinje and granule cells of the cerebellum, loss of anterior horn cells and dorsal root ganglion cells of the spinal cord, and loss of medullated fibres in peripheral nerves of some cases. General pathology studies show absence or abnormal development of the thymus and all lymphoid system elements.

Management of patients with ataxia telangiectasia involves the control of infections with antibiotics, monitoring for early signs of malignancy, the avoidance of multiple X-ray exposures, and the use of antitumour drugs rather than radiation therapy.

Cockayne’s syndrome

In the classic form of this rare, autosomal recessive, multisystem, degenerative disease, symptoms start at the end of the first year or beginning of the second year. Psychomotor development is retarded; there is growth failure and progressive mental and motor deterioration. The face assumes a wizened, progeria-like appearance with sunken orbits, large beak-like nose, prominent ears, and narrow mouth and chin. The hair is sparse and the skin thin and photosensitive, but skin cancer does not occur. Eye signs include photophobia, decreased lacrimation, cataracts, retinal pigmentary degeneration, optic atrophy, strabismus, and nystagmus. Neurological signs consist of nerve deafness, dysarthria, tremor, ataxia, and peripheral neuropathy. Death occurs in the second or third decade. An earlier-onset connatal type II variant and a later-onset type III form have also been described.

CT of the brain reveals calcifications in the basal ganglia and dentate nuclei, and on MRI there are white matter changes. Histological studies disclose both central and peripheral nerve demyelination.

Nucleotide excision repair of actively transcribed genes is impaired in Cockayne’s syndrome. After UV damage in Cockayne’s syndrome (CS), cells, DNA replication, and RNA synthesis fail to recover rapidly as in normal cells. Two complementation groups have been demonstrated, designated CSA and CSB. The CSA gene maps to chromosome 5 and the CSB gene to chromosome 10q11. The large majority of Cockayne’s syndrome patients have mutations in the CSB gene designated ERCCG.

Dementia syndromes

The major dementia syndromes are disorders of abnormal protein aggregation. Both genetic and sporadic forms of each illness exist and overlap has been found with parkinsonian–dementia syndromes. This section surveys the clinical genetics of dementia. See Chapter 24.4.2 for a more detailed account.

Alzheimer’s disease

Alzheimer’s disease accounts for about two-thirds of cases of progressive dementia. It begins with the insidious onset of loss of recent memory, increasing forgetfulness, disorientation, decreased abstraction ability, and word-finding difficulty. Behavioural problems arise including agitation, restlessness, insomnia, paranoia, and sometimes delusions or hallucinations. Depression is common. As the disease progresses the patient becomes increasingly immobile, incontinent, and mute with death occurring one to two decades after symptom onset.

Pathologically, amyloid-bearing neurotic plagues and neurofibrillary tangles are present within the cortex and subcortical nuclei. The neurotic plaques contain extracellular deposits of amyloid β‎-protein (Aβ‎) intimately associated with dystrophic neurites, activated microglia within the amyloid deposit, and reactive fibrillary astocytes surrounding the lesion. The tangles consist of masses of abnormal paired helical filaments (PHFs) and straight filaments in the perinuclear cytoplasm of selected neurons. The PHFs contain insoluble aggregates of the microtubule-associated protein tau in a hyperphosphorylated, largely insoluble form, often conjugated with ubiquitin. Fibrillar Aβ‎ deposits are also found in the basement membranes of cerebral capillaries, arterioles, and small arteries.

Although the age of onset patients is over 60 years in most Alzheimer’s disease, a small number of patients have a presenile onset. Early onset Alzheimer’s may be an autosomal dominant familiar disorder caused by mutations in specific genes. Three genes are implicated: the amyloid precursor protein gene (APP) on chromosome 21, the presenilin 1 gene on chromosome 14, or its homologous gene, presenilin 2, on chromosome 1. When mutated each of these genes cause over-production of the amyloid precursor protein. Also, the elevated dosage of the APP gene in Down’s syndrome readily explains the early onset of Alzheimer’s disease in patients with trisomy 21. Patients with the E4 allele of apolipoprotein E (apo-E4) also have increased susceptibility to Alzheimer’s disease.

Positron emission tomography (PET) and single photon emission CT (SPECT) are being used as adjunctive tests for patients with probable Alzheimer’s disease. For treatment, anticholinesterase inhibitors, antidepressants, and atypical antipsychotic agents are used. Current studies in transgenic Alzheimer’s disease animal models offer a possible basis for immunological approaches to remove Aβ‎ aggregates.

Frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia, accounting for 12 to 25% of the total. Originally, the concept of FTD arose with the recognition of dementia with Pick’s bodies (silver-staining intraneuronal inclusions) in the presence of circumscribed atrophy of the frontotemporal regions. However, as Pick’s bodies are present in a minority of cases, this finding is no longer an essential component of FTD.

Almost 50% of individuals with FTD have a positive family history, and 10 to 20% conform to an autosomal dominant pattern of inheritance.

Although the unifying theme in FTD is focal atrophy of the frontal lobes, temporal lobes, or both, either unilaterally or bilaterally, with greater pathology in the anterior than the posterior temporal lobe, FTD includes related disorders with substantial clinical and pathological overlap such as amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, and corticobasal degeneration.

FTD presents in the sixth decade in three subtypes. In the frontal variant, behavioural changes predominate. Patients with predominantly left hemisphere involvement experience progressive language deficits (nonfluent aphasia). In cases of left anterior lobe atrophy, there is progressive loss of the knowledge of words and objects (semantic dementia). However, patients ultimately progress to more global impairment in frontal and temporal lobe functions. Some patients will also develop parkinsonian features or motor neuron disease. SPECT shows bifrontal and bitemporal hypoperfusion.

FTD pathology can be classified into several distinct entities involving at least two different proteinopathies. In approximately one-half of patients with FTD, there are accumulations of insoluble hyperphosphorylated tau proteins in neurons and/or glial cells with little or no Aβ‎ pathology. The microtubule-associated protein tau (MAPT) gene located on chromosome 17q21 is expressed predominately in axons of central and peripheral nervous system neurons. Mutations in MAPT have been detected in familial cases, suggesting that they are pathogenic for FTD.

However, many FTD patients are negative for tau protein accumulation but are ubiquitin positive. Many of these patients, including both familial and sporadic forms, accumulate TDP-43 protein in the ubiquitin inclusions. This protein, which is encoded by a gene on chromosome 1, is involved in transcriptional repression and alternative splicing, and is also found in the motor neuron disease variant of FTD. Another FTD variant, NIFTD, is associated with abnormal neuronal aggregates of α‎-internexin.

Patients with FTD are managed symptomatically. Serotonin selective reuptake inhibitors and atypical antipsychotic agents have been useful.

Inherited neurodegenerative diseasesAlthough mutations in six unrelated genes, all transmitted in autosomal dominant manner, have been implicated in FTD, three are more common than the others: the tau gene, MAPT, on chromosome 17; the progranulin gene, GRN, which resides very near MAPT on chromosome 17; and the hexanucleotide repeat expansion on chromosome 9, C9ORF72. The rarer genes are TADRP, VCP, and CHMP2B. Disease in families caused by mutations in the GRN gene encoding progranulin displays neuronal inclusions containing both ubiquitin and the TADRP protein, TDP-43.

Inherited neurodegenerative diseasesA recently described condition known as ‘inclusion body myopathy associated with Paget’s disease of bone and/or frontotemporal dementia’ (IBMPFD) is a rare, remarkably pleiotropic disorder inherited in an autosomal dominant manner. IBMPFD should be considered in a patient with mid-adult-onset dementia, characterized by profound, progressive language deficits with relatively preserved memory, accompanied by proximal and distal muscle weakness and/or features of Paget’s disease of the bone.

Dementia with Lewy bodies

(see Chapter 24.4.2)

Lewy body dementia (DLB) is distinguished by the presence of intracytoplasmic aggregates of α‎-synuclein and other proteins within neurons, especially the CA2/3 region of the hippocampus. They are seen as well in some patients with Parkinson’s disease and in others with Alzheimer’s disease. DLB is mostly not familial. The apoE4 allele frequency is increased in DLB but the association is not as strong as in Alzheimer’s disease. Triplication of the α‎-synuclein gene itself is most strongly implicated in familial DLB as well as Parkinson’s disease (PD). Glucocerebrosidase mutations, which in the homozygous state cause Gaucher’s disease, are increasingly described in PD and also may contribute to DLB.

Clinically, there is overlap with Alzheimer’s disease. Signs include fluctuating cognition, recurrent visual hallucinations, parkinsonism, rapid eye movement (REM) sleep disorder, and depression. Treatment with acetylcholinesterase inhibitors can be beneficial but adverse cognitive reactions have been encountered to antipsychotic agents.

Prion disorders

(see Chapter 24.11.5)

Prion diseases have in common the accumulation of an abnormal isoform of the normal human protein PrP. The manner in which the conformational change from the normal form, PrPc, into the abnormal form, PrPsc, is unknown but the PrPsc form then becomes infectious. Prion diseases cause a spongiform change within brains associated with astrogliosis and neuronal loss. Most cases are sporadic but 15% have a familial basis and 1% are iatrogenic, arising from transplanted tissues or pituitary extracts obtained from infected individuals or from incomplete decontamination of surgical instruments.

Creutzfeldt–Jakob disease (CJD) generally presents between ages 50 and 70 with dementia, myoclonus, and ataxia. It is rapidly progressive with death usually within less than 1 year. The EEG of many of the patients contains 1- to 2-Hz triphasic periodic sharp waves. On MRI, hyperintensity is detectable on FLAIR and DWIs (diffusion-weighted images) in the neocortex, basal ganglia, thalamus, and cerebellum.

A variant of CJD (vCJD), believed to be caused by transmission of bovine spongiform encephalopathy (BSE or ‘mad cow disease’) to humans, has been seen in young adults (average age 29 years). It presents with psychiatric symptoms, painful dysaesthesias, ataxia, dementia, and a movement disorder. The median survival is longer than in CJD (c.14.5 months). Diagnosis requires brain or tonsillar biopsy to demonstrate PrPsc. The pathology of vCJD is distinctive with diffuse vacuolization and PrP-containing plaques surrounded by a halo of the spongiform change.

Another variant, Gerstmann–Sträussler–Scheinker syndrome (GSS), is an inherited form that occurs at an earlier age than CJD and progresses more slowly, with death resulting in 2 to 10 years. Signs include ataxia, decreased reflexes, and dementia. Amyotrophy and parkinsonian signs may also appear. EEG changes such as those in CJD are not present. Mild cerebral or cerebellar atrophy is present but there are fewer vacuolar changes than in CJD. There are extensive PrP-amyloid plaques and in some cases also neurofibrillary tangles.

In fatal familial insomnia (FFI), the insomnia is untreatable but cognitive function is spared until late in the disease. Other signs are ataxia, pyramidal and extrapyramidal dysfunction, and dysautonomia. Pathological examination reveals almost no vacuolization but neuronal loss and gliosis are found in the thalamus, inferior olives, and to a lesser degree in the cerebellum.

The PrP protein is encoded on chromosome 20. A codon 129 polymorphism with homozygosity for methionine or valine results in greater susceptibility for sporadic or iatrogenic CJD, whereas heterozygosity at this codon is protective. Methionine homozygosity at this codon results in increased susceptibility to vCJD. FFI is associated with a mutation at codon 178 plus methionine on the polymorphic codon 129. If a valine residue is present at the polymorphic codon 129, CJD results rather than FFI. Amino acid substitutions at several other codons cause GSS.

Epilepsy—genetic aspects

Seizures, i.e. the paroxysmal, spontaneous, involuntary discharge of cortical neurons, result from abnormalities in the regulation of neuronal excitability. The genetic bases for many of the idiopathic generalized epilepsies are now known. Epilepsy syndromes may be classified based on the genetic contribution to their etiology as monogenic or mendelian epilepsies, caused by mutation(s) in a single gene; and complex epilepsies, caused by the interaction of a few or several genetic variants, and influenced by environmental factors. In many instances, monogenic disorders involve genes regulating voltage- or ligand-gated ion channels. Both clinical and genetic heterogeneity occur.

Benign familial neonatal convulsions

Apnoea and focal or generalized seizures begin in the first week of life and remit after some weeks or months. They may recur in later life in 10% of individuals. Although development is normal in most, a small proportion of patients may develop neurological sequelae. Three separate loci for benign familial neonatal convulsions (BFNCs) have been found. Each involves mutations in a voltage-gated potassium channel gene, KCNQ2 on chromosome 20q13, KCNQ3 on chromosome 8q24, and a third locus that maps to chromosome 5.

Benign familial infantile convulsions

The onset of seizures is between 3 and 8 months; the seizures consist of clusters of behavioural arrest, horizontal deviation of head and eyes, and limb jerking. They stop by 1 year of age. The interictal EEG is normal. Linkage to genes on chromosomes 16q and 2 have been suggested, including one family with a SCN2A (sodium channel) mutation.

Inherited neurodegenerative diseasesFebrile seizures

Febrile seizures (FS) are provoked by fever (>38°C) and are not always recurrent, but they may be familial and associated with other forms of epilepsy. Febrile seizures occurring between 6 months and 5 years are the most common form of childhood seizures, occurring in 2 to 6% of infants. Six susceptibility loci have been identified on chromosomes 8q13–q21 (FEB1),19p (FEB2), 2q23–q24 (FEB3), 5q14–q15 (FEB4), 6q22–q24 (FEB5), and 18p11 (FEB6).

Generalized epilepsy with febrile seizures-plus

Seizures often first occur in early childhood in association with fever but continue after the age of 6 in the absence of fever. Seizures may be tonic-clonic, myoclonic, atonic, or absence seizures, or even myoclonic-astatic epilepsy; vary rarely focal temporal lobe epilepsy has been described. In most children, neurological development is normal and the seizures stop in mid-adolescence. Sodium channel genes, encoding the α‎1, β‎1, and α‎2 subunits have been implicated: SCN1A encoded on chromosome 2q24, SCN1B located on 19q13.1, and SCN2A, also mapped to chromosome 2q24, respectively. Mutations in the γ‎-aminobutyric acid (GABA) receptor γ‎-subunit gene, GABRG2, located on chromosome 5q34 have also been found in the generalized epilepsy with febrile seizures-plus (GEFS+) phenotype.

Inherited neurodegenerative diseasesSevere myoclonic epilepsy of infancy and intractable childhood epilepsy with generalized tonic-clonic seizures

Severe myoclonic epilepsy of infancy (SMEI), first described by Dravet in 1978, is a rare disorder characterized by early-onset febrile seizures, followed by frequent afebrile seizures of several types: generalized tonic-clonic seizures, myoclonic seizures, absences, and partial seizures, with psychomotor retardation. Although a family history of seizures is common, a mendelian pattern of inheritance may not be obvious. Ohtahara syndrome or intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), is described in Japanese literature and is characterized by onset of febrile generalized tonic-clonic seizures before 1 year of age, and tending to status epilepticus. Cognitive decline and other neurologic deficits may be associated. Mutations in SCN1A have been found in most cases of these syndromes.

Generalized epilepsy with febrile seizures and absence

These individuals have clinical features similar to GEFS+ but absence seizures tend to predominate. These patients have mutations in GABA-receptor genes including GABRD, mapped to chromosome 1p36, and GABRG2, on chromosome 5q34.

Juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) may comprise 5 to 10% of epilepsy patients. Such individuals present between age 8 and 20 with myoclonic jerks on awakening in the morning, possibly proceeding to generalized tonic–clonic seizures. About one-third will also have absence seizures. The EEG demonstrates bilateral symmetrical 4 to 6 Hz polyspike–wave complexes.

Both autosomal dominant and autosomal recessive modes of inheritance have been suggested. Genes implicated in JME include EFHC1 located on chromosome 6p12–p11, BRD2 mapped to chromosome 6p21.3, CACNB4, a calcium channel gene, on chromosome 2q22–23, CLCN2, a chloride channel gene, encoded on chromosome 3q26, and the GABA receptor gene, GABRA1, found on chromosome 5q34. A voltage-dependent potassium channel gene, KCNQ3 (chromosome 8q24), a calcium-activated potassium channel gene, KCNMB3, and a nicotinic acetylcholine receptor gene, CHRNA-7 (chromosome 15q14) have also been implicated in various JME family studies. Thus, JME is a complex epilepsy syndrome with significant genetic heterogeneity.

Childhood and juvenile absence epilepsy

Childhood and juvenile absence epilepsy (CAE) is estimated to occur in 13 to 17% of individuals with epilepsy. It is present in children aged 4 and 10, and is characterized by multiple daily episodes of impairment in consciousness in association with generalized 3-Hz spike-and-wave discharges. Fluttering of the eyelids, mouth movements, and myoclonic jerks of the extremities may accompany the periods of absence. Two-thirds will stop having seizures although others will go on to have JME or continued absences and generalized seizures as adults. Those with juvenile-onset absence epilepsy have less impairment in consciousness but may progress to have generalized tonic–clonic seizures as adults. Loci identified with CAE include the GABAA receptor subunit GABRG2 (chromosome 5q34) and the voltage-gated chloride channel CLCN2 (chromosome 3q26).

Progressive myoclonus epilepsy

The progressive myoclonic epilepsies include three lysosomal storage diseases—the neuronal ceroid lipofuscinoses, neuronopathic Gaucher’s disease, and the cherry-red spot–myoclonus epilepsy syndrome—a mitochondrial disorder—myoclonus epilepsy with ragged red fibres (MERFF)—and two other entities—Lafora’s body disease and Unverricht–Lundborg disease (Baltic myoclonus epilepsy syndrome). They are characterized by progressive neurological deterioration, various seizure types including polymyoclonus, which becomes unresponsive to antiepileptic medication, and dementia. Levetiracetam has been helpful in some cases.

Neuronal ceroid lipofuscinoses

This class of hereditary neurodegenerative lysosomal storage diseases is a common cause of childhood-onset seizures with an estimated incidence of 1 in 25 000. Common features are decline in cognition and motor functions, and blindness. Autofluorescent lipopigment accumulates within neurons and inclusion bodies characteristic of each variant can be seen by electron microscopy (EM).

Infantile neuronal ceroid lipofuscinosis (CLN1) is characterized by blindness before age 2, seizures, and marked cerebral atrophy. The ultrastructural appearance of the stored substance is predominantly granular, osmiophilic, dense material. Late infantile CLN2 patients present at age 2 to 3 with sleeplessness, seizures, and then visual loss. Curvilinear bodies are present on electron microscopy. The juvenile-onset patients (CLN3) develop retinal pigmentary degeneration in mid to late childhood and then seizures, and, as teens, cerebellar and extrapyramidal signs appear. On electron microscopy a pattern of fingerprint bodies predominates. Death in infantile NCL (CLN1) occurs in childhood whereas survival into adolescence or adult life is the norm for the other variants. See Chapter 12.6 for further details about the neuronal ceroid lipofuscinoses.

Neuronopathic Gaucher’s disease

Gaucher’s disease is characterized by lysosomal storage of the glycosphingolipid, glucocerebroside, within the reticuloendothelical system, involving principally the spleen, liver, and bone. It is due to deficiency of the hydrolytic enzyme, glucocerebroside β‎-glucosidase, encoded on chromosome 1; in the most common type 1 patient it rarely causes CNS complications. However, patients with the rare type 2 form fail to develop neurologically, become cachectic, with multiple brainstem signs and seizures. In the type 2 patient, death usually occurs before the age of 2 from pneumonia.

Approximately 5% of patients with Gaucher’s disease worldwide have, in addition to visceromegaly, slowly progressive neurological involvement which includes gaze initiation failure, strabismus, developmental delay, and, in a few patients, cardiac symptoms. Some develop myoclonic seizures, which progress in frequency and severity and become unresponsive to anticonvulsant therapy.

Diagnosis of this autosomal recessive disease can be made by assay of blood β‎-glucosidase activity. Enzyme replacement therapy is effective in correcting the haematological abnormalities (anaemia, thrombocytopenia), and promotes reduction in the size of the liver and spleen but has proved ineffective in halting the progression of the myoclonic encephalopathy.

Cherry-red spot–myoclonus epilepsy syndrome (sialidosis type 1)

This autosomal recessive lysosomal storage disease begins in late childhood or early adolescence with action myoclonus. Subsequently, generalized seizures and polymyoclonus develop. A cherry-red spot may be seen in the macula early in the course of the disease, with blindness ensuing before significant cognitive decline occurs. Eventually the patient becomes bedridden and totally disabled by multiple myoclonic jerks. Vacuolated lymphocytes are present in peripheral blood and foamy histiocytes may be found in the bone marrow. Within urine, there is a marked increased in sialic acid-containing oligosaccharides. The disorder is due to a deficiency of lysosomal α‎-neuraminidase located on chromosome 6p21.3.

Myoclonic epilepsy with ragged red fibres

Patients with MERFF present in early adult life with short stature, myoclonus, seizures, ataxia, muscle weakness, and sensory neuropathy. Subsequently, dementia, hearing loss, and optic atrophy occur. This is a lactic acidosis and ragged red fibres are seen on a muscle biopsy with Gomori’s trichrome stain. The principal neuropathological findings are degeneration of the dentate nuclei and superior cerebellar peduncles, the spinocerebellar tracts and the posterior columns of the spinal cord. The cause in most cases is a point mutation at position 8344 of the mitochondrial gene for tRNALys.

Lafora’s body disease

This autosomal recessive disease begins in late childhood or early adolescence and progresses to death within 5 years. Tonic–clonic and myoclonic seizures, polymyoclonus, and progressive mental deterioration occur. Cerebellar ataxia, optic atrophy, rigidity, and exaggerated reflexes develop later. On MRI there is moderate cerebellar atrophy and intracellular inclusion bodies composed of polyglucosan are present within neurons of the cerebral cortex, cerebellar dentate nuclei, liver, muscle, and axillary sweat glands. The last is a preferred site for a diagnostic biopsy. Most patients have a mutation in the EPM2A gene located on chromosome 6q23–25 coding for the protein laforin. A few patients have a mutation in EPM2B instead which codes for malin.

Unverricht–Lundberg disease (Baltic myoclonus)

This autosomal recessive progressive encephalopathy is particularly frequent in Finland and Estonia, hence the term ‘Baltic myoclonus’. Onset is in childhood or adolescence and begins with generalized seizures. They are more frequent on awakening. Various stimuli will intensify the polymyoclonic activity. Cerebellar ataxia, dysarthria, pyramidal signs, distal muscle wasting, and over time mental deterioration become evident. Nerve cell loss occurs in the cerebellar cortex, dentate nuclei, and thalami, and sometimes also in the basal ganglia, brainstem, and anterior horn cells of the spinal cord. This disorder is caused by a sequence alteration in the cystatin B gene (CSTB) on chromosome 21, which involves expansion of a dodecamer (CCCCGCCCCGCG) in the 5-′‎flanking area of CSTB. A few patients with point mutations have also been described. Some patients have benefited from 5-hydroxytryptophan, piracetam, or baclofen, but the condition may be worsened by phenytoin which should be avoided.

Pyridoxine-dependent seizures

The seizures in neonatal-onset epileptic encephalopathy are resistant to antiepileptic drugs but respond immediately to the administration of pyridoxine in greater than the normal physiological requirement. Plasma and urinary levels of δ‎1-piperidine-6-carboxylate (P6C) and α‎-aminoadipic semialdehyde (α‎-AASA) are increased due to mutations in ALDHTAI, the gene encoding antiquitin, an α‎-AASA dehydrogenase. The accumulating P6C inactivates pyridoxal-5-phosphate, which is needed for GABA production, a central inhibitory neurotransmitter. Failure to recognize and treat this condition early can lead to permanent brain damage and lifelong intellectual impairment.

Glucose transporter 1 deficiency syndrome

Clinical manifestations of this infantile-onset disorder include severe seizures, intermittent ataxia, confusion, movement abnormalities, spasticity, sleep disturbances, and recurrent headaches. There is deceleration of head growth with acquired microcephaly, developmental delay, and cognitive impairments. Early appearance of episodic eye movements simulating opsoclonus has led to work-up for an occult neuroblastoma.

The absolute level of cerebrospinal fluid glucose is low and cerebrospinal fluid lactate concentration is also reduced. The disorder is due to new heterozygous mutations in GLUTI, which encodes a glucose transporter that is highly expressed in brain and red blood cells. The diagnosis may be confirmed by measuring the uptake of 3-O-methyl-d-glucose into erythrocytes. The seizures are refractory to conventional anticonvulsant medications and are exacerbated by phenobarbital, but respond to a ketogenic diet.

Alpers’ syndrome

Progressive encephalopathy with intractable seizures, diffuse neuronal degeneration, and cortical spongiosis with and without liver disease are features of Alpers’ disease. It usually affects infants and young children but rare juvenile cases are also known. Development delay may precede the onset of seizures, which may start abruptly and consist of various types in individual patients including a marked myoclonic component. Marked motor retardation and intellectual impairment with blindness ensue. Liver dysfunction with jaundice and hepatomegaly may develop. CT and MRI show progressive cerebral atrophy. Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ‎ (POLGI) have been found in a wide phenotypic spectrum of patients with this autosomal recessive disease.

Menkes’ kinky hair disease

This X-linked disorder of copper transport causes profound neurological deterioration with the early onset of seizures, abnormal face and hair, hypothermia, skeletal abnormalities, and arterial degeneration. The scalp hair is sparse, stubby, and greyish in colour. Under a microscope, the hairs are seen to be twisted and display partial breaks. Seizures including myoclonic jerks are almost constant and survival is generally less than 2 years. Serum copper and ceruloplasmin levels are very low, and brain copper is reduced due to poor absorption of copper from the intestine. The disease is caused by mutations in the ATP7A (MNK) gene encoded on chromosome Xq13.3.

Dentatorubral-pallidoluysian atrophy

See under ‘Hereditary ataxias’.

Epileptic encephalopathy due to other inborn errors of metabolism

Numerous hereditary metabolic encephalopathies other than those described above are associated with seizures. In the neonatal period and early infancy these include disorders of amino acids and organic acids, urea cycle disorders, biotinidase deficiency, peroxisomal and mitochondrial diseases, sulphite oxidase deficiency, and 3-phosphoglycerate dehydrogenase deficiency. Seizures presenting in the late infantile and early childhood period may indicate a lysosomal disorder, GABA transaminase deficiency, or creatine synthase deficiency. Disorders to consider when seizures present in later childhood or adolescence include, in addition to those listed above, acute intermittent porphyria and early onset Huntington’s disease. In all cases in which the diagnosis is obscure, routine work-up should include a metabolic screen of blood and urine, plasma amino acids, total, free, and acylcarnitines, urine organic acids, brain CT or MRI, very-long-chain fatty acids for peroxisomal disease, blood lactate and pyruvate for mitochondrial disorders, and skin biopsy for electron microscopy to rule out a lysosomal disease.

Leucodystrophies

The term ‘leucodystrophy’ is applied to those diseases that have a genetic basis, a progressive clinical course, primary involvement of white matter, and a demonstrable biochemical or molecular defect. In contrast, the leucoencephalopathies are those disorders of white matter that lack the genetic, progressive, or other qualities of the leucodystrophies.

Primary leucodystrophies are those inherited diseases with predominately white matter involvement whereas, in secondary leucodystrophies, the involvement of brain grey matter and other structures leads to destruction of both axons and myelin by a more diffuse process.

The primary leucodystrophies can be classified into three subgroups: (1) classic dysmyelinative disorders; (2) hypomyelinative disorders with delayed or decreased myelin production; and (3) vacuolating myelinopathies. Within the category of the secondary leucodystrophies are metabolic, mitochondrial, and muscular dystrophy, and various syndromic (genetic) disorders.

Classic dysmyelinative leucodystrophies

Adrenoleucodystrophy (see also Chapter 12.9)

X-linked adrenoleucodystrophy (X-ALD), caused by a defect in the gene ABCD1, is the most common peroxisomal disorder with a pan-ethnic disease incidence of 1 in 20 000 males. ABCD1, which maps to Xq28, codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. Alterations in ABCD1 result in defective peroxisomal β‎ oxidation and the accumulation in all tissues of saturated very-long-chain fatty acids (VLCFAs), particularly hexacosaenoic (C26:0) and tetracosaenoic (C24:0) acids. Phenotypic manifestations of X-ALD range from childhood-, adolescent-, and adult-onset, rapidly progressive cerebral forms, usually seen in affected males, to an adult-onset, slowly progressive myeloneuropathic form in males and carrier females. Varying degrees of primary adrenal insufficiency (Addison’s disease) are invariably found in affected males whereas this endocrine disorder very rarely appears in females. Definitive diagnosis is established in males by demonstration of elevated levels of VLCFAs, which show abnormally high concentrations of C26:0 as well as high ratios of C24:0 and C26:0 to C22:0. As the test results for VLCFAs may be falsely negative or equivocal in 10 to 15% of heterozygous women, mutation analysis of the ABCD1 gene is often recommended to confirm the carrier state.

The childhood cerebral form usually presents between 4 and 8 years of age, never before the age of 2.5 years, with behavioural symptoms. The child becomes withdrawn and less verbal, and has difficulty with auditory and visual discrimination. Spastic paraparesis, incontinence, seizures, and feeding difficulties ensue with rapid progression to a vegetative state. MRI of the brain shows a characteristic pattern of demyelination, found in approximately 80% of cases, involving confluent T2-weighted hyperintensity and Tl-weighted prolongation of the deep parieto-occipital white matter, which progresses in a centrifugal manner within a caudorostral direction. There is gadolinium enhancement on T1-weighted imaging at the periphery of the involved white matter corresponding to regions of active demyelination and inflammation. A reverse pattern with frontal involvement is seen in another 15% of cases.

Adults with adrenomyeloneuropathy (AMN) present with a slowly progressive paraparesis, together with sensory and sphincter disturbances. It is associated with a noninflammatory distal axonopathy involving the dorsal column and corticospinal tract in the lower thoracic and lumbar regions, as well as more proximal segments of the corticospinal tracts in the internal capsule. In 30 to 40% of all male patients with AMN, there is inflammatory cerebral involvement detectable at the earlier stages of presentation or several years later. MRI often shows no abnormalities in the AMN phenotype, apart from infrequent spinal cord atrophy and T2-weighted hyperintensity. Of males affected by X-ALD 70% have Addison’s disease, in most instances associated with cerebral ALD or AMN; however, a smaller proportion of patients may have an ‘Addison-only’ phenotype of X-ALD, which is indistinguishable from Addison’s disease attributable to other causes. Plasma VLCFA assay should, therefore, be performed in all patients with idiopathic Addison’s disease, especially males. Pathologically, ballooning of cytoplasm with the presence of lamellar cytoplasmic inclusions is seen initially, most prominently in the zona fasciculata, followed by cytolytic cell death at a later stage. Approximately 50% of women who are heterozygous for X-ALD develop an AMN-like syndrome, typically occurring in the late 30s; progression is slower than in affected males.

Treatment includes general supportive care and symptomatic treatment for the patient. Adrenal hormone replacement therapy can be life saving, so all male patients should be adequately monitored for adrenal insufficiency. Lorenzo’s oil, which is a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, combined with moderate reduction of fat in the diet, normalizes or significantly lowers the levels of plasma VLCFAs, although it does not significantly alter the rate of progression in symptomatic individuals. Lorenzo’s oil may provide a preventive benefit in asymptomatic boys aged between 18 months and 8 years who are at the greatest risk for the development of the cerebral form of X-ALD and for whom the brain MRI is normal. Haematopoietic stem cell transplantation (HSCT) provides the most favourable outcome in children at the early stage of the illness with 5-year survival rates of 92%, and a superior neurological and functional status compared with the group that have not received a transplant. As HSCT may accelerate the rate of progression, it is contraindicated in patients with advanced cerebral involvement. Other approaches, including phenylbutyrate, arginine butyrate, and lovastatin, as well as long-term gene replacement therapy, are under investigation. ALD gene transfer into autologous hemopoietic stem cells is under investigation and may represent an alternative to allogeneic HCT. A new method for newborn screening is being developed which may alter the detection, monitoring, and treatment of X-ALD based on the measurement of C26:0 lysophosphatidylcholine applied to samples of dried blood on a filter-paper matrix. As X-ALD poses a significant burden to patients and families, professional genetic counselling is recommended. X-ALD heterozygous screening for women, together with prenatal diagnosis and preimplantation diagnosis, is available for families at risk.

Metachromatic leucodystrophy

Metachromatic leucodystrophy (MLD) is a sulphatide lipidosis caused by a deficiency of the lysosomal enzyme sulphatidase (arylsulphatase A, ASA), which catalyses the first step in the degradation of the sulphatide, 3-O-sulphogalactosyl-ceramide (cerebroside sulphate), or, in a few rare instances, a deficiency of cofactor saposin B (Sap-B). This leads to the accumulation of the substrate, cerebroside sulphate, in the white matter of the CNS and peripheral nervous system, which when stained with cresyl violet or toluidene blue reveal a brownish or reddish birefringence (metachromasia). There is another distinct clinical form of ASA deficiency, multiple sulphatase deficiency, in which at least seven different sulphatases are defective due to an abnormality in their processing and functional maturation. MLD is an autosomal recessive disorder with an estimated frequency of 1 in 121 000, ranging between 1 in 40 000 and 1 in 300 000. Diagnosis is based on demonstration of low ASA activity levels in the peripheral blood leucocytes or skin fibroblasts. About 10% of the general population has a pseudodeficiency of ASA, i.e. low activity on testing in vitro due to the presence of a polymorphism but with no clinical neurological disease. This needs to be excluded before a conclusive diagnosis of MLD is made. Increased excretion of urinary sulphatides is indicative of true ASA deficiency, whereas urinary sulphatides are normal in pseudodeficiency. Some genotypic–phenotypic correlation is possible: homozygosity of null alleles usually causes a late-infantile form of the disease, a combination of null allele and an allele with residual activity is associated with juvenile-onset, whereas two alleles with residual activity results in adult- or juvenile-onset disease.

Most patients are equally divided between late-infantile and juvenile onset, and about 20% of patients have an onset in adolescence or later. In the late-infantile form, the clinical signs begin between 15 months and 2 years with frequent falls followed by the inability to walk, flaccid weakness, and peripheral neuropathy. The ability to sit without support is lost between 2 and 3 years of age. Speech becomes slow and indistinct, truncal titubation develops, optic atrophy becomes apparent, and deep tendon reflexes are initially diminished and then lost. Spasticity develops in the legs but the arms remain hypotonic. Spinal root and peripheral nerve involvement cause exquisite sensitivity to touch. Electrophysiological testing shows slowing of the motor and sensory nerve conduction velocities. The cerebrospinal fluid protein level is elevated. Brain MRI T2-weighted images reveal centrifugally expanding, progressive, confluent, symmetrical white matter disease, with posteroanterior gradient. In the later stages of late-infantile MLD children are quadriplegic and spastic, with decerebrate, decorticate, or dystonic posturing, in association with loss of speech, seizures, hypertonic fits, bulbar palsy, and blindness. Death occurs 1 to 7 years after the onset of symptoms.

Juvenile MLD presents between age 4 and 12 years, with poor school performance and gait imbalance, followed by confusion and inability to follow directions. The speech becomes slurred; spasticity and inability to walk ensue. Tremor, tonic spasms, and seizures may also occur. There is visual failure. Peripheral neuropathy is common but not invariable. Most patients with juvenile MLD do not live into adulthood.

Adult MLD presents insidiously in late adolescence or early adult life with deterioration in school performance, disorganized thinking, poor memory, and a schizophrenia-like psychosis. The widespread use of MRI, which shows preferential involvement of the subcortical white matter in the frontal regions in the adult-onset form, has improved recognition of this variant in psychiatric patients. The gait is ataxic with pyramidal signs such as hypertonia and hyperreflexia. Peripheral neuropathy may or may not be associated with the adult-onset variant of MLD. Incontinence can develop relatively early. Despite the presence of optic atrophy, vision and the patient’s awareness of his or her environment are preserved until the end-stage of the disease. The progression is usually slower than in the early onset disease with spastic quadriparesis, decorticate posturing, and pathological reflexes noted after 5 to 10 years, but survival for several decades is possible.

Progression of MLD may be slowed or halted when bone marrow transplantation (BMT) or umbilical cord stem cell transplantation is undertaken in presymptomatic patients or early in the course of the disease when neuropsychological signs are not advanced. Brain gene therapy with adeno-assoicated vector of serotype 5 (AAV5) driving the expression of human ARSA cDNA is under investigation.

Multiple sulphatase deficiency (Austin’s disease)

Mutations in SUMF1, which encodes a protein (the human C(α‎)-formylglycine-generating enzyme) involved in the processing of the catalytic site of all sulphatases, lead to a defective post-translational modification of several sulphatases and a neurovisceral disorder, multiple sulphatase deficiency (MSD), characterized by tissue accumulation of sulphatides, glycosaminoglycans (mucopolysaccharides), and cholesteryl sulphate. The clinical features of MSD overlap between the neurological findings of early infantile MLD and the dysmorphic facial features and skeletal deformities (i.e. dysostosis multiplex) seen with mucopolysaccharidosis (MPS). Urinary excretion of sulphatides, heparan sulphate, and dermatan sulphate is high. Clinical features include ichthyosis in young infants with psychomotor retardation, hepatosplenomegaly, deafness, and peripheral neuropathy. Diagnosis of MSD is based on characteristic clinical manifestations and demonstration of deficiencies of the arylsulphatases A, B (N-acetylgalactosamine-4-sulphate sulphatase), and C (steroid sulphatase), and four other sulphatases involved in the degradation of specific glycosaminoglycans.

Globoid cell leucodystrophy (Krabbe’s disease)

Collier and Greenfield described unusual ‘globoid’ cells in the white matter of patients with acute infantile diffuse ‘sclerosis’, a condition reported initially in two siblings by Krabbe, a Danish neurologist, in 1916. This condition, now termed Krabbe’s disease, is caused by deficiency of galactocerebroside β‎-galactosidase (β‎-GALC; galactosylceramidase), which normally cleaves galactosylceramide into ceramide and galactose. Pathologically, there is rapid destruction of myelin and myelin-forming cells, i.e. oligodendrocytes and Schwann cells with reactive astrocytic gliosis and tissue infiltration by multinucleated macrophages, i.e. globoid cells filled with PAS (periodic acid–Schiff)-positive materials. Psychosine (galactosylsphingosine), a toxic metabolite that accumulates in the brain, is considered to be detrimental to the myelin-forming cells. Disease incidence in the general population is estimated at 1 in 200 000. The diagnosis of Krabbe’s disease is made based on deficient β‎-GALC activity in peripheral leucocytes or cultured skin fibroblasts. There are at least 40 reported mutations in the β‎-GALC gene that cause Krabbe’s disease.

Most cases present as an early infantile form, with an onset between 3 and 6 months of life. They have marked irritability, rapidly progressive generalized rigidity, and tonic spasms. Clenched fists and myoclonic jerks may be the earliest noted signs. Blindness and optic atrophy with pendular nystagmus develop later. The earliest objective findings in Krabbe’s disease are abnormalities of the brainstem auditory-evoked response (ABR) as well as the visual-evoked potential (VEP). Brain MRI shows symmetrical T2-weighted signal abnormalities in the periventricular region of the posterior cerebral hemispheres. Nerve conduction studies reveal markedly reduced nerve conduction velocities, while cerebrospinal fluid protein is elevated. Visceral organs as well as the skeletal system are unaffected. Death occurs between the ages of 1 and 2 years secondary to respiratory difficulties and/or bronchopneumonia.

About 10 to 15% of patients present with the late-infantile or juvenile form of the disease at approximately 5 years of age. They have a progressive gait disorder, spastic paraparesis, and cerebellar ataxia. Dystonia and visual failure may be associated. Behavioural changes and intellectual impairment may be the presenting features in juvenile-onset patients.

There is no definitive treatment for Krabbe’s disease. Low-dose morphine may be effective in controlling the irritability. HSCT, using umbilical cord blood, is effective in modifying the clinical course and improving the neurological status of infantile Krabbe’s disease; however, it is most effective if performed in the presymptomatic stages. Newborn screening has been recommended for early detection and intervention to improve outcome.

Alexander’s disease

Alexander’s disease, a sporadic autosomal dominant condition, first reported by WS Alexander in 1949, is an unusual form of leucodystrophy presenting clinically and pathologically with white matter dysfunction but caused by mutations in the rod domain of the glial fibrillary acidic protein (GFAP) gene, resulting primarily in astrocytic dysfunction. A pathological hallmark of Alexander’s disease is the presence in the astrocytes of eosinophilic, refractile, often rod-shaped, cytoplasmic inclusions termed ‘Rosenthal fibres’, which contain the intermediate filament protein GFAP in association with αβ‎-crystalline, small heat-shock proteins. These are predominantly distributed in the subependymal, subpial, and perivascular regions, in the basal ganglia and thalamus, and in the brainstem. There is widespread myelin deficiency in infantile cases associated frequently with cystic degeneration and cavitation. The arcuate fibres as well as occipital lobes and cerebellum are spared. In the juvenile-onset form the white matter degenerates whereas adult-onset disease may have only patchy zones of myelin pallor or cavitation.

The most common infantile form, with age of onset between birth and 2 years, is a relentlessly progressive lethal condition presenting as megalencephaly, seizures, hydrocephalus, and psychomotor retardation, and progressing to spastic quadriplegia. Survival varies from a few weeks to several years, but rarely beyond the early teens.

Juvenile-onset Alexander’s disease between ages of 4 and 10 years presents with slowly progressive ataxia, spasticity, and bulbar signs, including speech and swallowing difficulties with relatively preserved intellect. Adult-onset presentation, increasingly recognized and no longer considered a very rare form of the disease, is often characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Clinical variability ranges from a presentation similar to juvenile-onset Alexander’s disease, slowly progressive dementia to relapsing–remitting neurological symptoms mimicking multiple sclerosis that becomes recognizable as Alexander’s disease upon neuropathological examination.

Classic brain MRI findings in the infantile presentation include extensive white matter involvement, with frontotemporal predominance, abnormalities of the basal ganglia, especially the caudate, and sometimes the thalami, and in some cases contrast enhancement associated with variable ventricular enlargement. Periventricular structures may appear swollen and cystic. Alexander’s disease should be entertained in the differential diagnosis, especially in juvenile or adult cases, when brain MRI shows predominant or isolated involvement of posterior fossa structures, multifocal, tumour-like, brainstem lesions and brainstem atrophy, diffuse signal changes involving the basal ganglia, thalamus, or both, with contrast enhancement, as well as a garland-like appearance of the ventricular wall.

Hypomyelinative leucodystrophies

Pelizaeus–Merzbacher disease

Pelizaeus–Merzbacher disease (PMD), the prototypical X-linked recessive hypomyelinating disorder, is caused by alterations in the proteolipid protein (PLP) gene (PLP), which in oligodentrocytes encodes two major CNS myelin proteins: PLP and its spliced isoform DM20. The phenotypic spectrum of PMD ranges from PMD type II (connatal form) >PMD type III (transitional form) >PMD type I (classic form) >spastic paraplegia type 2 (SPG2; complicated form) >SPG2 (pure form), and is closely related to the genotype. Missense mutations in the highly conserved region of the DM20-related protein family cause the most severe forms, whereas substitutions of less conserved amino acids, as well as gene alterations that do not affect the DM20 isoform such as duplications, truncations, or deletions, cause less severe forms of PMD and SPG2. Large duplications including the entire PLP gene are the most frequently encountered mutations. Seitelberger delineated the neuropathological characteristics in PMD, which correlate well with the severity of the clinical presentation. The common pathological characteristics include lack or reduction of myelin sheaths in large areas of the white matter, with a patchy appearance of relatively conserved thin myelin islets, resulting in a ‘tigroid’ pattern. The structure of neurons and their processes including axons is well preserved.

The typical early manifestations of the more common classic form include hypotonia, nystagmus, and delayed motor development within the first year of life, followed by spasticity, cerebellar dysfunction, dystonia, and choreoathetotic movements and then disappearance of the nystagmus. Seizures may or may not be present. Patients often show slow development in the first decade of life; up to 45% of patients may be able to assume a sitting posture and some may be able to walk and acquire language capabilities. Slow deterioration begins in the second decade until death in mid-adulthood. In the connatal form there is congenital psychomotor developmental arrest with feeding problems, stridor, and spasticity, leading to progressive contracture of extremities, often accompanied by seizures. Death occurs in the first decade of life.

In patients with SPG2, which is allelic to PMD based on partial overlap of clinical manifestations with PMD and the discovery of PLP1 mutations in SPG2, normal motor development occurs in the first year of life, but progressive weakness and spasticity of the lower limbs develop between the ages of 2 and 10. In addition some clinical features seen in PMD, such as nystagmus, optic atrophy, ataxia, dysarthria, and intellectual impairment, although less prominent, may be associated with SPG2. Later-onset spastic diplegia with no additional neurological complications (the pure form of SPG2) has also been reported. Most female carriers of PLP mutations are asymptomatic; however, in rare families, including the family described by Pelizaeus, manifestations ranging from mild spastic diplegia to progressive leucodystrophy with dementia have been reported. Female carriers for PLP mutations causing a mild phenotype in males tend to be symptomatic, whereas those carrying mutations causing severe phenotypes in males are usually asymptomatic in female carriers. This may be related to a skewed pattern of X inactivation in cells in which the mutated X chromosome is active or to the elimination of oligodendrocytes expressing severe mutations during early myelination, unlike those expressing milder mutations that persist.

The fact that PMD is characterized by delay in myelination and not by demyelination is reflected in T2-weighted images on brain MRI as diffuse hyperintensity, which typically involves all the white matter, unlike many other demyelinating leucodystrophies, where abnormalities are often confined to specific regions. T1-weighted signals from white matter in PMD are usually normal or isointense. Extensive but nonprogressive abnormalities of multimodal evoked potentials are observed in PMD. Electromyogram and nerve conduction studies are normal.

Currently, there is no definitive therapy for PMD. Symptomatic management of spasticity, feeding difficulties, and dystonia is recommended.

18q− syndrome

18q− syndrome, one of the most common chromosomal deletion syndromes, was first described by DeGrouchy in 1964. The clinical picture is distinguished by several dysmorphic features including short stature, microcephaly, midface hypoplasia, malformed ears, stenotic ear canals, flat philtrum, carp-shaped mouth, prognathism, tapered fingers, proximal thumbs, and prominent fingerprint whirls, as well as numerous neurological deficiencies such as hypotonia, hearing loss, nystagmus, and intellectual impairment. MRI studies show a high incidence of dysmyelination in about 95% of cases. The deleted 2-Mb region of 18q22–23 contains seven known genes, one of which encodes for myelin basic protein (MBP), which is a key structural protein of CNS myelin. As the deletion most often involves the distal portion of the long arm of chromosome 18 from q21 to qter, haploinsufficiency of MBP is implicated in the delayed or incomplete development of myelin seen on brain MRI; however, proton MR spectroscopy (MRS) studies suggest the possibility of active demyelination or increased myelin turnover. The characteristic pattern of dysmyelination on brain MRI T2-weighted images, which shows low grey matter–white matter contrast, persists in individuals with 18q– beyond their first decade. The severity of dysmyelination appears to correlate with the severity of other features of the 18q syndrome, implicating the role of other deleted genes more proximal to the MBP locus in defective myelination in these patients.

Pelizaeus–Merzbacher-like disease with GJA12 mutations

Following the first report by Uhlenberg et al. in 2004 several groups have reported children with Pelizaeus–Merzbacher-like disease (PMLD) with mutations in GJA12, which encodes connexin 47 (Cx47), and is highly expressed in oligodendrocytes. Patients with PMLD and GJA12 mutations show the characteristic clinical symptoms such as nystagmus and impaired motor development in infancy, followed by ataxia, choreoathetotic movements, dysarthria, and progressive spasticity. Up to 70% of these patients have been reported to acquire walking capability; their intellectual functions were well preserved compared with their motor impairment. Epileptic seizures and peripheral neuropathy have been reported in a few cases. In patients with GJA12 progression of mutations is slower, their cognition is better preserved, and there is partial myelination of pyramidal tracts compared with classic PMD. Brain MRI is similar to that of PMD with high T2-weighted signal throughout the cerebral white matter and pyramidal tracts.

Most recently, a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD has been identified with a homozygous missense mutation in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60).

Severe hypomyelination associated with increased N-acetylaspartylglutamate in the cerebrospinal fluid

A rare disorder that must be considered in the differential diagnosis of connatal forms of PMD has been reported in two unrelated girls with almost complete absence of myelin on cerebral MRI, as shown by a homogeneous high signal of white matter on T2-weighted images and a low signal on T1-weighted images in association with highly elevated concentrations of N-acetylaspartylglutamate (NAAG) in their cerebrospinal fluid. Clinical features include |rotatory nystagmus within the first 2 months, epilepsy, feeding difficulty, and acquired microcephaly. Initial pyramidal signs were followed by hypotonia and loss of reflexes secondary to peripheral neuropathy. No mutation could be found in the gene encoding the NAAG-degrading enzyme.

Hypomyelination with atrophy of the basal ganglia and cerebellum

In 2002, van der Knaap et al. described seven unrelated patients without parental consanguinity who had a previously unidentified leucodystrophy with an MRI picture of diffuse myelin deficiency in the central white matter and atrophy of the neostriatum (caudate and putamen) and cerebellum (vermis greater than hemispheres). The clinical picture was progressive but variable, ranging from visual failure and absent motor development to being able to walk supported or unsupported, but with frequent falls associated with learning disability without severe intellectual impairment. Later manifestations included increasing spasticity, ataxia, and extrapyramidal abnormalities. On MRI, there was diffuse myelin deficiency with high signal intensity on T2-weighted images in the cerebral white matter including the corpus callosum, internal capsule, and pyramidal tracts in the midbrain and pons. With progression of the disease there was dilatation of the lateral ventricles and atrophy of the caudate nucleus, putamen, and cerebellum. The genetic cause and the pathogenesis of this condition have not been elucidated.

Hypomyelination and congenital cataract

Hypomyelination and congenital cataract (HCC) is an autosomal recessive hypomyelinating leucodystrophy, described by Zara et al. in 2006, caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. In addition, there is progressive neurological impairment and congenital cataract. Most patients have cataract surgery within their first few months and intellectual impairment and developmental delay are evident by 1 year. Almost all achieve the ability to walk with support but lose this ability over time due to slowly progressive pyramidal and cerebellar dysfunction, as well as peripheral neuropathy manifesting as lower limb muscle weakness and wasting. Neurological findings include dysarthria, truncal hypotonia, brisk tendon reflexes, and bilateral extensor plantar responses along with cerebellar signs, such as truncal titubation and intention tremor. Brain MRI shows diffuse cerebral hypomyelination and progressive white matter atrophy with preservation of the cortex and deep grey matter structures. Electrophysiological studies show evidence of demyelination as well as axonal pathology in most patients.

Leucoencephalopathy with ataxia, hypodontia, and hypomyelination

Wolf et al. in 2005 described four patients with early onset progressive ataxia, short stature, and a distinctive pattern of hypodontia, hypomyelination, and cerebellar atrophy. Motor development was normal or slightly delayed and mental development was mildly retarded. Brain MRI T2-weighted images show a diffusely hyperintense signal and a normal hyperintense signal on T1-weighted images compatible with mild-to-moderate hypomyelination. Cerebellar atrophy, particularly in the vermis, was also noted. Extensive genetic as well as metabolic investigation failed to reveal the aetiology of this probable autosomal recessive disorder.

Vacuolating leucoencephalopathies

Canavan’s disease

Aspartoacylase, expressed exclusively in the CNS in oligodendrocytes, normally hydrolyses NAA which is derived from neurons to aspartic acid and acetate. The acetate moiety is presumably further utilized as a building block for myelin lipids. Canavan’s disease, an autosomal recessive disorder caused by deficiency of aspartoacylase, leads to a build-up of NAA in the brain, as well as to NAA acidaemia and NAA aciduria. Pathologically, intermyelinic oedema, widespread vacuolation in the lower layers of the cerebral cortex, and subcortical white matter and lack of myelin occur, along with astrocytic swelling and mitochondrial changes resulting in spongy degeneration of the brain white matter. Canavan’s disease is pan-ethnic but there is a high prevalence of the carrier state, estimated at 1 in 37 to 1 in 50, in the Ashkenazi Jewish community. Two point mutations (at positions 693C and 854A in the coding sequence) are responsible for 97% of mutant alleles in Ashkenazi Jews, whereas C914A is the most common mutation among non-Jews, found in 40% of mutant alleles. Most cases present early in infancy but a few milder cases with a later onset have been encountered. Infants with Canavan’s disease appear normal at birth, but developmental delay and hypotonia, including head lag, are evident between 2 and 6 months of age followed by macrocephaly and severe impairment of motor development by 1 year.

Optic atrophy, spasticity, and often seizures soon ensue with the affected children become increasingly debilitated with age, and unable to move voluntarily or to swallow. Death typically occurs before adolescence. Urine organic acid screen showing elevation of urine NAA is often the first diagnostic clue in evaluation of patients with Canavan’s disease. Diffuse loss of white matter including the subcortical U-fibres, which are usually spared in most other forms of leucodystrophy, is evident on brain MRI. There is a marked increase in the NAA peak in brain white matter on MRS. The deficiency in aspartoacylase activity can be confirmed in cultured skin fibroblasts from patients but enzyme determinations in cultured amniotic fluid cells are not reliable.

Calcium acetate has been tried in Canavan’s disease to replace the deficient acetate and acetazolamide has been used to slow the pace of macrocephaly. Gene therapy for Canavan’s disease has thus far not been successful. Prevention strategies have included testing for carriers in Ashkenazi Jewish couples and prenatal diagnosis in at risk pregnancies using NAA quantification in amniotic fluid and molecular analyses of chorionic villous cells and amniocytes.

Megalencephalic leucoencephalopathy with subcortical cysts

Megalencephalic leucoencephalopathy with subcortical cysts (MLSC) is an autosomal recessive disorder caused by alteration in the gene mapped to chromosome 22qtel, which encodes a membrane protein that is highly expressed in brain, especially in astrocytes. Based on the pattern of localization it is speculated that the MLC1 protein is involved in astrocytic regulation and/or transport of ions or other substances. At least 50 mutations have been found thus far in MLC1; however, members of the Agarwal ethnic group of northern India, in whom the disease is more prevalent, share a common homozygous mutation, 320insC, suggesting a founder effect. Histopathology shows a spongiform leucoencephalopathy in the subcortical white matter without cortical involvement. The outermost lamellae of myelin sheaths contain countless vacuoles with sparing the middle or inner parts of myelin sheaths. Although most vacuoles are covered by single myelin lamellae, some vacuoles were partially covered by multi-lamellar myelin sheaths or oligodendroglial cell extensions.

MLSC is characterized clinically by macrocephaly noted within the first year or at birth, slow progressive decline in motor functions including ataxia and spastic paraparesis several years later, leading to inability to walk, and seizures in about 60% of patients. Cognitive functions are only mildly impaired with some decline in the second decade. Characteristic MRI findings that distinguish MLSC from other megalencephalic leucodystrophies include diffusely abnormal and swollen cortical cerebral white matter and bilateral cystic changes, the appearance of which resembles that of cerebrospinal fluid in all sequences, especially in the temporal lobes, occasionally in the frontoparietal regions but sparing the occipital lobes. In addition, the cerebellar white matter may exhibit mildly abnormal T2 signal but there is no swelling. Eventually the swelling resolves and cortical atrophy develops. The number and size of the cysts progressively increase, such that they eventually occupy a significant portion of the frontoparietal cortex. The EEG shows multifocal epileptiform discharges. Supportive treatment, including treatment of seizures, is recommended.

Vanishing white-matter disease (childhood ataxia with CNS hypomyelination)

Childhood ataxia with CNS hypomyelination (CACH), a pan-ethnic autosomal recessive disease, also described as vanishing white matter disease (VWM) or myelinopathia centralis diffusa, was first identified in 1992. Astute application of molecular genetics in a population of a limited geographical region in the eastern part of the Netherlands led to the discovery that mutations in any one of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) cause CACH/VWM and the recognition of a wider clinical spectrum. The eIF2B protein complex has a key regulatory role in protein synthesis through initiation of translation. Regulation of the activity of eIF2 is a protective mechanism for cells in response to stress. Mutated eIF2B could impair the ability of cells to regulate protein synthesis, resulting in increased susceptibility to various physiological stress conditions. On gross examination of the brain, the cortical grey matter is of normal consistency in marked contrast to the white matter of the centrum semiovale which is softened, atrophic, and gelatinous. There is rarefaction with moderate-to-severe vacuolation of the white matter with relative sparing of axons and subcortical U-fibres. The distinguishing feature of CACH/VWM is the presence of foamy oligodendrocytes, which on ultrastructural analysis show abnormal abundant cytoplasm containing membranous structures and numerically increased and morphologically abnormal mitochondria. Abnormally shaped coarse astrocytes and gliosis are present. In the severe forms, there is a reduction of the number of astrocytes and possibly astrocyte progenitors, but not of oligodendrocyte progenitors

Clinically, early development and head circumference are normal while some patients may present with speech and cognitive delay. The most common initial presentation is new-onset ataxia between ages 1 and 5 years. The disorder may be heralded by coma or a dysmetric tremor following mild head trauma or a febrile illness and apparently, even after an acute fright, can occur spontaneously. Subsequent deterioration is generally progressive with gait difficulty, cerebellar signs, pyramidal signs, dysarthria, and seizures. The course is often remitting–relapsing and patients may remain stable for years at any phase of the illness. Dysphagia and optic atrophy are seen late in the disease; the peripheral nervous system is usually unaffected. Death typically occurs during the first or second decade of life. There is a wide phenotypic spectrum which includes congenital forms with manifestations in organs besides the brain, a rapidly as well as a subacutely fatal infantile form, a slowly progressive form with onset after age 5 years that is often associated with ovarian insufficiency (dysgenesis), termed ‘ovarioleucodystrophy syndrome’, and an adult-onset disease variant. Brain MRI shows symmetrically and diffusely abnormal subcortical white matter with hypointense signal on T1-weighted MRI and hyperintense signal intensity on T2 images with sparing of the cortex. Cystic degeneration with a radiating stripe-like pattern or cavitation within the white matter is best seen on proton density or FLAIR sequences; there is no gadolinium enhancement of these lesions on post-contrast T1-weighted MRI. Early and selective involvement of the inner rim of the corpus callosum (septo-callosal surface) is recently described as a distinguishing sign from other leucodystrophies.

Supportive management such as avoidance of stress situations, use of antipyretics and antibiotics, physical therapy for motor disabilities, and carbamazepine for seizures is recommended. In families with a known mutation prenatal diagnosis can be offered.

Progressive cavitatory leucoencephalopathy

Progressive cavitatory leucoencephalopathy (PCL) was initially reported in 2005 by Naidu et al. as childhood-onset progressive cavitatory leucoencephalopathy associated with an increase in lactate in brain, blood, and cerebrospinal fluid. There may be subtle developmental delay followed by acute onset of irritability or neurological deficits occurring after 2 years of age, followed by steady or intermittent clinical deterioration with death between 11 months and 14 years of life. Brain MRI shows irregular asymmetrical patchy areas of white matter abnormality that evolved to multicystic degeneration. MRS shows elevated lactate in the affected structures. PCL appears to be a distinct genetic entity, possibly involving mitochondrial dysfunction, but the exact molecular basis is yet to be elucidated.

Secondary inherited leucoencephalopathies

Metabolic disorders

Mitochondrial diseases

See Chapter 24.24.5 for further description.

Lysosomal storage diseases

See Chapter 12.8 for further description.

Amino acidaemias

Neurological manifestations including leucoencephalopathy are frequently present in the amino and organic acidaemias (see Chapter 12.2). Patients with maple syrup urine disease (MSUD) were reported after a relaxed treatment protocol to have myelin abnormalities demonstrated on T2-weighted brain MRI as increased signal in the mesencephalon and/or brainstem (cerebral peduncles and dorsal brainstem), less so in the basal ganglia–thalamus and globus pallidus, and less prominent areas of decreased signal intensity in T1-weighted images. More severely involved patients had supratentorial changes, especially in the occipital periventricular and cerebellar white matter. The myelin abnormality may be due to chronic exposure of the brain to branched-chain amino acids or to a deficit of essential large neutral amino acids, the transport of which across the blood–brain barrier is impaired by an excess of the branched-chain amino acids.

In phenylketonuria (PKU), white matter changes on MRI are typical of the adolescent and adult with PKU. However, the distribution of MRI signal abnormality is most marked in supratentorial regions and only in more severe cases does it extend into the basal ganglia, brainstem, or cerebellum.

Organic acidaemias

Cerebral MRI has revealed bilateral white matter changes in several organic acidopathies, including l-2-hydroxyglutaric aciduria, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Glycogen storage disease type IV/adult polyglucosan body storage disease

Glycogen storage disease type IV (GSD IV), an autosomal recessive disorder, results from deficient activity of the branching enzyme 1,4-glucan-6-glucosyltransferase mapped to chromosome 3p14. It presents in infancy with severe liver disease, causing cirrhosis, portal hypertension, and early death. A fatal neonatal neuromuscular form and a milder nonprogressive hepatic form are known.

A late-onset variant, referred to as adult polyglucosan storage disease (APBD), first described in 1971, is characterized by onset in the fifth or sixth decade of progressive upper and lower motor neuron dysfunction, sensory polyneuropathy, bladder and bowel incontinence, and, in some patients, dementia. Not all patients with APBD have deficiency of the glycogen-branching enzyme. Neurophysiological studies reveal an axonal sensorimotor peripheral neuropathy. The MRI shows extensive, nonenhancing, bilateral, symmetrical, periventricular and subcortical white matter changes with the T2 signal abnormality extending to the cervicomedullary junction. There is progressive atrophy of the brain and spinal cord. Sural nerve biopsy, which can be diagnostic, shows frequent enlargements of myelinated fibres that stain positive with PAS. PAS-positive inclusions are also found within skeletal muscle fibres and the apocrine gland cells of the skin.

Congenital muscular dystrophy

See Chapter 24.24.2.

Sjögren–Larsson syndrome

Sjögren–Larsson syndrome (SLS) is an autosomal recessive disorder resulting from mutations in the gene for the microsomal enzyme fatty aldehyde dehydrogenase (FALDH), first described in 1957 by Sjögren and Larsson in a consanguineous cohort from the county of Vasterbotten in northern Sweden. The worldwide prevalence of this pan-ethnic disorder is probably less than 0.4 per 100 000. FALDH catalyses the oxidation of medium- and long-chain fatty aldehydes to the corresponding carboxylic acids. Deficiency in FALDH leads to elevation of free fatty alcohols in the plasma and leukotriene B4 (LTB4) in the urine. The accumulation of fatty alcohols or aldehyde-modified marcromolecules disrupts the integrity of multilamellar membranes in skin and myelin. Neuropathologically, there is reduction in myelinated nerve fibres in cerebral and cerebellar white matter, loss of neurons in the cortex and basal ganglia, and deposition of pigments. PAS-positive lipoid substances are found in the subpial, subependymal, and perivascular glial layers as well as in cerebral and cerebellar white matter, and there are perivascular macrophages containing lipofuscin-like pigments and spheroid bodies in the neuropili of several brainstem nuclei.

Babies with the condition may be born preterm with ichthyosis, which is generalized brownish-yellow in colour and associated with a severe pruritus. Developmental delay and spasticity are apparent by the first or second year, leading to contractures in the lower extremities and wheelchair dependency. Cognition is impaired in most patients. Pseudobulbar dysarthria, delayed speech, and seizures are common. Ophthalmological abnormalities include photophobia, macular dystrophy, and decreased visual acuity. After several years, glistening white dots surround the macular region of the retina. EEG shows symmetrical slow background activity with no epileptiform pattern. Cerebral MRI studies reveal multifocal areas of delayed myelination, hyperintense signal abnormality in the periventricular zone, and mild ventricular enlargement in the oldest patients. On MRS of the cerebral white matter and basal ganglia, there is a distinct diagnostic sharp lipid peak, believed to arise from the accumulation of long-chain fatty alcohols or aldehydes.

Treatment has been attempted with a low-fat diet supplemented with medium-chain fatty acids but was not successful. Beneficial effects have been described using the LTB4 synthesis inhibitor Zileuton. The hypolipidaemic drug, bezafibrate, has been shown to induce residual FALDH activity in patient fibroblasts and may be a therapeutic option.

Cerebrotendinous xanthomatosis

This rare but underdiagnosed disorder should always be considered in the differential diagnosis of a leucodystrophy, because it is a treatable condition. Among Moroccan Jews the incidence of cerebrotendinous xanthomatosis (CTX) is 1 in 108 and in the general US population its prevalence is estimated to be 3 to 5 in 100 000. The 5α‎-dihydro-derivative of cholesterol, cholestanol, is increased 10- to100-fold in CTX. It is present in the diet but its accumulation in the nervous system apparently results from increased endogenous production and impairment to its egress as a result of the blood–brain barrier. Mutations in the sterol 27-hydroxylase gene (CYP27) cause a block in bile acid synthesis, leading to absence of chenodeoxycholic acid in the bile and excretion of bile alcohols (bile acid precursors) in the bile and urine. Absence of the endproduct upregulates endogenous bile acid synthesis.

Symptoms commonly appear in childhood or during the second decade, but patients may present in the neonatal period or in middle age. There may be difficulty in school due to slowly progressive intellectual impairment, behavioural difficulties, and psychiatric symptoms. Other manifestations include cataracts, tendon and tuberous xanthomas (especially of the Achilles tendon), diarrhoea, osteoporosis, and bone fractures. Within the neonatal period, prolonged cholestatic jaundice may be observed. Eye signs in addition to cataracts include optic disc pallor, premature retinal senescence, palpebral xanthelasmas, corneal lipoid arcus, and proptosis. Neurological findings almost invariably develop and include cerebellar and pyramidal tract signs, peripheral neuropathy, and seizures.

Imaging studies disclose diffuse brain and spinal cord atrophy and brain white matter hypodensity. The cerebellar white matter is especially involved and there is hypersensitivity of the dentate nuclei bilaterally on the FLAIR sequence. A mainly spinal cord syndrome can occur with white matter abnormalities in the lateral and dorsal columns of the spinal cord.

Long-term oral therapy with chenodeoxycholic acid (750 mg/day), most effective in presymptomatic individuals, has been shown to suppress the abnormal bile acid synthesis, correct the biochemical abnormalities, and reverse the progression of CTX. Although HMG-CoA (hydroxymethylglutaryl coenzyme A) reductase inhibitors reduce serum cholesterol levels, caution is exercised because they can exacerbate the mitochondrial impairment.

Vascular disorders

CADASIL

CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, an adult-onset autosomal dominant disorder, is caused by mutations in Notch3 encoded on chromosome 19p13. The major pathology is in small and median-sized arteries within the brain’s white matter. The smooth muscle cells of the media are replaced with deposits of basophilic, granular, electron-dense material known as granular osmophilic material (GOM). There are 34 epithelial growth factor-like repeats (EGFRs) comprising the extracellular domain of the Notch3 receptor, each containing six cysteine residues that form disulphide linkages. Almost all mutations causing CADASIL result in the gain or loss of a cysteine. Diagnosis can be confirmed by Notch3 gene sequencing or by electron microscopic evaluation of a skin biopsy for the presence of GOM.

The clinical course is characterized by a history of migraine with or without aura in the late second or third decade (30 to 40% of patients), onset of cerebrovascular disease between 30 and 60 years of age, progressing to dementia, with MRI of the brain showing diffuse white matter lesions and subcortical infarcts. Later stages of the disease are characterized by transient ischaemic attacks (TIAs), strokes, behavioural changes, and memory loss. There is usually a family history with one parent or close relative with a similar clinical course. Vascular risk factors such as hypertension and atherosclerosis are usually absent.

Patchy white matter involvement on brain MRI may be noticed in childhood in asymptomatic patients. By the third or fourth decade, the white matter lesions have coalesced. Involvement of the anterior temporal lobes is a distinct and diagnostic feature. Infarcts may also be seen in the basal ganglia and brainstem, and the external capsules are also affected.

A young-adult onset arteriosclerotic leucoencephalopathy, termed CARASIL because of its autosomal recessive mode of inheritance, has been described in Japanese patients with many similarities to CADASIL. It is accompanied by alopecia and back pain.

Acetazolamide has been used in reducing migraine-like attacks. Antiplatelet agents and statin drugs are also prescribed for stroke prevention but there are no studies demonstrating their efficacy.

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is a rare autosomal dominant syndrome presenting, as the name implies, with retinopathy, nephropathy, and stroke. Electron microscopic studies reveal a vasculopathy consisting of multilayered basement membrane in capillary and arteriolar endothelial cells in the brain and other organs. Renal insufficiency with proteinuria and haematuria, and progressive visual loss due to macular oedema, capillary dropout and perifoveal microangiopathic telangiectases, are characteristic. Neurological symptoms appearing in the third and fourth decades include migraine-like headaches, psychiatric dysfunction, dysarthria, hemiparesis, and apraxia. Brain MRI demonstrates frontoparietal, contrast-enhancing, subcortical lesions with surrounding oedema.

Three other dominantly inherited cerebroretinal vasculopathies with leucoencephalopathy have also been described. Two, in addition to HERNS, show linkage to the same chromosome 3p21 locus. The third condition, hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leucoencephalopathy, is not linked to chromosome 3p21. The leucoencephalopathy is accompanied by dilatation of perivascular spaces, microbleeds, and, in two of six symptomatic family members, silent deep cerebral infarcts.

Other leucoencephalopathies with childhood onset

Aicardi–Goutières syndrome

Aicardi–Goutières syndrome (AGS), an autosomal recessive leucoencephalopathy, is associated with developmental arrest, intracerebral calcifications, and chronic cerebrospinal fluid lymphocytosis. Mutations in the genes encoding any of the three subunits of human ribonuclease H2 enzyme (RNase H2) located on chromosomes 3p21 (AGS1), 13q14.3 (AGS2), and 11q13.2 (AGS3) can cause AGS. RNase H2 serves in antiviral defence by degrading DNA–RNA hybrids formed in the process of reverse transcription. By analogy with double-stranded (ds)RNA and dsDNA, which are known to stimulate interferon-α‎ production, it is suggested that the DNA–RNA hybrids formed during retroviral reproduction will also stimulate interferon-α‎ production. Reduced destruction of these hybrids because of mutations in RNase H2 subunits will therefore lead to overproduction of interferon-α‎ and the phenotypic appearance of an in utero viral infection.

A very early encephalopathy noted in the first month, or a delayed onset by 6 to 10 months with loss of acquired skills and secondary microcephaly, spasticity, truncal hypotonia, and dystonic posturing, is the usual manifestation. The children are severely developmentally delayed, have no purposeful speech, and do not walk. Generalized seizures occur in 30% of patients. Serial CT scans demonstrate progressive periventricular, basal ganglia and subcortical calcifications, cerebral atrophy, and loss of white matter. Some patients develop swelling and acrocyanosis of the toes with peeling of the skin with no coolness of the extremities. There is a persistent synthesis of cerebrospinal fluid interferon-α‎ as well as thrombocytopenia, hepatosplenomegaly, elevated hepatic transaminases, and intermittent fever, all of which suggest a congenital viral infection. However, TORCH studies are negative and no infectious cause has been found.

Cockayne’s syndrome

See ‘Defects in DNA repair’, earlier in this chapter.

Other leucoencephalopathies with adult onset

Fragile-X tremor ataxia syndrome

See Chapter 24.7.5.

Autosomal dominant leucodystrophy

The locus for autosomal dominant leucodystrophy (ADLD), a condition described in 1984 in an Irish–American kindred, was mapped in a large Swedish family to chromosome 5q23, and subsequently a tandem genomic duplication in the gene encoding the nuclear membrane protein lamin B1 (LMNB1) was identified as the cause of ADLD. Pathology shows white matter degeneration with microscopic vacuolation, preservation of U-fibres as well as of the grey matter, and absence of an inflammatory response or gliosis. The initial clinical presentation involves abnormalities of the autonomic nervous system, including bowel and bladder dysfunction, impotence, orthostatic hypotension, and decreased sweating in the fourth or fifth decade. A slowly progressive course with loss of fine motor skills and other pyramidal tract and cerebellar signs is noted. Survival after symptom onset is 20 years. CT scans show white matter lucencies in the frontoparietal region progressing to the parietal and occipital lobes, corresponding with brain MRI T2-weighted signal changes in these areas as well as in the brainstem and cerebellar white matter.

Hereditary diffuse leucoencephalopathy with spheroids and pigmentary orthochomatic leucodystrophy

Inherited neurodegenerative diseasesThere is compelling clinical, pathological, and radiological evidence that hereditary diffuse leucoenphalopathy with spheroids (HDLS), also known as leucoencephalopathy with neuroaxonal spheroids (LENAS), and pigmentary orthochromatic leucodystrophy (POLD) belong to the same disease spectrum. Both are autosomal dominant, progressive, neurodegenerative diseases pathologically characterized by generalized demyelination of white matter, including that of the descending tracts in the brainstem, with sparing of U-fibres and frontal lobe predominance. In HDLS, neuroaxonal spheroids are scattered throughout the vacuolated white matter, which stain for ubiquitin. In familial POLD, widespread myelin and axon destruction is seen in a similar distribution. Presence of pigmented macrophages, with sudanophilic pigment that is autofluorescent and stains with periodic acid-Schiff, Masson–Fontana coloration, and variably for iron, is a distinctive feature. The mean age of onset in a large Swedish pedigree with 17 affected individuals was 36 years (range 8 to 60 years) and mean age at death 57 years (range 39 to 89 years). The cardinal symptoms of HDLS and POLD are behavioural changes, depression, dementia, motor impairment including parkinsonism, spasticity, hemiparesis, paraparesis, or tetraparesis and ataxia, and epilepsy. Psychiatric as well as neurological features dominate the picture with depression, anxiety, and aggressiveness, in addition to dementia, seizures, gait imbalance, and urinary incontinence. The brain MRI shows atrophy and patchy white matter changes in the frontal and frontoparietal areas, extending through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem.

Movement disorders

Wilson’s disease

(see Chapter 12.7.2)

Wilson’s disease is an autosomal recessive disorder of copper metabolism causing liver cirrhosis and neurological dysfunction in untreated individuals. It is caused by mutations in the ATP7B gene on chromosome 13q14.3. Copper transport is defective, leading to low serum copper and ceruloplasmin, an excess of urinary copper excretion, and copper deposition in tissues including the liver, kidney, brain, and cornea. Approximately 40% of patients first present with signs of liver disease including recurrent episodes of jaundice and portal hypertension. Neurological signs may herald the onset of the disease in 40% of cases but only after late childhood or adolescence. The first sign may be tremor in one arm or rigidity about the mouth with dysarthria and dysphagia. A masked face and characteristic grin develop and chewing and swallowing become difficult. Rigidity, tremor, dyskinesias, and speech and gait difficulties develop. Other extrapyramidal signs may appear such as choreoathetosis and in some cases cerebellar ataxia and intention myoclonus.

A psychiatric disturbance is the main presenting feature in 20% of patients with loss of emotional control, cognitive change, and intellectual decline. On MRI of the brain signal changes are noted in the caudate and lenticular nuclei and the thalami and dentate nuclei, with cerebral and cerebellar atrophy in long-standing cases. PET scans demonstrate reduction in the regional cerebral metabolic rate of glucose consumption, especially in the striatum and cerebellum.

Neuropathological studies reveal pigmentation and spongy degeneration of the putamen and to a lesser extent the dentate nuclei, substantia nigra, cerebellar cortex, and thalamic and midbrain nuclei. In addition to the loss of neurons and axonal degeneration, giant protoplasmic astrocytes (Alzheimer’s cells) and Opalski’s cells are found, the latter being present particularly in grey matter.

Diagnosis is aided by the measurement of serum ceruloplasmin and urinary copper. More definitive are the assay of hepatic copper (> 3.9 µmol/g dry weight versus 0.2 to 0.6 µmol in normal liver) from a liver biopsy and/or screening for mutations in the ATP7B gene. In a mixed European population, one mutation, H1069Q, accounts for 35 to 45% of disease-causing alleles. Among Asians, 57% of the alleles contain the R778L mutation and, in Russian patients, 40 to 45% have the H714Q and delC2337 mutations. About 1% of the population are carriers.

Copper-chelating agents are used to treat Wilson’s disease. Triethylene tetramine (trientine) and ammonium tetrathiomolybdate are favoured because they have no side effects compared with an earlier drug, penicillamine, which was associated with initial worsening of neurological symptoms. Zinc salts are also used to block intestinal absorption of copper. In many cases, the liver damage and neurological signs and symptoms are reversed within 1 to 2 years of initiating therapy and asymptomatic patients remain free of overt disease.

Huntington’s disease

Huntington’s disease is most often a disease of mid-adult life but 6 to 12% of those with the condition develop symptoms before age 20. It presents with changes in personality and behaviour as well as with involuntary motor movements. Either one can occur before the other. Memory deficits, agitation, depression, impulsiveness, delusions and hallucinations, and poor judgement may occur. Over time patients develop hand clumsiness, gait abnormalities, parkinsonism, chorea, dystonia, dysphagia, and tremor, as well as oculomotor disturbances. In juvenile patients, the clinical picture is one of bradykinesia, rigidity, seizures, and dementia. Global decline in cognition occurs with average survival of 10 years in juvenile-onset and 15 to 20 years in adult-onset patients.

Brain imaging discloses marked flattening of the head of the caudate nucleus and atrophy of the putamen. In juvenile patients there is also generalized brain atrophy with loss of cerebellar Purkinje’s cells. Even before caudate atrophy appears on CT or MRI, PET may demonstrate hypometabolism in the caudate nucleus.

Huntington’s disease is an autosomal dominant disorder with an incidence of 3 to 7 in 100 000. It is caused in most cases by a CAG triplet repeat expansion in exon 1 of the IT15 gene on chromosome 4q16.3, which codes for the protein huntingtin. Fewer than 26 CAG repeats at this locus is normal; over 40 repeats is characteristic of patients with Huntington’s disease and more than 70 occur in the severe juvenile variant. A paternal origin of the expanded repeat is found in 80% of juvenile patients whereas small expansions or even contractions in repeat length are found in the children of women who have Huntington’s disease.

Therapy for the symptoms of Huntington’s disease includes neuroleptics, antiparkinsonian agents, psychotropic drugs, and a supportive stimulating environment. Tetrabenazine, a central monoamine depleter, and amantadine have both shown improvement in the mean total maximal chorea (TMC) scores from the Unified Huntington Disease Rating Scale. Family members seeking information about their risk of developing Huntington’s disease should seek psychological assessment and review of their options from a genetic counselling service.

Huntington’s disease-like syndromes

A small percentage of patients with Huntington’s disease-like (HDL) syndrome may test negative for a CAG repeat expansion in IT15 and could, in fact, have another genetic disorder. Four such HDL syndromes have been described: HDL1 is an autosomal dominant disorder caused by extra octapeptide repeats in the prion protein (PRNP) gene on chromosome 20p12. HDL2, especially common in the black South African population, is caused by a CTG–CAG triplet-repeat expansion in the junctophilin 3 (JPH3) gene on chromosome 16q24.3. An autosomal recessive variant present in Saudi Arabia has been named HDL3 and maps to chromosome 4p15.3. HDL4 is an autosomal dominant, triplet-repeat disorder caused by mutation of the TATA box-binding protein (TBP) gene located on chromosome 6q27. This is synonymous with spinocerebellar ataxia type 17. As only 93% of those with the classic clinical phenotype of Huntington’s disease have a Huntington’s disease-associated IT15 gene mutation, these HDL syndromes should be considered as alternative diagnoses in the absence of a family history or failure to show the classic Huntington’s disease molecular lesion.

Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Incidence rates are 8 to 18/100 000 person-years with a higher prevalence among men than among women and an average age of onset of 60 years. The cardinal clinical features are tremor at rest, slowed movement (bradykinesia), rigidity, and postural instability. Secondary motor symptoms include hypomimia, dysarthria, dysphagia, sialorrhoea, decreased arm swing, shuffling gait, micrographia, positive glabellar reflex, blepharospasm, and dystonia. Motor block or freezing is particularly disabling, involving a sudden inability to move the feet. Common nonmotor manifestations are autonomic failure, cognitive decline, depression, apathy, hallucinations, and sleep disorders.

Patients with onset below age 50 have the tremor-dominant form of Parkinson’s disease and slower progression of their disease than older patients who have postural instability gait difficulty with more rapid disease progression. Younger patients are also at higher risk for levodopa-induced dyskinesias than older patients.

Symptoms begin typically after 50 to 80% of dopaminergic neurons in the substantia nigra are no longer functional. The remaining intact nigral neurons may contain intracytoplasmic inclusions (Lewy bodies) composed of aggregates of α‎-synuclein. Neuroimaging studies with PET and SPECT are useful tools for imaging presynaptic dopaminergic neurons.

The diagnosis of Parkinson’s disease is a clinical one and includes response of symptoms to levodopa. Other disorders with parkinsonian-like symptoms include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, essential tremor, drug-induced parkinsonism, postencephalitic disorders, Lewy body dementia, and Alzheimer’s disease. It is also prominent in certain genetic neurodegenerations: SCA2 and SCA3, Huntington’s disease, dopa-responsive dystonia, familial prion disease, frontotemporal dementia, Wilson’s disease, and X-linked dystonia–parkinsonism syndrome (Lubag). Most of these other diseases do not, however, respond to levodopa.

Disease susceptibility is increased by serious head trauma, exposure to environmental toxins (MPTP, pesticides), drinking well water, and rural living. Pathogenesis is believed to result from mitochondrial dysfunction (especially complex 1 deficiency), oxidative stress, and misfolding and impaired trafficking of α‎- synuclein.

Although 75 to 90% of cases are sporadic, single gene abnormalities have been identified in a subset of Parkinson’s disease patients. These include autosomal dominant, autosomal recessive, and X-linked forms. The most common known cause of familial and sporadic parkinsonism is mutations in the LRRK2 (leucine-rich repeat kinase 2) gene. The gene is located on chromosome 12q12 and encodes the protein dardarin. The most frequent and best-studied mutation is G2019S, which accounts for 1.5% of all index cases with late-onset, classic parkinsonism. It is especially frequent among North African Arabs and Ashkenazi Jews with Parkinson’s disease. The lifetime penetrance is 32% so many carriers may have no sign of disease on neurological examination. LRRK2 is highly expressed in striatal neurons that receive dopaminergic input.

The α‎-synuclein (SNCA) gene was the first to be linked to familial parkinsonism. Besides point mutations, duplication of this gene is also observed in cases of Parkinson’s disease. The phenotypic spectrum of SNCA, which is mapped to chromosome 4q21–q23, is broad and penetrance similar to LRRK2. Both LRRK2 and SNCA are inherited as autosomal dominant genes.

Mutations in a third gene, PRKN, linked to chromosome 6q25.2–q27, are responsible for half the early onset cases of autosomal recessive Parkinson’s disease. The gene product parkin is involved in proteasomal degradation of target proteins and may therefore play a role in Lewy body formation. Other known genes with autosomal recessive inheritance identified with mutations in Parkinson’s disease are PINK1 (chromosome 1 p35–p36), encoding PTEN-induced putative kinase 1, and DJ-1 (chromosome 1p36), producing protein DJ-1.

Other much rarer neurogenic forms of parkinsonism are also described involving mutations in only a single or very small number of families. Linkage to other loci has been described but the genes responsible have not yet been identified. In addition, several susceptibility genes have been mapped in familial cases of Parkinson’s disease. One of these, the glucocerebrosidase gene, is mutated more often in patients with Parkinson’s disease than would be expected by chance alone. This observation has been verified in both Ashkenazi Jews who are at higher risk for Gaucher’s disease, an autosomal recessive disease caused by glucocerebrosidase deficiency, and non-Jews. Whether the cause is an elevated level of glucocerebroside at the cellular level or the presence of mutated protein, either of which might promote aggregation of α‎-synuclein, has not been demonstrated.

Pantothenate kinase-associated neurodegeneration

This autosomal recessive neurodegenerative disorder of brain iron accumulation and pantothenate kinase deficiency represents a phenotypic spectrum of which there are three main variants. Classic pantothenate kinase-associated neurodegeneration (PKAN) manifests in childhood before age 6 years (mean 3.4 years) with gait and postural difficulties. Extrapyramidal findings are predominant with dystonia, rigidity, and choreoathetosis. Dysarthria occurs early and tremor may also be present. Corticospinal tract involvement with spasticity, hyperflexia, and Babinski’s signs, as well as cognitive decline, are also common findings. About two-thirds of typical patients develop retinopathy and a few have optic atrophy. Most become nonambulatory within 15 years of disease onset.

In patients with the atypical form of PKAN, the onset is in the second to third decade, and progression of disease is slower with most patients continuing to walk for 15 or more years. The extrapyramidal signs are less severe and corticospinal tract involvement including spasticity and hyperflexia is common. Patients with the atypical variant are also more likely to have psychiatric symptoms, speech difficulties, and cognitive decline.

MRI shows bilateral areas of hyperintensity within a region of hypointensity in the medial global pallidus on T2-weighted images, producing the ‘eye of the tiger’ sign. PKAN is due to mutations in the gene on chromosome 20p13–p12.3 encoding pantothenate kinase 2 (PANK2), which is a key regulatory enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B5), and deficiency of which may cause oxidative stress in the iron-rich globus pallidus.

A third disorder, HARP, is allelic to PKAN. In addition to the early onset of extrapyramidal signs (dystonia, choreoathetosis, and rigidity), spasticity and dementia, retinal pigmentary degeneration, hypoprebetalipoproteinaemia, and acanthocytosis occur. Neuropathological features include bilateral degeneration of the globus pallidus and substantia nigra pars reticulata, deposition of iron in the affected regions, and neuronal axonal spheroids. These patients also have the ‘eye of the tiger’ sign on MRI and mutations within the PANK2 gene.

Neurocanthocytosis

Several rare hereditary neurodegenerative diseases are associated with abnormally appearing red blood cells referred to as acanthocytes. These are contracted erythrocytes containing irregularly spaced, thorny surface projections and are best visualized under a scanning electron microscope. As described above, they are present in a small percentage of patients with PKAN. They are also present in three other movement disorders, autosomal recessive chorea–acanthosis, X-linked McLeod’s syndrome, and HDL2, and in abetalipoproteinaemia. Acanthocytosis is also a predisposing factor for nonketotic, hyperglycaemia-induced hemichorea–hemiballism in patients with diabetes.

Bassen–Kornzweig syndrome

Acanthocytosis was first recognized in conjunction with Bassen–Kornzweig syndrome. This is an autosomal recessive disorder manifested by fat malabsorption, pigmentary degeneration of the retina, progressive ataxia, and neuropathy. Serum apolipoprotein B-containing lipoproteins (apoB), and very-low-density (VLDLs) and low-density lipoproteins (LDLs) are absent, causing very low serum cholesterol and triglyceride levels and deficiency of fat-soluble vitamins A, E, and K. Myelinated fibres in the posterior columns, spinocerebellar tracts, and peripheral nerves are affected. Progression of the disease can be slowed by treatment with high doses of vitamin E supplemented with vitamin A.

Chorea–acanthocytosis

Chorea–acanthocytosis is an autosomal recessive disorder manifesting clinically between ages 20 and 40 (mean 35 years), with chorea and involuntary movements in the orofacial region. However, in 42% of cases, seizures may precede other clinical manifestations by up to 15 years. The orofacial and buccal dyskinesias with tongue thrusting can cause tongue and lip biting, vocalizations, dysphagia, and dysarthria. Repetitive motor tics, dystonia, trunk spasms, and bizarre gait occur and can proceed to parkinsonism. Neuropsychiatric symptoms may precede or accompany the movement disorder. A personality change associated with obsessive–compulsive behaviour, depression, agitation, and cognitive decline is common. Autonomic disturbances include paroxysmal dyspnoea, sleep disturbance, and orthostatic hypotension. Other manifestations are ocular motor impairments, distal muscle weakness and atrophy, peripheral neuropathy, and areflexia. Those patients with seizures may present with temporal lobe epilepsy and may require multidrug therapy. The use of carbamazepine or lamotrigine in these individuals may exacerbate the movement disorder. Patients with chorea–acanthocytosis are not candidates for epilepsy surgery. In most patients muscle creatine phosphokinase is elevated in the serum. The percentage of acanthocytes in the blood varies from 5% to 50%.

The findings on neuroimaging are similar to those in Huntington’s disease. There is caudate atrophy, often more generalized, with an increased T2-weighted signal abnormality on MRI of the caudate and putamen. PET studies show a reduction in blood flow and glucose metabolism in the caudate, putamen, and frontal cortex, and reduction in [18F]fluorodopa uptake in the posterior putamen.

Neuropathology examinations confirm atrophy of the caudate, putamen, and to a lesser extent the pallidum and ventrolateral part of the substantia nigra. On muscle biopsy there is neurogenic muscle atrophy and, in peripheral nerve biopsies, depletion of large myelinated fibres. Ultrastructural studies of peripheral nerve reveal axonal swellings filled with accumulations of neurofilaments.

Chorea–acanthocytosis is the result of mutations in the VPS13A (‘vascular protein sorting’) gene on chromosome 9q21. This codes for chorein, which is believed to be involved in trafficking of membrane proteins between cellular compartments. The presence of a specific deletion in French–Canadian patients and another in Japanese families suggests a founder effect in these two populations. The diagnosis of chorea–acanthocytosis may be confirmed by western blot analysis for chorein deficiency or molecular sequencing of VPS13A.

McLeod’s syndrome

This rare, X-linked disorder has many of the clinical manifestations of chorea–acanthocytosis. It develops in men in the fifth decade and has a slowly progressive course. Women may show symptoms but they are generally milder. Limb chorea and facial hyperkinesia are common but lip and tongue biting are rare and parkinsonism is generally not present. As the disease progresses, many patients will manifest dystonic movements, epileptic seizures, cognitive impairment, and psychological disturbances. Other nervous system signs include muscle weakness and atrophy, and areflexia. Hepatomegaly and splenomegaly may occur and two-thirds of patients develop cardiac disease leading to severe cardiomyopathy and death.

The neuroimaging findings are similar to those in chorea–acanthocytosis and Huntington’s disease with atrophy of the caudate nucleus and abnormal signals in the basal ganglia on MRI. SPECT indicates a reduction in striatal dopamine D2-receptors. Analysis by PET discloses absent metabolism of the basal ganglia and reduced metabolism in the frontal and parietal cortex.

Muscle biopsy specimens reveal type 2 fibre atrophy and serum levels of muscle creatine kinase are elevated. Nerve biopsies confirm electrophysiological findings of axonal degeneration.

McLeod’s syndrome is caused by absence of functional XK gene product. The XK gene is located on chromosome Xp21 and expresses the precursor substance for Kell antigen, the third most important blood group system after ABO and rhesus. Therefore, in McLeod’s syndrome, Kell antigens are extremely reduced or absent. Kell is an endothelin-processing enzyme and, as endothelins serve as basal ganglia neurotransmitters, the deficiency of Kell could be relevant to the pathogenesis of McLeod’s syndrome.

Huntington’s disease-like 2

HDL2 is an autosomal dominant disorder appearing in the third or fourth decade with chorea, dystonia or parkinsonism, and progressive cognitive impairments. It is due to a CTG/CAG repeat expansion in the junctophilin 3 gene (JPH3) on chromosome 16q24.3. Age of onset is inversely proportional to the size of the repeat expansion. The gene product, junctophilin 3, seems to have a role in junctional membrane structures.

Treatment of the neuroacanthosis syndrome

As in Huntington’s disease, treatment is symptomatic. To control the choreiform movements, dopaminergic function is reduced through the use of atypical antipsychotic agents or tetrabenazine. Focal dystonia interfering with eating may be treated with botulinum toxin injection into the genioglossus muscle. Anticonvulsants such as phenytoin, clonazapam, and valproate are used to treat seizures, and pharmacotherapy is also directed towards the psychiatric issues. Lesioning of the subthalamic nucleus or globus pallidus pars interna and deep brain stimulation have been used to treat chorea with mixed results. Patients with McLeod’s syndrome should have periodic Holter monitoring and echocardiography for arrhythmia and cardiomyopathy. They should also have autologous blood banked to avoid potential blood transfusion reactions. Physical, occupational, and speech and language therapy are valuable adjuncts as are nutritional consultation and assistive devices.

Hereditary ataxias

Friedreich’s ataxia

This disorder is an example of a spinocerebellar degeneration and is dominated by progressive ataxia with an onset in childhood or adolescence. The condition is inherited as an autosomal recessive trait and afflicts 1 in 30 000 individuals. The gene responsible has been localized to chromosome 9q13–q21 and is due to an expanded GAA repeat in a noncoding region of the gene for frataxin, a mitochondrial protein involved in iron homoeostasis. Degeneration of the larger dorsal root ganglion cells occurs, with consequent loss of the larger myelinated fibres in the peripheral nerves and degeneration in the dorsal columns. Degeneration is also evident in Clarke’s column, the spinocerebellar tracts, and the corticospinal pathways. There is variable loss of Purkinje’s cells in the cerebellum.

The average age of onset is 11 to 12 years, but cases of later onset may occur. The initial symptom is almost invariably ataxia of gait, although foot or spinal deformity may antedate this. At first it is noted that the child walks awkwardly with a tendency to stumble and fall readily; in cases of early onset, walking may never have been normal. As the disease progresses, the gait slowly becomes more irregular and clumsy. The patient walks on a broad base and tends to lurch from side to side. Involvement of the upper limbs develops later, at first giving rise to clumsiness of fine movements, subsequently for all movements. A coarse intention tremor becomes obvious. The trunk is also affected, leading to oscillation of the body when standing or sitting unsupported. A regular tremor of the head (titubation) occasionally appears. Nystagmus is present in about a quarter of the cases. Dysarthria of cerebellar type develops and may become severe enough to make speech almost unintelligible.

Initially weakness is not obtrusive, but this develops as the disease advances, starting in the legs and later involving the upper limbs. It results from degeneration in the corticospinal pathways and tends to vary in severity between cases. The plantar responses become extensor, but tone is not usually increased because of the accompanying disturbance of the afferent fibres from muscle spindles. There may be mild wasting of the anterior tibial and small hand muscles related to loss of anterior horn cells. Bladder and bowel function is usually unaffected.

Loss of the larger dorsal root ganglion cells leads to impairment of the sense of joint position, of vibration, and to some extent of touch–pressure sensibility, initially distally in the limbs. The impairment of proprioception superimposes a sensory element on the cerebellar ataxia. The tendon reflexes are depressed or absent.

Apart from occasional nystagmus, the ocular movements are usually intact. The pupils are unaffected. Optic atrophy is present in about a third of cases and 10% develop sensorineural deafness with particular difficulty in speech discrimination.

Associated skeletal deformities are common, in particular foot deformities (pes cavus and pes equinovarus) and kyphoscoliosis. Contractures of the knees may develop in the later stages. ECG demonstrates widespread T-wave inversion and ventricular hypertrophy in almost 70% of patients. Echocardiography may suggest the presence of hypertrophic obstructive cardiomyopathy, but these findings are not specific and the ECG is a more sensitive indicator of cardiomyopathy. The ECG changes are present early in the disease and tend not to be associated with symptoms. Cardiac failure occurs late and is usually precipitated by supraventricular arrhythmias.

Although progressive dementia is not a feature of the disease, reduced intelligence is present in some cases. There is an increased incidence of diabetes mellitus in Friedreich’s ataxia (10%).

The disease is slowly progressive, the average age of death being in the latter part of the fourth decade. The foot and spinal deformities may require orthopaedic correction. Current therapeutic trials aim to counter the effects of oxidative stress using free radical scavengers such as idebenone or mitochondrial enhancers such as coenzyme Q1, and to increase expression of frataxin with histone deacetylase inhibitors. Ultimately patients become bedridden. Death is usually from an intercurrent infection or cardiac failure.

Autosomal dominant spinocerebellar ataxias

Inherited neurodegenerative diseasesThis category of hereditary ataxias includes at least 29 clinically and genetically heterogeneous disorders. Although each is associated with extensive cerebellar atrophy involving all cellular layers and the deep cerebellar nuclei, many have involvement of the brainstem. In some, there is also involvement of the basal ganglia, cerebral cortex, spinal cord, and peripheral nerves. Other features are relatively unique such as retinal degeneration in SCA7 and epilepsy in SCA10. Action tremor is a feature of SCA12 and psychiatric manifestations, chorea, parkinsonism, and dementia occur in SCA17. The prevalence rates in different European regions range from 0.9 in 100 000 to 3.0 in 100 000.

The average age at onset is between 30 and 40 years, but can be much earlier, even infantile. Gait difficulty and imbalance are the most common initial manifestations, which progress insidiously to impaired coordination of the arms, dysarthria and dysphagia, and oculomotor symptoms such as diplopia or oscillopsia. A spectrum of other symptoms and signs evolves in several subtypes, involving both the central as well as peripheral nervous system: pyramidal signs, peripheral neuropathy, dystonia, and cognitive disturbances. It is often a challenge to predict the genotype based on the phenotype as the overlap in the subtypes is significant. However, some of these nonataxic features are distinctive of a particular genotype, such as, macular degeneration in SCA7, chorea in SCA17 and DRPLA, and motor neuron involvement in SCA3 and SCA36. Based on their molecular genetics, three major classes of SCAs can be delineated. The first are the polyglutamine diseases, so called because the defective gene in each contains a CAG repeat expansion that encodes an unstable polyglutamine tract. These six SCAs, namely SCA1, -2, -3, -6, -7, and -17, account for more than 50% of affected families worldwide.

The second group also involves nucleotide repeat expansions but they are in noncoding regions of the gene. In this category are SCA8, -10, and -12. The third category includes SCAs with conventional mutations in specific genes. Four are known: SCA5, -13, -14, and -27.

The repeat expansions are subject to the phenomenon of anticipation in which with each succeeding generation the expansion enlarges and, the larger the expansion, the earlier the onset and the more severe the disease. This is particularly severe in SCA7. A summary of the clinical and genetics of the SCAs is presented in Table 24.17.1.

Table 24.17.1 Classification of spinocerebellar ataxias (SCAs)

SCA type

Gene locus

Symptoms

SCA1

6p23; CAG expansion in ATXN1 gene; polyQ disease

Ataxia with ophthalmoparesis, and pyramidal and extrapyramidal findings

SCA2

12q24; CAG expansion in ATXN2 gene; poly Q disease

Ataxia with slow saccades, peripheral neuropathy; less frequent extrapyramidal findings

Machado–Joseph disease/SCA3

14q32; CAG expansion in ATXN3 gene; polyQ disease

Ataxia with ophthalmoparesis; pyramidal, extrapyramidal, and amyotrophic signs

SCA4

16q22

Ataxia with sensory axonal neuropathy and pyramidal signs

SCA5

11p13; mutations in SPTBN2 gene

Relative pure cerebellar ataxia with dysarthria; includes Lincoln descendants

SCA6

19p13; CAG expansion CACNA1a gene; polyQ disease

Pure cerebellar ataxia with dysarthria, nystagmus; occasional mild sensory loss

SCA7

3p14; CAG expansion in ATXN7 gene; polyQ disease

Ataxia with ophthalmoparesis, retinal degeneration, dysarthria, variable pyramidal signs

SCA8

13q21; CTG/CAG expansion in ATXN8 gene

Gait ataxia, dysarthria, nystagmus, spasticity, and reduced vibratory sensation

SCA10

22q13; ATTCT expansion in ATXN10 gene

Gait ataxia, dysarthria, nystagmus, frequent seizures; neuropathy

SCA11

15q14–q21.3 by linkage

Slowly progressive, relatively mild gait and limb ataxia

SCA12

5q32; noncoding CAG expansion in PPP2R2B

Ataxia with tremor; dysarthria, increased reflexes; occasional dystonia, late-onset dementia

SCA13

19q13.3–q14.4; mutations in KCNC3 gene

Ataxia, varying onset including childhood; occasional delayed motor development and intellectual impairment

SCA14

19q13.4; mutations in PRKCG gene

Ataxia with dysarthria; facial myokymia; occasional myoclonus, dystonia; vibratory loss; late onset can be pure ataxia

SCA15

3p24.2-3pter

Slowly progressive, relatively pure cerebellar ataxia

SCA16

3p26.2-pter

Ataxia with head tremor, dysarthria

SCA17

6q27; CAG expansion in TBP gene; polyQ disease

Ataxia with dementia, extrapyramidal signs; widespread cerebral and cerebellar atrophy

SCA18

7q22–q32

Ataxia with sensorimotor neuropathy

SCA19

1p21–q21

Slowly progressive ataxia hyporeflexia, cognitive impairment; occasional tremor and myoclonus

SCA20

Chromosome 11

Ataxia with dysarthria; dentate calcification on CT

SCA21

7p21–p15

Ataxia with dysarthria, extrapyramidal features, cognitive defects; hyporeflexia

SCA22

1p21–q23

Pure cerebellar ataxia with dysarthria, nystagmus

SCA23

20p13–12.3

Slowly progressive ataxia with vibration loss

SCA25

2p21–p13

Ataxia with severe sensory neuropathy; gastrointestinal symptoms

SCA26

19p13.3

Pure cerebellar ataxia with dysarthria

SCA27

13q34; mutations in FGF14 gene

Ataxia with tremor; orofacial dyskinesias; psychiatric symptoms and cognitive deficits

SCA28

18p11.22–q11.2

Ataxia with dysarthria, ophthalmoparesis, hyperreflexia

SCA29

3p26

Early onset, nonprogressive ataxia, vermian hypoplasia

Soong B-W and Paulson HL. Current Opinion in Neurology 2007; 20:438–446.

The various symptoms are managed with conventional therapies. The extrapyramidal features in SCA3 may respond to levodopa and acetazolamide has helped patients with SCA6 due to repeat expansion in a voltage-sensitive calcium channel gene (CACNA1A).

Familial episodic ataxia

Severe types of episodic ataxia (EA) are known. The attacks in EA1 last a few minutes and occur several times a day. They can be precipitated by exercise or startle and are associated with facial and manual myokymia, which may persist between attacks. It is caused by mutations in the potassium channel gene KCNA1, which maps to chromosome 12p13.

The episodes in EA2 may last hours to days and can be precipitated by stress, exercise, or fatigue. Interictal diplopia and headache have occurred. EA2 is allelic to familial hemiplegic migraine and is caused by mutations in the calcium channel gene CACNA1A4 on chromosome 19p13. Acetazolamide has been used to treat both EA1 and EA2 but is more effective in EA2.

At least four other hereditary forms of episodic ataxia have been described. EA5 is attributed to mutation in a gene encoding a calcium channel β‎ subunit. The cause of EA6 is a mutation in a gene encoding a glutamate transporter.

Dentatorubral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegeneration caused by a glutamine-encoding repeat expansion in the atrophin gene on chromosome 12p13.3. Ataxia, dystonia, and dementia are characteristic.

Juvenile patients develop progressive myoclonic epilepsy whereas, in those patients with symptoms beginning after age 20, choreoathetosis and psychiatric difficulties are more prominent. The MRI and neuropathological examinations show cerebellar and brainstem atrophy, especially of the pontine tegmentum. Nerve cell loss and gliosis occur in the dentate nucleus, red nucleus, pallidum, and corpus luysi. Degenerative changes are also found in the striatum, cerebellar cortex, and corticospinal tract. The caudate nuclei are normal and the ventricles may be enlarged.

Most patients inherit the disease from their father but, if from their mother, symptoms begin earlier and are more severe even though the degree of expansion is smaller than in the case of paternal transmission. An allelic form of this disease, known as Haw River syndrome, has been described in an African–American family.

Fragile X tremor/ataxia syndrome

The fragile X syndrome is an X-linked disorder with an estimated incidence of 1 in 4000. Cardinal manifestations in the male are developmental delay, intellectual impairment, dysmorphic facial features, large testes, and autistic features. It is due to expansion of a CGG repeat (more than 230 methylated repeats) in the 5′‎-untranslated region of the fragile X gene, FMRI. Some females with the same molecular defect are affected but less severely than males.

Older males with a premutation allele (55 to 200 CGG repeats) will develop progressive gait ataxia and intention tremor, in association with neuropsychiatric abnormalities, parkinsonism, autonomic dysfunction, and peripheral neuropathy. Neuropsychological tests reveal deficits in executive functioning and memory. Anxiety, agitation, apathy, and depression are part of the neuropsychiatric profile. Penetrance of the disorder is age related, with 17% of adult premutation carriers manifesting tremor and ataxia in the 50- to 59-year age group and 75% in the cohort aged over 80 years.

MRI reveals cerebral atrophy, ventricular widening, thinning of the corpus callosum, and volume loss of the middle cerebral peduncles, cerebellar cortex, pons, and midbrain. Abnormal signal intensity in the cerebral white matter is also observed. Neuropathological studies confirm the presence of significant cerebral and cerebellar white matter disease. Eosinophilic intranuclear inclusions are found in neurons and astroglial cells of the brain and spinal cord proportionate to the CGG repeat length.

The prevalence of fragile X tremor/ataxia syndrome (FXTAS) in men aged 50 years or more is estimated to be 1 in 3000. Female premutation carriers are at risk for premature ovarian failure and early menopause, but are rarely affected with FXTAS. Men aged 50 or older with sporadic ataxia and a hyperintense signal on MRI in the middle cerebellar peduncles, as well as women with premature ovarian failure, should be offered screening for the fragile X premutation allele.

Other hereditary metabolic and degenerative ataxias

Numerous other hereditary metabolic diseases not already discussed in this chapter can cause cerebellar ataxia. These include abetalipoproteinaemia (compare Baseen–Kornzweig syndrome), ataxia with vitamin E deficiency (AVED), Leigh’s syndrome (compare Chapter 24.24.5), pyruvate dehydrogenase deficiency, Refsum’s disease, congenital defect of glycosylation, succinic semialdehyde deficiency, and juvenile neuroaxonal dystrophy.

Mitochondrial diseases

(see Chapter 24.24.5)

Mitochondrial disorders constitute the most common neurometabolic disease of childhood with an estimated risk of 1 in 5000.

Mitochondrial genetics is complicated by the fact that mitochondria have their own DNA (mtDNA) but the vast majority of mitochondrial proteins are encoded by nuclear DNA (nDNA). Therefore, the inheritance pattern of mitochondrial diseases may be autosomal dominant or recessive, if secondary to a nuclear gene defect, or else maternally inherited or sporadic, if the mitochondrial genome is mutated. Mitochondria are ubiquitous in every tissue in the body, each cell containing many thousands of copies, all originating from the oocyte of the mother. Patients with pathogenic mtDNA mutations possess a mixture of mutated and wild-type mtDNA creating heteroplasmy. As the percentage of mutated mtDNA can vary among offspring within the same family and from organ to organ in the same individual, disease expression is highly variable. For a full description of mitochondrial diseases, see Chapter 24.24.5.

Lysosomal diseases (see Chapter 12.8)

Approximately 70 diseases are known in which failure to degrade one or more macromolecules results in their accumulation within tissues (Table 24.17.2). Together these disorders have an incidence of 1 in 5000 to 7000 births. The stored materials are byproducts of the cellular turnover of complex glycoproteins, glycolipids, glycosaminoglycans (mucopolysaccharides), and oligosaccharides.

Table 24.17.2 Lysosomal storage diseases

Stored substrate

Disease

Enzyme/protein deficiency

Gene locus

Sphingolipids

GM2 gangliosides, glycolipids, globoside oligosaccharides

Tay–Sachs disease

α‎ Subunit of β‎-hexoaminidase

15q23–24

GM2 gangliosides (three types)

β‎ Subunit of β‎-hexoaminidase

5q13

Sandhoff’s disease

GM2 activator

5q32–33

GM2 gangliosides

GM2 gangliosides, AB variant

GM1 gangliosides, oligosaccharides, keratin sulphate, glycolipids

GM1 gangliosides (three types)

β‎-Galactosidase

3p21-3pter

Sulphatides

Metachromatic leucodystrophy

Arylsulphatase A (galactose-3-sulphatase)

22q13.31-qter

GM1 gangliosides, sphingomyelin, glycolipids, sulphatide

Metachromatic leucodystrophy variant

Saposin B activator

10q21

Galactosylceramides

Krabbe’s disease

Galactocerebrosidase

14q31

α‎-Galactosylsphingolipids, oligosaccharides

Fabry’s disease

α‎-Galactosidase A

Xq22

Glucosylceramide, globosides

Gaucher’s disease (three types)a

β‎-Glucosidase

1q21

Glucosylceramide, globosides

Gaucher’s disease (variant)

Saposin C

10q21

Ceramide

Farber’s disease (seven types)

Acid ceramidase

8p22–21.2

Sphingomyelin

Niemann–Pick disease types A and B

Sphingomyelinase

11p15.1–15.4

Mucopolysaccharides (glycosaminoglycans)

Dermatan sulphate and heparin sulphate

MPS I, Hurler–Scheie

α‎-l-Iduronidase

4p16.3

MPS II, Hunter

Iduronate-2-sulphatase

Xq27.3–28

Heparan sulphate

MPS IIIA, Sanfilippo A

Sulphamidase

17q25.3

MPS IIIB, Sanfilippo B

α‎-N-Acetylglucosaminidase

17q21.1

MPS IIIC, Sanfilippo C

Acetyl-CoA:α‎-glucosaminide-N-acetyltransferase

MPS IIID, Sanfilippo D

N-acetylglucosamine-6-sulphatase

12q14

Keratan sulphate

MPS IVA, Morquio A

Galactosamine-6-sulphatase

16q24.3

MPS IVB, Morquio B

β‎-d-Galactosidase

3p21.33

Dermatan sulphate

MPS VI, Maroteaux–Lamy

N-Acetylgalactosamine-4-sulphatase

5q13–14

Dermatan sulphate and heparan sulphate

MPS VII, sly

Hyaluronidase

7q21.1–22

Hyaluronan

MPS IX

β‎-d-Glucuronidase

3p21.3

Glycogen

Glycogen

Pompe’s disease, glycogen storage disease type IIA

α‎-d-Glucosidase

17q25

Glycogen

Danon’s disease

Lysosomal associated membrane protein-2 (LAMP-2)

Xq24

Oligosaccharides/glycopeptides

α‎-Mannoside

α‎-Mannosidosis

α‎-Mannosidase

19p13.2–q12

β‎-Mannoside

β‎-Mannosidosis

β‎-Mannosidase

4q22-25

α‎-Fucosides, glycolipids

α‎-Fucosidosis

α‎-Fucosidase

1p34.1–36.1

α‎ -N-Acetylgalactosaminide

Schindler–Kanzaki disease

α‎ -N-Acetylgalactosaminidase

22q13.1–13.

Sialyloligosaccharides

Sialidosis

α‎-Neuraminidase

6p21.3

Aspartylglucosamine

Aspartylglucosaminuria

Aspartylglucosaminidase

4q34-35

Multiple enzyme deficiencies

Glycolipids, oligosaccharides

Mucolipidosis II (I-cell disease); mucolipidosis III (pseudo-Hurler’s polydystrophy)—three complementation groups)

N-Acetylglucosamine-1-phosphotransferase

4q21–q23

Mucolipidosis III subtype C

γ‎ subunit mutations on 16p

Galactosialidosis

Protective protein/cathepsin A

20

Sulphatides, glycolipids, glycosaminoglycans

Multiple sulphatases

SUMF-1

3p26

Lipids

Cholesterol esters

Wolman’s disease, cholesteryl ester storage disease

Acid lipase

10q23.2–q23.3

Cholesterol, sphingomyelin

Niemann–Pick disease type C

NPC1; HE1

18q11–12; 14124.3

Monosaccharides/amino acid monomers

Sialic acid, glucuronic acid

Salla’s disease, infantile free sialic acid storage disease

Sialin

6q14–15

Cystine

Cystinosis

Cystinosis

17p13

Peptides

Bone proteins

Pyknodysostosis

Cathepsin K

1q21

S-Acylated proteins

Palmitoylated proteins

Infantile neuronal ceroid lipofuscinosis

Palmitoyl-protein thioesterase

1p32

Pepstatin-insensitive lyosomal peptidase

Late infantile neuronal ceroid lipofuscinosis

Pepstatin-insensitive lysosomal peptidase

11p15

Clinical genetics

Among Ashkenazi Jews, the frequency of the carrier state for certain of the lysosomal storage diseases (LSDs) is higher than in the general population. For this reason, screening of young adults and couples before conception or in the early stages of a pregnancy is being done to determine their carrier status for these disorders, which include Tay–Sachs disease, Niemann–Pick disease types A and B, and mucolipidosis IV. In each pregnancy of a couple in which both partners are carriers of the same recessive trait, there is a 25% risk of an affected fetus; monitoring of their pregnancies by amniocentesis or chronic villous biopsy could permit interruption at an early stage if the tests prove positive.

As, among Ashkenazi Jews, Gaucher’s disease does not ordinarily cause neurodegeneration, pregnancy monitoring of carrier–carrier couples for Gaucher’s disease is generally not done. Another type of prevention programme, popular among the Orthodox Jewish population, involves nonstigmatizing premarital testing permitting marriages to be arranged that avoid the possibility of two carriers for the same disease trait marrying.

Families in which an affected child has already been born can access prenatal testing of the conceptus using either information on the mutations present in the family or through testing of enzyme activity in the chorionic villous cells or the cultured amniotic fluid cells. Newborn screening is also being developed for those LSDs in which an intervention, such as umbilical cord stem cell transplantation, may be done in the early newborn period to prevent disease progression. In all cases in which a diagnosis of an LSD is made, family members should be offered genetic counselling and should be encouraged to inform relatives of their increased risk of carrying the trait for the disease.

Whereas lysosomal enzymes are ubiquitously expressed, the substrate on which they act may be confined to a single organ or system, as in Krabbe’s disease, or distributed more widely causing multisystemic manifestations, as in Gaucher’s disease. Signs of disease manifestations may become evident prenatally, at birth, or at any time from infancy to adulthood. Here LSDs that involve the central and/or peripheral nervous system are considered.

Sphingolipidoses

The sphingolipidoses are characterized by abnormalities in the metabolism of various glycolipid substrates that are present within membranes of nerve cells and myelin. Most of these disorders are neurodegenerative in nature.

Glycosphingolipids (GSLs) undergo degradation within lysosomes through the sequential action of specific acid hydrolases with the assistance of nonenzymatic glycoprotein cofactors, so-called sphingolipid activator proteins (or saposins [SAPs]). Ultrastructural studies of tissues from patients with GSL storage diseases typically reveal the presence of characteristic inclusions such as the membranous cytoplasmic bodies (MCBs) present in patients with GM1 and GM2 gangliosidoses.

Gangliosidoses

The gangliosides are a group of complex lipids with a ceramide backbone, to which hexoses and sialic acids are attached. They are found predominantly in brain grey matter. Disorders of ganglioside metabolism are classified according to the specific enzyme deficiency and the resultant accumulation of its substrates. The nomenclature of these substrates was assigned by Svennerholm, based on the placement of their sialic acid residues and their distinct chromatographic mobility. Each disorder is further categorized by age of onset into classic (early or late) infantile or later-onset (juvenile or adult) forms. Age of onset and degree of disease expression are influenced, in part, by the degree of residual enzyme activity. Secondary ganglioside accumulation occurs in other LSDs such as the MPSs and Niemann–Pick disease type C.

GM1 gangliosidosis

GM1 gangliosidosis, caused by deficiency of the enzyme β‎-galactosidase (β‎-Gal), is associated with the neuronal storage of the monosialoganglioside GM1. Normally 20% of all gangliosides found in the brain and 80% of gangliosides in myelin are the monosialoganglioside GM1. Several other substrates of β‎-galactosidase, including galactose-containing glycoproteins, N-acetylgalactosamine, lactose, and keratan sulphate (a glycosaminoglycan), also accumulate and this may explain the presence of dysmorphic facial features reminiscent of the MPS disorders in the early infantile form of GM1 gangliosidosis. Histological examination of the brain in infantile GM1 gangliosidosis shows neurons and glial cells with distended cytoplasm and eccentrically placed pyknotic nuclei. Electron microscopy shows concentrically arranged inclusion bodies, which largely replace normal cytoplasmic constituents. In later-onset forms marked GM1 ganglioside storage is seen in the basal ganglia.

Early infantile GM1 gangliosidosis presents with hypotonia, feeding difficulties, and failure to thrive in the first weeks of life. A macular cherry-red spot is found in about 50% of cases, and there is a startle response similar to that seen in Tay–Sachs disease. Cherry-red spot represents the appearance of the normal ganglion cell-free region of fovea against the pale retina, where lipid-laden ganglion cells produce a white ring or halo. Dysmorphic facial features such as frontal bossing, wide depressed nasal bridge, gingival hypertrophy, or thickened alveolar ridges are prominent. Hepatosplenomegaly as well as bone deformities referred to as dysostosis multiplex, similar to those found in the MPS disorders, including hypoplasia and anterior beaking of the thoracolumbar vertebrae and widening of the diaphysis of long bone, are also noted. Cardiac complications include enlargement of the heart with thickening of the heart valves and endocardial fibroelastosis, leading to valvular incompetence and cardiac failure. Hydrops fetalis may be the presenting feature at birth in 6% of cases.

The course is relentlessly progressive leading to spasticity, tonic spasms, and pyramidal signs with decerebrate rigidity by the second year with or without seizures. Respiratory failure and bronchopneumonia lead to death, usually by 2 years.

The late infantile form has an onset usually between 12 and 18 months, often with walking difficulty and frequent falls. Facial dysmorphism, skeletal deformities, and organomegaly are less prominent. Progression of the disease leads to seizures, spastic quadriparesis, and pseudobulbar signs such as drooling and dysphagia. Death occurs between the ages of 3 and 10 years.

The juvenile or late-onset form is a protracted illness with dysarthria, dystonia and mild-to-moderate intellectual impairment, usually developing in late childhood or adolescence, but signs and symptoms may be delayed until the third or fourth decade of life. There is vacuolation of peripheral blood lymphocytes, and the presence of galactose-containing oligosaccharides and keratan sulphate in urine, findings that help to distinguish GM1 gangliosidosis from mucolipidosis II (I-cell disease), because both can present with dysmorphic facial features and hepatosplenomegaly. Diagnosis is established by assay of β‎-Gal activity in peripheral blood leucocytes and cultured skin fibroblasts, or prenatally using cultured chorionic villous sample (CVS) or amniocytes. Only symptomatic treatment is available. A chemical chaperone therapy with N-octyl-4-epi-β‎-valienamine (NOEV) has been shown to be effective in mice.

GM2 gangliosidoses

The GM2 gangliosidoses are a group of heterogeneous clinical variants associated with the neuronal storage of the monosialoganglioside GM2, caused by mutations in genes encoding the α‎ (Tay–Sachs disease) or β‎ (Sandhoff’s disease) subunit of hexosaminidase A (Hex-A) or the GM2 activator protein (in the AB variant). The Hex-A enzyme, with molecular mass of approximately 100 kDa, is a trimer consisting of one α‎- and two β‎-subunits, encoded by genes situated on different chromosomes. Mutations in the β‎-subunit lead to deficiency of Hex-B as well, which is a tetrameric homopolymer of β‎ subunits. The B1 variant of GM2 gangliosidosis, which has a high incidence in Portugal, results from altered substrate specificity of Hex-A. In this variant the mutated enzyme retains the ability to degrade the artificial substrate used in diagnostic assays, but not the natural substrate in vivo or the sulphated artificial substrate.

Ultrastructural examination reveals neuronal GM2 ganglioside storage throughout the cortex and the deep grey nuclei, the spinal cord, and the autonomic ganglia. Characteristic pathological features are axonal hillock enlargement, known as meganeurite formation, and sprouting of new synapse-covered dendritic neurites at the axon hillock termed ‘ectopic dendritogenesis’, as well as axonal spheroid formation or neuroaxonal dystrophy. Spheroids are focal enlargements of various sizes distributed along myelinated and unmyelinated axons in the grey and white matter, consisting of multivesicular and dense bodies, mitochondria, and other organelles. This suggests that there is defective endocytic trafficking within axons. The incidence in the general population has been estimated at 1 in 112 000 live births, although the disease was highly prevalent among Ashkenazi Jews (1 in 3900 live births). Successful implementation of carrier screening programmes for at-risk couples has remedied this situation.

The ‘classic’ infantile form of Tay–Sachs disease (TSD), named after a British ophthalmologist, Warren Tay, and an American neurologist, Bernard Sachs, presents in infancy with psychomotor deterioration, poor head control, easy startle, axial hypotonia, bilateral pyramidal signs, and cortical blindness (pupillary responses are preserved). A characteristic hallmark of the disease is the presence of a macular cherry-red spot. In the second year of life, brain enlargement and not hydrocephalus leads to progressive megalencephaly; however, with further loss of the neurons and gliosis, the ventricles dilate. Progressive neurological deterioration leads to a spastic state and cachexia. Generalized tonic–clonic and simple motor seizures can occur in the terminal stages. Death usually occurs between 3 and 5 years of age. The AB variant, caused by deficiency of the GM2 activator, has a phenotype that is indistinguishable from the infantile form. This diagnosis is suspected when the laboratory test results for assays of Hex-A and -B enzyme activity using artificial substrates are normal and the clinical presentation suggests gangliosidoses.

The later-onset forms of GM2 gangliosidosis follow a protracted course and there is no ethnic predilection. Differences in the age of onset and disease progression, presumably determined by the severity of the underlying mutation, distinguish the childhood form, which has an onset between ages 3 and 6 years (chronic GM2 gangliosidosis) from the adult-onset variant or late-onset TSD (LOTS), appearing in the teens or early adulthood. The phenotype of the B1 variant is similar to that of the childhood-onset form. Affected children develop dysarthria and gait difficulty, due to spastic paraparesis, which may be accompanied by tonic–clonic or myoclonic seizures. Disease progression is marked by spasticity, rigidity, and dementia, ending in a vegetative state leading to death by the age of 15 years. Proximal muscle weakness, ataxia with cerebellar atrophy, and fasciculations are prominent in the later-onset forms, often leading to a wheelchair-dependent state. Psychiatric disturbances, including frank psychosis, may be the initial manifestation of disease, particularly among adult-onset patients. Late-onset GM2 gangliosidosis should be considered in the differential diagnosis of adult patients with signs of lower motor neuron and cerebellar dysfunction. Vision and optic fundi are normal, although some cognitive decline is frequently encountered. Adult-onset patients may live into their 50s or 60s.

Sandhoff’s disease (SD), a pan-ethnic disorder, is caused by mutations in the β‎-subunit of Hex-A and -B. Although the age of onset and clinical course are similar to TSD, organomegaly, N-acetylglucosamine-containing oligosaccharides in urine, and occasional cardiomyopathy are distinguishing features. Extremely rare cases of juvenile or late-onset SD have been reported.

The diagnosis is ascertained by assays of total hexosaminidase and Hex-A activity in leucocytes, and cultured skin fibroblasts complemented by analysis of the underlying Hex-A gene mutations. Prenatal diagnosis of the GM2 gangliosidoses is available. Biochemical and/or molecular tests are preformed on cultured cells obtained by CVS or amniocentesis.

There is no definitive therapy for GM2 gangliosidoses. However, substrate reduction therapy, based on the inhibition of glucosylceramide synthesis using the iminosugar miglustat, and gene therapy are under investigation. Jacob sheep, a recently described naturally occurring animal model of Tay–Sachs disease offers promise as a means for trials of gene therapy.

Fabry’s disease (see Chapter 12.6)

Gaucher’s disease

Gaucher’s disease, the most common lysosomal storage disorder with an estimated frequency of about 1 in 50 000, is caused by the deficiency of the lysosomal enzyme glucocerebrosidase (acid β‎-glucosidase), leading to the accumulation of its substrate, glucocerebroside (glucosylceramide) within cells of monocyte/macrophage lineage. The three major clinical subtypes are delineated based on the presence or absence of neurological involvement as well as the age of onset, rapidity of disease progression, and the rate and severity of neurological deterioration, when present.

Type I Gaucher’s disease, a pan-ethnic disorder with high prevalence among the Ashkenazi Jewish population (carrier frequency about 1 in 20), refers to the non-neuropathic disease associated with hepatosplenomegaly, anaemia and thrombocytopenia, pulmonary involvement, and bone disease (see Chapter 12.8). Recent evidence suggests an association with Lewy body disorders, including Parkinson’s disease, in a small proportion of patients and carriers of acid β‎-glucosidase mutations.

In type II Gaucher’s disease, disease onset is before 12 months of age. In this acute neuropathic form, infants develop spasticity with head retraction (opisthotonus), dysphagia, and a rapidly fatal course; death usually occurs between 2 and 3 years of age. Laryngeal stridor, trismus, and aspiration pneumonia are frequent complications.

Type III Gaucher’s disease, found in about 5% of patients with Gaucher’s disease, is a chronic disorder with variable age of onset, usually before the age of 10 years. Neurological features include gaze initiation failure, tonic–clonic and myoclonic seizures, ataxia, and extrapyramidal rigidity. Severe pulmonary involvement is often present. The Norbottnian variant of type III Gaucher’s disease presents with neurological problems which may be restricted to supranuclear horizontal gaze palsy despite the presence of significant extra-neurological systemic problems.

In contrast to the large amount of lipid stored in the liver and spleen, there is no significant accumulation of glucocerebroside in the brain. Severe glucocerebrosidase deficiency leads to production of glucosylsphingosine (psychosine), an alternative neurotoxic metabolic byproduct, which could play a contributory role in the primary neurological involvement seen in certain subtypes of Gaucher’s disease. Neuropathological studies reveal lipid-filled cells in the perivascular Virchow–Robin spaces and neuronophagic microglial nodules in several regions of the brain (e.g. cortex, thalamus, basal ganglia, brainstem, and cerebellum) and in the spinal cord.

Enzyme replacement therapy (ERT) is now the mainstay of treatment for Gaucher’s disease, although it does not alter the course of neurological deterioration in patients with type II Gaucher’s disease. Recently, substrate reduction therapy (SRT) has been shown to be effective in ameliorating several clinical features of Gaucher’s disease, although its role in neuropathic Gaucher’s disease still has to be elucidated.

Niemann–Pick disease, including types A and B

Niemann–Pick disease (NPD) represents a group of autosomal recessive disorders causing progressive storage of sphingomyelin (phosphorylcholine) in the reticuloendothelial system. NPD subtypes A (infantile neuropathic) and B (later-onset non-neuropathic) represent the spectrum of allelic variants associated with mutations of the ASM gene, resulting in primary deficiency of sphingomyelinase. NPD subtypes C and D are also allelic disorders due to mutations of either the NPC1 or the NPC2 gene, which may be associated with mild secondary ASM deficiency. Mutations in NPC1 or -2 leads to disruption in the trafficking and/or metabolism of cholesterol and sphingolipid.

Early infantile NPD type A presents within the first few weeks or months with failure to thrive and hepatomegaly, followed by neurological regression and the appearance of the macular cherry-red spot, ultimately leading to liver failure with ascites and jaundice, cachexia, rigidity, and opisthotonus. Death occurs in the second or third year of life. NPD type B is associated with visceral involvement and pulmonary infiltration in late infancy or early childhood. There are vacuoles within peripheral lymphocytes and monocytes, as well as foam cells in the bone marrow. Deficient ASM activity in leucocytes or cultured skin fibroblasts confirms the diagnosis of NPD types A and B.

NPD type C has an estimated incidence of 1 in 150 000. Mutations in the gene NPC1, which encodes a large transmembrane glycoprotein localized primarily in the late endosomes, causes approximately 95% of cases, whereas a smaller group of patients has been shown to have a defect of the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties. It is a neurovisceral lipid storage disorder neuropathologically characterized by axonal spheroids, intraneuronal cytoplasmic inclusions, and neuronal loss.

About 50 to 60% of cases are considered to have the classic presentation with a benign, self-limiting jaundice in early infancy, followed by normal initial development. Between the ages of 3 and 8 years these children develop hepatosplenomegaly, clumsiness, ataxia, and supranuclear vertical gaze palsy, accompanied by blinking or head thrusting, eventually progressing to dysarthria, dysphagia, and dementia. Characteristic neurological manifestations include saccadic eye movement abnormalities or vertical supranuclear gaze palsy, cerebellar signs, and gelastic cataplexy. Seizures and dystonia are also common. Late-onset forms are increasingly recognized with typical as well as atypical features. A severe form of NPD type C presents at birth with ascites, jaundice, and a rapidly progressive fatal course. NPD type D was described among the French Acadians in Nova Scotia (Canada) with a disease onset usually between age 2 and 4 years. A founder mutation in NPC1 has subsequently been described in this population.

Management of patients with NPD type C is primarily symptomatic. A trial using substrate reduction therapy with miglustat is under way for NPD type C. Miglustat is an iminosugar that inhibits glycophingolipid synthesis. A 12-month randomized trail showed miglustat stabilization of neurological disease progression in paediatric patients and it was recently approved in Europe to treat progressive neurologic manifestation in NPD type C.

Metachromatic leucodystrophy (sulphatide lipidosis)

See ‘Leucodystrophies’ above.

Krabbe’s disease (globoid cell leucodystrophy)

See ‘Leucodystrophies’ above.

Mucopolysaccharidoses (for individual discussion see Chapter 12.8)

The MPSs are a group of heterogeneous disorders resulting from deficiency of lysosomal glycosidases and sulphatases involved in the sequential degradation of glycosaminoglycans (GAGs). Each follows an autosomal recessive inheritance pattern except MPS II, which is X linked. Their collective incidence is estimated at about 1 in 25 000 to 1 in 50 000. Incomplete hydrolysis and accumulation of GAGs leads to deposition of different types of intralysosomal inclusion bodies in tissues, the most characteristic of which are the zebra bodies. Increased urinary excretion of the substrates dermatan sulphate, heparan sulphate, keratan sulphate, and chondroitin sulphate is often used as a screening test for MPS in suspected cases; however, a definitive diagnosis of a particular MPS subtype is based on specific enzyme assays using plasma, leucocytes, or cultured skin fibroblasts.

Despite being aetiologically distinct, several non-neurological clinical features are shared by MPSs, mainly coarse facial features and dysostosis multiplex. The latter refers to the typical skeletal and radiographic findings, e.g. bullet-shaped phalanges, and flattening and anterior beaking of the vertebral bodies. Ophthalmic complications include corneal opacity, pigmentary retinal degeneration, optic atrophy, and glaucoma. Developmental regression is noted in several MPS subtypes. Hydrocephalus can result from the deposition of GAGs and histiocytic infiltration in the meninges, i.e. pachymeningitis. GAG storage at various sites may lead to nerve compression syndromes such as carpal tunnel syndrome and spinal cord compression.

MPS type I

See Chapter 12.8 for further discussion.

Glycoproteinoses

Deficiency of lysosomal exoglycosidases involved in the hydrolysis of the carbohydrate side chains attached to the peptide backbone of glycoproteins by the N-glycosidic asparagine links leads to disorders of glycoprotein degradation termed the ‘glycoproteinoses’. The clinical features of glycoproteinoses are similar to the MPS disorders, such as coarsening of facial features, dysostosis multiplex, intellectual impairment, and hepatosplenomegaly. Patients with glycoproteinoses have excessive urinary excretion of oligosaccharides; however, identification of the underlying enzyme deficiency requires assays use of leucocytes or cultured skin fibroblasts.

Mannosidosis

Mannosidosis results from a deficiency of either α‎- or β‎-mannosidase. Two clinical forms of α‎-mannosidosis are distinguished based on the age of onset. The more severe infantile form (type I) is associated with severe mental deterioration, facial dysmorphism, dysostosis multiplex, and hepatosplenomegaly, with death occurring usually between the ages of 3 and 10 years. In the relatively milder type II form intellectual impairment is evident by 2 or 3 years of age with delayed speech and poor motor performance. There are superficial corneal opacities, spoke-like posterior lens opacities, deafness, subtle facial dysmorphism, and skeletal abnormalities on radiographs. The clinical course is protracted, extending into adulthood. Late neurological complications include hydrocephalus and spastic quadriplegia. Widening of the diploic space with underdevelopment of the sinuses and prominent periventricular Virchow–Robin spaces are seen on MRI of the brain. Destructive arthropathy due to storage of oligosaccharides may be seen in children and adults. β‎-Mannosidosis presents with severe psychomotor retardation, hearing loss, and seizures.

Fucosidosis

Deficiency of α‎-fucosidase leads to accumulation of fucose-containing oligosaccharides, glycopeptides, and, to a lesser extent, mucopolysaccharides and glycolipids in tissues associated with their excessive urinary excretion. There is prominent neurological dysfunction in all subtypes. The early onset form with neurological deterioration between 6 and 18 months of age rapidly progresses to a decerebrate state. The later-onset form is relatively slowly progressive; neurological regression occurs in the second or third year of life. Death usually occurs between the ages of 4 and 6 years in both subtypes. A third group of patients may show slowly progressive neurological deterioration into adolescence or adulthood. Brain MRI shows extensive and progressive changes in the signal intensity of the white matter and the internal medullary laminae of the thalami, as well as high signal intensity on T1-weighted images and low signal intensity on T2-weighted and FLAIR images in the globus pallidus and substantia nigra. The diagnosis is based on demonstration of decreased α‎-fucosidase activity in leucocytes or cultured skin fibroblasts.

Aspartylglucosaminuria

Aspartylglucosaminuria is described largely in Finland and results from a deficiency of aspartylglucosaminidase (AGA). This enzyme cleaves the bond between asparagine and N-acetylglucosamine of N-linked glycoproteins. Speech problems and severe behavioural abnormalities, with alternating periods of hyperactivity and apathy, are predominant in the clinical picture. Recurrent infections and diarrhoea are common in the early months and years of life. Insidious motor and mental deterioration, often with seizures, develop between the ages of 5 and 15 years. Mild coarsening of the facial features and skeletal abnormalities such as deformities of the vertebrae, periosteal thickening of the long bones, and thickening of the calvarium are evident by adolescence.

Increased aspartylglucosamine in urine and decreased AGA activity in plasma, leucocytes, or cultured skin fibroblasts confirm the diagnosis.

Sialidosis

Sialidosis types I and II are clinical variants associated with the deficiency of α‎-neuraminidase (sialidase) and increased urinary excretion of sialyloligosaccharides. In sialidosis type I progressive visual loss with a typical eye finding of a macular cherry-red spot, myoclonus, and seizures develop in late childhood or adolescence. Irregular myoclonic jerks are precipitated by action, sensory stimuli, emotional upset, menstruation, and smoking. The progressive nature of the disease leads to difficulties with speech, walking, and feeding, followed by blindness, optic atrophy, and intellectual deterioration. Brain imaging shows cerebral and cerebellar atrophy.

In sialidosis type II, also known as mucolipidosis type I, there are neurological, visceral, and skeletal abnormalities including dysostosis multiplex, a Hurler-like phenotype, intellectual impairment, and hepatosplenomegaly. The diagnosis is based on deficient α‎-neuraminidase activity, preferably in cultured skin fibroblasts or leucocytes.

Galactosialidosis results from the combined deficiency of α‎-neuraminidase and β‎-galactosidase, due to defects in the protein cathepsin A (PPCA), which offers protection against rapid proteolytic degradation. It is clinically characterized by cerebellar ataxia, myoclonus, and visual failure in late childhood or adolescence. Additional features include the cherry-red macular spot, dysmorphic facial features, hepatomegaly, and skeletal changes.

The diagnosis of galactosialidosis is based on deficient activity of both α‎-neuraminidase and β‎-Gal in leucocytes or cultured skin fibroblasts, and/or mutations in the gene encoding the PPCA. Galactosialidosis can be distinguished from GM1 gangliosidosis by normal β‎-Gal activity in serum or plasma, unlike GM1 gangliosidosis.

Schindler’s/Kanzaki’s disease (a-N-acetylgalactosaminidase deficiency)

This rare disorder, initially described by D Schindler, is a form of neuroaxonal dystrophy, which results from deficiency of a glycosyl-hydrolase, α‎-N-acetylgalactosaminidase (NAGA). Progressive motor and mental deterioration, with myoclonic seizures, pyramidal signs with hyperreflexia, hypotonia, and optic atrophy were described in two brothers who were bedridden by age 4 years. Subsequently, in 1989, Kanzaki and colleagues described a group of adult Japanese patients, without overt neurological manifestations and diffuse angiokeratoma, who had NAGA deficiency and increased urinary excretion of several glycopeptides.

Mucolipidoses

The mucolipidoses feature the combined tissue storage of GAGs and sphingolipids and are a group of disorders with clinical features similar to MPSs, except for the absence of urinary excretion of GAGs.

Mucolipidosis type I or sialidosis type II

This condition is described under ‘Sialidosis’ above.

Mucolipidosis type II and type III

Mucolipidosis type II (I-cell disease) and type III (pseudo-Hurler’s polydystrophy) are caused by abnormal transport of newly synthesized enzymes to the lysosome. I-cell disease manifests with progressive severe psychomotor retardation, dysmorphic facial features, gingival hypertrophy, and dysostosis multiplex. ML-III has a similar clinical picture; in addition stiffness of the fingers and shoulder, a ‘claw-hand’ deformity, short stature, and scoliosis may be noted. Mild coarsening of the face, corneal clouding, and retinopathy with progressive bone and cardiac valve involvement are also commonly seen.

The diagnosis of ML-II and -III is based on a demonstration of markedly increased lysosomal enzyme activities in the plasma while the corresponding activities in leucocytes and cultured skin fibroblasts are markedly decreased.

Mucolipidosis type IV

Mucolipidosis IV (ML-IV) is caused by mutations in the gene MCOLN1, mapped to chromosome 19p13.3–13.2. It encodes a protein called mucolipin, which normally functions as a calcium (Ca2+)-permeable cation channel but is also involved in lysosomal biogenesis and membrane trafficking. The disease has a protracted course characterized by early arrest in neurological development, corneal clouding, absent speech, intellectual impairment, and motor retardation, with no dysmorphic facial features, hepatosplenomegaly, or skeletal abnormalities. ML-IV is prevalent among the Ashkenazi Jewish population with two common mutations accounting for 95% of the alleles. Electron microscopic examination of conjunctival and skin biopsies shows characteristic lysosomal inclusions as well as enlarged lysosomes in all cell types. However, molecular genetic analysis of common mutations is often used for diagnostic purposes.

Glycogen storage disease type II (Pompe’s disease)

See Chapter 12.3.1.

Sialic acid storage disorders

These autosomal recessive disorders, caused by mutations in the sialin gene, SLC17A5, encoding a protein involved in the transport of sialic acid (N-acetylneuraminic acid), include the following allelic disorders: infantile free sialic acid storage disease (ISSD) and Salla’s disease (or the Finnish variant). The severe infantile form (ISSD) presents with nonimmune hydrops, hypertrophic cardiomyopathy, ascites, hepatosplenomegaly, inguinal hernias, coarse facies, and dysotosis multiple, causing death in the first 2 years of life. Clinical features of the juvenile form include developmental delay and growth retardation, seen in early childhood with mild coarsening of the facial features, hepatomegaly, and psychomotor retardation.

In Salla’s disease, named after a region in north-eastern Finland, affected children manifest with mild coarsening of features, exotropia, hypotonia, ataxia, and learning disabilities during the first year of life without visceromegaly or skeletal abnormalities.

Increased amounts of free sialic acid are found in the serum and urine, as well as in cultured skin fibroblasts and several tissues, including the brain

Neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCLs) represent a group of childhood-onset disorders with a combined prevalence of approximately 1 in 12 500 births characterized by the intralysosomal aggregation of autofluorescent proteinaceous ageing pigments, i.e. ceroid and lipofuscin. There are eight major subtypes based on age at onset, presentation, and pathological findings. The infantile form of NCL, caused by mutations in CLN1, the gene encoding the enzyme palmitoyl protein thioesterase 1 (PPT1), presents with deceleration of head growth, muscular hypotonia, ataxia, motor clumsiness, irritability, sleep disturbance, and visual failure after a period of normal development during the first year. Rapid developmental deterioration occurs during the second year of life with loss of all motor abilities and social interest, blindness and increasing spasticity, seizures, and myoclonus. Fine motor skills are affected with purposeless, characteristic hand movements (hyperkinesias) such as those seen in Rett’s syndrome.

Late infantile NCL, caused by mutations in CLN2, which encodes the enzyme tripeptidyl-peptidase 1, presents at approximately the third year of life with unexpected delay of psychomotor development or epilepsy of sudden onset. Seizures are generalized tonic–clonic or partial, frequently of a severe myoclonic type, which may soon become resistant to drug treatment.

Juvenile NCL, caused by mutations in CLN3, presents with visual failure, noticed around the age of 4 to 7 years leading to blindness usually within a few years, gradual psychomotor deterioration during early school years, and seizures at about age 10 years. Adult-onset (Kufs’) disease with onset around 30 years of age is distinguished from the other subtypes by the absence of visual failure.

Intralysosomal inclusions, described as osmiophilic granular deposits, curvilinear bodies, or fingerprint deposits that are somewhat specific for each subcategory of NCL, are observed by electron microscopy of the skin. Enzyme estimation of PPT1, and tripeptidyl-peptidase 1 (TPP1), activity in peripheral blood leucocytes is diagnostic for CLN1- and CLN2-related disorders respectively. Treatment is symptomatic with aggressive control of the seizure disorder. Gene therapy for the late infantile variant is under investigation.

Motor neuron diseases

Spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of spinal cord motor neurons causing muscle weakness and atrophy. It occurs in 1 in 10 000 births and has a carrier frequency of 1 in 40 to 1 in 60. Three major clinical subtypes of childhood-onset SMA are recognized. All three subtypes are the result of deletions or mutations in the SMN1 gene located on chromosome 5q13.

Type I, also referred to as Werdnig–Hoffman disease, begins in the first 6 months of life with severe hypotonia, absent tendon reflexes, and failure to achieve independent sitting. Their weakness of intercostal muscles leads to respiratory insufficiency and early death.

Type II SMA starts in early childhood before age 18 months. The child can sit independently but cannot stand or walk unassisted. A milder type III form known as Kugelberg–Welander disease develops in childhood after independent walking is achieved but weakness progresses, leading to wheelchair dependence.

Electromyographic (EMG) studies reveal spontaneous activity including sharp waves, fasciculations, and fibrillations suggestive of degeneration. The muscle biopsy demonstrates grouped atrophy with islands of hypertrophic fibres consistent with neurogenic atrophy.

The SMN protein is ubiquitous but the neuron is particularly vulnerable to SMN deficiency because of its role in axonal transport of mRNAs in motor neurons. The severity of SMA is correlated with the extent of truncation of the SMN protein, i.e. the degree of gene deletion, e.g. type I patients are more likely to have deletions of both exon 7 and exon 8 whereas type II patients are usually missing exon 7 but retain exon 8. A homologous gene, SMN2, is retained in SMA and has been induced to produce full-length SMN protein in cell culture and animal models of SMA using inhibitors of histone deacetylase. However, clinical trials in SMA patients showed no improvement in functional motor scores.

Other rarer forms of SMA

A severe lethal form of SMA with arthrogryposis has been mapped to Xp11. Another severe infantile form, spinal muscular atrophy with respiratory distress type 1 (SMARD1), produces eventration of the diaphragm, causing respiratory failure and death.

Distal SMA is inherited as an autosomal recessive, autosomal dominant, and sporadic disease. It causes distal limb weakness and progresses slowly. At least four genetic loci have been demonstrated.

In Kennedy’s disease, there is spinal and bulbar muscular atrophy and gynaecomastia. This X-linked disease is due to an expansion of a CAG trinucleotide repeat in the first exon of the androgen receptor gene (SBMA) on chromosome Xq13. A list of genes associated with lower motor neuron disease is shown in Table 24.17.3.

Table 24.17.3 Cloned genes causing lower motor neuron disease

Disease

Locus

Mode

Protein

Attribute/Function

Aggregation

CMT2A

1p36

AD

Mitofuscin

Mitochondrial GTPase

CMT2B

3q13

AD

RAB7

GTPase

CMT2D

7p14

AD

GARS

Aminoacyl-tRNA synthetase

CMT2E

12q13

AD

NFL

Cytoskeletal protein

Yes

CMT2F

7q11

AD

HSPB1

Chaperone protein

Yes

CMT2L

12q24

AD

HSPB8

Chaperone protein

Yes

CMTDIB

19q12

AD

Dynamin 2

GTPase

CMTDIC

1p34

AD

YARS

Aminoacyl-tRNA synthetase

HMN5

11q13

AD

Seipin

ER membrane protein

Yes

HMN7

2p13

AD

Dynactin 1

Microtubular motor

Yes

CMT2A

1q21

AR/AD

Lamin A/C

Nuclear membrane

CMT2K

8q21

AR/AD

GDAP1

Mitochondrial protein

ALS1

21q

AD

SODI

Superoxide dismutase

Yes

ALS2

2q33

AR

Alsin

Guanine exchange factor

ALS4

9q34

AD

Senataxin

RNA helicase

ALS8

20q13

AD

VAPB

Endosome membrane protein

Yes

ALS-ANG

14q11

AD

Angiogenin

RNase

BSMA

Xq12

X linked

Androgen receptor

Transcription factor

Yes

SMA

5q

AR

SMN protein

RNA-binding protein

SMARD1

11q13

AR

IGHMPB2

Transcription factor

AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; ANG, angiogenin; AR, autosomal recessive; BSMA, bulbospinal muscular atrophy; CMT, Charcot–Marie–Tooth disease; ER, endoplasmic reticulum; GARS, glycine aminoacyl-tRNA synthetase; GDAP1, ganglioside-induced, differentiation-associated protein 1; GTPase, guanosine triphosphatase; HMN, hereditary motor neuropathy; IGHMPB2, immunoglobulin μ‎-binding protein 2; NFL, light neurofilament; RAB7, ras-associated protein 7; SMA, spinal muscular atrophy; SMARD1, spinal muscular atrophy with respiratory distress type 1; SMN, sensory motor neuropathy; SOD1, superoxide dismutase 1; tRNA, transfer RNA; VAPB, vesicle-associated, membrane protein-associated protein B; YARS, tyrosyl aminoacyl-tRNA synthetase.

Canete-Soler R, Schlaeper W (2007). Ann Neurol, 62, 8–14, with permission.

Amyotrophic lateral sclerosis (see also Chapter 24.15)

Amyotrophic lateral sclerosis (ALS) causes degeneration of motor neurons in the motor cortex, brainstem, and spinal cord. Symptoms of progressive limb weakness with involvement of bulbar and respiratory muscles begin in the fifth or sixth decade of life and in most cases result in death 3 to 5 years later. Spasticity occurs due to upper motor neuron involvement, which may precede distal limb weakness by a year or more (primary lateral sclerosis). The prevalence is 2 to 3 in 100 000 with a male:female ratio of 1.3:1.6:1.

Motor neurons exhibit immunoreactivity for neurofilament proteins and ubiquitin. The proximal segments of motor axons are often swollen and distal motor axons undergo wallerian degeneration. Finally cell bodies shrink and dendrites become attenuated. Most cases are sporadic but approximately 10% of the total are familial. Penetrance for ALS in these familial forms is, however, incomplete.

ALS-1

Mutations in the SOD1 gene on chromosome 21q22.11 account for 10 to 20% of autosomal dominant familial ALS cases. More than 120 mutations in this gene have been identified, of which A4V accounts for half of all North American cases. SOD1 encodes Cu/Zn superoxide dismutase 1, an enzyme that catalyses the conversion of oxygen radicals to oxygen and hydrogen peroxide. The mutant protein is believed to cause aggregation of proteins through a toxic gain-of-function property affecting axonal transport.

ALS-2

A juvenile-onset autosomal recessive form of ALS is due to mutations in the gene ALS2 on chromosome 2q33, encoding alsin. Symptoms begin in the first or second decade and progress slowly for 10 to 15 years. Mutations in alsin have also been observed in patients with hereditary spastic paraplegia and primary lateral sclerosis.

ALS-4

ALS-4 is another juvenile-onset form of ALS. It maps to chromosome 9q34 and follows an autosomal dominant mode of inheritance. The abnormal gene, SETX, codes for senataxin, which is also mutated in ataxia–oculomotor apraxia type 2.

ALS-5

This locus on chromosome 15q15.1-q21 is also associated with a juvenile-onset autosomal dominant form of familial ALS.

DCTN1

A mutation in the p150 subunit of dynactin encoded by DCTN1 has been identified with a slowly progressive autosomal form of ALS.

Other genes associated with familial ALS have been designated ALS3 on chromosome 18q21, ALS6 located on chromosome 16q12, and ALS7 mapped to chromosome 20q13. Mutations in the TAR–DNA-binding protein (TDP-43) gene TARDBP located on chromosome 1p36.22 are yet another cause of familial and sporadic ALS. ALS has also been associated with frontotemporal dementia, leading to the identification of additional loci on chromosome 9 as well as on 17q21, where the MAPT gene is located. It also appears that the expression level of the SMN gene can confer an increased risk for developing ALS. Cloned genes implicated in lower motor neuron disease are set out in Table 24.17.3.

Hereditary spastic paraplegia

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of diseases characterized by spastic weakness in the legs, an early and severe feature of the phenotype, pyramidal tract signs, urinary urgency, and mild diminution in vibratory sensation in the feet. Lower limb spasticity precedes upper limb involvement by several years; upper limbs may never be involved. Neurological signs are bilateral and symmetrical, and confined to the lower limbs. There are pure and complicated forms of HSPs. The complicated or complex forms include added signs such as ataxia, peripheral neuropathy, cerebellar atrophy, thin corpus callosum, extrapyramidal signs, visual dysfunction, deafness, ichthyosis, learning disabilities, and seizures. Symptoms progress over decades without significantly shortening life expectancy, at least for pure forms of the disease. This slow progression distinguishes HSP from other motor neuron diseases like ALS or primary lateral sclerosis (PLS).

There are multiple genes and loci involved with autosomal dominant, autosomal recessive, and X-linked forms delineated (compare Tables 24.17.4 and 24.17.5). Penetrance and disease severity can vary even within the same family. The autosomal dominant (AD) forms are primarily of the pure type and comprise 70 to 80% of all HSPs. Of these the most common is SPG4, responsible for approximately 40% of the total. The SPG4 locus is on chromosome 2p22 and codes for spastin. Mean age of onset is 30 years but an earlier age of onset occurs in the presence of a rare ser44leu spastin polymorphism.

Table 24.17.4 Autosomal dominant and X-linked forms of hereditary spastic paraplegias (HSPs)

Locus

Chromosome region

Gene of protein

Discriminating features

Autosomal dominant

Pure forms

SPG3A

14q12–q21

Atlastin

Predominantly early onset

SPG4

2p22

Spastin

SPG6

15q11.2-q12

NIPA1

Predominantly adult onset

SPG8

8q24

KIAAO196

Predominantly adult onset

SPG10

23q13

KIF5A

Predominantly early onset

SPG12

19q13

Unknown

Predominantly early onset

SPG13

2q24–q34

HSP60

Predominantly adult onset

SPG19

9q33–q34

Unknown

Predominantly adult onset

SPG31

2p12

REEP1

Predominantly adult onset

SPG33

10q24.2

ZFYVE27

SPG37

8p21.1–q13.3

Unknown

Complex forms

SAX1

12p13

Unknown

Spastic ataxia

SPG9

10q23.3–q24.2

Unknown

Cataract, motor neuropathy, short stature, skeletal abnormalities, gastro-oesophageal reflux

SPG17

11q12–q14

BSCL2/Seipin

Silver’s syndrome—severe distal wasting

SPG29

1p31–p21

Sensorineural hearing impairment, pes cavus, neonatal hyperbilirubinaemia without kernicterus, hiatal hernia

X linked

SPG1

Xq28

L1CAM

Onset in infancy, corpus callosum hypoplasia, retardation adducted thumbs, spastic paraplegia, hydrocephalus

SPG2

Xq21

PLP

Early onset, quadriparesis, congenital nystagmus, intellectual impairment, seizures

SPG16

Xq11.2

Unknown

Onset in infancy, pure spastic paraplegia (severe)

Depienne C, et al. (2007). Curr Opin Neurol, 20, 674–80, with permission.

Table 24.17.5 Autosomal recessive forms of hereditary spastic paraplegias (HSPs)

Gene

Protein

Locus

Age at onset (years)

Associated Signs

Pure forms

SPG5

Unknown

8p

1–40

SPG24

Unknown

13q

1

SPG28

Unknown

14q

6–15

SPG30

Unknown

2q

12–21

Complex forms

SPG7

Paraplegin

16q

11–42

Cerebellar signs, PNP, pes cavus, optic atrophy

SPG14

Unknown

3q

∼30

Distal motor neuropathy, intellectual impairment, pes cavus, visual agnosia

SPG27

Unknown

10q

2–45

Cerebellar ataxia, PNP, intellectual impairment, microcephaly, facial and skeletal dysmorphia, blepharophimosis

  • SPG11

  • (AR-HSP-TCC)

Spatacsin

15q

1–23

Intellectual or cognitive impairment, PNP, TCC

  • SPG15

  • (Kjellin’s syndrome)

Unknown

14q

13–23

Pigmented maculopathy, wasting, dysarthria, cerebellar signs, intellectual impairment

SPG20 (Troyer syndrome)

Spartin

13q

Early childhood

Intellectual impairment, cerebellar signs, developmental delay and short stature

  • SPG21

  • (Mast syndrome)

Maspardin

15q

20–40

Extrapyramidal syndrome, premature ageing, cognitive decline, dysarthria, TCC, periventricular white matter hyperintensities, cataract, dystonia, cerebellar signs, PNP, chorea, distal wasting

  • SPG23

  • (Lison syndrome)

Unknown

1q

Early childhood

Abnormalities of skin and hair pigmentation, facial and skeletal dysmorphia, postural tremor, cognitive impairment, premature ageing

SPG25

Unknown

6q

30–46

Prolapsed intervertebral discs, multiple disc herniation, bilateral cataract, congenital glaucoma

SPG26

Unknown

12cen

22–42

Intellectual impairment, distal muscle wasting, dysarthria, PNP

SPG32

Unknown

14q

6–7

Pontine dysraphia, intellectual impairment, TCC

TCC + epilepsy

Unknown

8q

1–7

Mental deterioration, epilepsy, TCC

SPOAN

Unknown

11q

Infancy

Optic atrophy, PNP

ARSACS

Sacsin

13q

Early childhood

Ataxia, dysarthria, distal wasting, nystagmus, retinal striation, PNP

ARSAL

Unknown

2q

Variable

Spastic ataxia with leucodystrophy

SAX2

Unknown

17p

Variable

Cerebellar ataxia dysarthria

AR, autosomal recessive; ARSACS, autosomal recessive spastic ataxia of Charlevoix Saguenay; ARSAL, autosomal recessive spastic ataxia with frequent leucoencephalopathy; PNP, polyneuropathy; SAX2, spastic ataxia 2; SPOAN, spastic paraplegia, optic atrophy, and neuropathy; TCC, thin corpus callosum.

Depienne C, et al. (2007). Curr Opin Neurol, 20, 674–80, with permission.

The second most frequent AD HSP gene is SPG3A, coding for atlastin. It accounts for 10% of cases. It begins in childhood or adolescence but is otherwise indistinguishable from SPG4 HSP. The third most frequently gene affected is REEP1, causing SPG31. If SPG6 is included, these four forms account for approximately 65% of the AD HSP cases.

Of the autosomal recessive (AR) forms, 16 loci are known. Five involve a thin corpus callosum and mental impairment. The most frequent is SPG11, representing approximately half of the AR cases. It has an early onset (mean age 11.8 years) and patients become wheelchair bound in their third or fourth decade. Other features are mild-to-moderate intellectual impairment, abnormal appearance of the white matter, and pseudobulbar dysarthria. Complex HSPs with cerebellar ataxia occur in ARSACS, SAX2, ARSAL, and SAX1. Cerebellar atrophy is observable on MRI. For further details consult Tables 24.17.4 and 24.17.5.

According to Fink, several pathogenic mechanisms may be involved in the HSPs including: (1) abnormalities in primary axonal transport; (2) Golgi abnormalities; (3) mitochondrial dysfunction; (4) myelin abnormalities; and (5) abnormal corticospinal tract development. Particularly in sporadic cases of HSP it is important to rule out other neurological diseases that may present with spastic paraplegia. These include a wide variety of conditions such as multiple sclerosis, primary lateral sclerosis, thoracic cord tumours, infections, and metabolic diseases. Examples of the last include disorders of intermediary metabolism, such as cobalamin C deficiency, arginase deficiency, biotinidase deficiency, phenylketonuria and nonketotic hyperglycaemia, dopamine synthesis defects, and cerebral folate deficiency, and disorders of complex molecule metabolism, including cerebrotendinous xanthomatosis, adrenomyeloneuropathy, metachromatic leucodystrophy, Krabbe’s disease, Sjögren–Larsson syndrome, and polyglucosan body disease.

Spasticity may be alleviated by oral baclofen or dantrolene, or micturition, improved by oxybutynin, with foot drop improved by ankle–foot orthoses, and general fitness and weakness addressed with physical therapy.

Hereditary neuropathies

Hereditary neuropathies affect approximately 1 in 2500 individuals and therefore are the most common inherited diseases of the nervous system. Phenotypically, demyelination and/or axonal loss leads to progressive dysfunction of motor, sensory, and/or autonomic nerves in a length-dependent manner. The first descriptions by Charcot, Marie, and Tooth more than a century ago were of a dominantly inherited progressive disorder affecting both motor and sensory axons. The term ‘Charcot–Marie–Tooth disease’ (CMT) continues to be used to describe a genetically heterogeneous disorder of insidious onset and slow progression affecting primarily peripheral nerves in a nonsyndromic manner.

The individual variants of inherited neuropathies may be classified according to clinical, electrophysiological, histological, and molecular genetic features. In most cases the mode of inheritance is AD but AR forms and an X-linked variant are also described. Demyelinating forms are defined by a median nerve conduction velocity (NCV) below 38 m/s, and axonal subtypes are based on median NCV above 38 m/s. A third category is now recognized with an intermediate NCV of 25 to 40 m/s. Although demyelinating disease suggests primary involvement of the Schwann cell and an axonal disorder might indicate predominately axon dysfunction, both are likely to become involved due to the interdependence of the Schwann cell and axon.

Table 24.17.6 lists the nonsyndromic inherited neuropathies and the Mutation Database of Inherited Peripheral Neuropathies (http://www.molgen.ua.ac.be/CMTMutations) may be consulted for more detail on the molecular genetics of each disorder.

Table 24.17.6 Nonsyndromic inherited neuropathies

Disease

Locus

Gene

CMT1 (dominant demyelinating)

HNPP

17p11

PMP22

CMT1A

17p11

PMP22

CMT1B

1q22–23

MPZ

CMT1C

16p13

SIMPLE

CMT1D

10q21

EGR2

CMT1X

Xq13.1

GJB1

Dominant intermediate CMT

DI-CMTA

10q24.1–25

DI-CMTB

19p12–13.2

DMN2

DI-CMTC

1p35

YARS

CMT2 (autosomal dominant axonal/neuronal)

CMT2A1

1p36.2

KIF1B

CMT2A2

1p36.2

MFN2

CMT2B

3q21

RAB7

CMT2C

12q23–24

CMT2D

7p15

GARS

CMT2E

8p21

NEFL

CMT2F

7q11.23

HSPB1

CMT2G

12q12–q13.3

CMT2

3q13.1

CMT2-PO

1q22

MPZ

CMT2L

12q24

HSPB8

Hereditary neuralgic amyotrophy

17q25

SEPT9

Severe (dominant or recessive) demyelinating neuropathies

Déjérine–Sottas neuropathy/

17p11

PMP22

HMSN-III/CMT3

1p22

MPZ

Xq13.1

GJB1

10q21

EGR2

19q13.1

PRX

8p21

NEFL

Congenital hypomyelinating neuropathy

10q21

EGR2

17p11

PMP22

1p22

MPZ

Autosomal recessive demyelinating neuropathy (CMT4)

CMT4A

8q13–q21.1

GDAP1

CMT4B

11q22

MTMR2

CMT4B-2

11p15

MTMR13

CMT4C

5q32

SH3TC2

CMT4D-Lom

8q24.3

NDRG1

CMT4E

10q21

EGR2

CMT4F

19q13

PRX

HMSN-R

10q23.2

CMT4H

12p11.21–q13.11

Autosomal recessive demyelinating neuropathy (CMT4)

CMT4A

8q13–q21.1

GDAP1

CMT4B-1

11q22

MTMR2

CMT4B-2

11p15

MTMR13

CMT4C

5q32

SH3TC2

CMT4D-Lom

8q24.3

NDRG1

CMT4E

10q21

EGR2

CMT4F

19q13

PRX

HMSN-R

10q23.2

CMT4H

12p11.21–q13.11

Autosomal recessive axonal neuropathy

AR-CMT2A

1q21.2

LMNA

AR-CMT2B

19q13.3

MED25

Early onset/neonatal

CMT2K

8q13–q21.1

GDAP1

Congenital

5q deletion

Hereditary sensory and autonomic neuropathies (HSANs)

HSAN1

9q22.1–22.3 dominant

SPTLC1

HSAN1B

3p22–24 dominant

HSAN2

12p13.33 recessive

HSN2

HSAN3

9q31 recessive

IKBKAP

HSAN4

1q21–q22 recessive

NTRKA

HSAN5

1p163.1 recessive

NGFB

Primary erythermalgia

2q24 dominant

SCN9A

Cold-induced sweating

19p12 recessive

CRLF1

HSN with cough and gastro- oesophageal reflux

3p22–p24 dominant

Hereditary motor neuropathies (HMNs)

HMN I

Dominant

HMN II

12q24 dominant

HSPB8

HMN II

7q11.23 dominant

HSPB1

HMN III and IV

11q13 recessive

HMN V

7p15 dominant

GARS

HMN V

11q13 dominant

BSCL2

HMN VI/SMARD1

11q13.2–13.4 recessive

IGHMBP2

HMN VII

2p13 dominant

DCTN1

HMN VII

2q14 dominant

HMN X-linked

Xq13.1–q21

HMN/ALS4

9q34 dominant

SETX

Congenital distal SMA

12q23–q24 dominant

HMN Jerash

9p21.1–p12 recessive

Lippincott Williams & Wilkins, Philadelphia 2008. p. 437.

Duplication of the PMP22 (peripheral myelin protein 22) gene accounts for 70% of all patients with hereditary neuropathy. These individuals present with distal muscle weakness in the legs, diminished or absent deep tendon reflexes, and impaired sensation. As a result of weakness of the intrinsic foot muscles, patients develop foot deformities, i.e. pes cavus or hammer toe. There is atrophy of the calf muscles and a high steppage gait. Later the weakness can progress to affect the hands and forearms with weakness of intrinsic hand muscles, leading to a ‘claw-hand’ deformity. Onset is before the second decade, but progression is slow so that by age 40 almost all patients are still ambulatory.

Nerve biopsy shows thinly myelinated axons and reduction in myelinated axons, especially in the large fibres. Nerve conduction velocities are slow, even well before clinical onset of disease. However, motor amplitudes and number of motor units correlate with clinical disability so that axonal loss and not conduction velocity is a better measure of disease severity.

Deletion of one copy of the PMP22 gene will cause hereditary neuropathy with liability to pressure palsies (HNPP). These patients have episodic mononeuropathies due to nerve compression but may recover with little or no deficit. Some patients experience a progressive generalized sensorimotor neuropathy and a third will have absent ankle jerks. On neuropsychological testing distal motor latencies are prolonged, sensory velocities are mildly slowed, and conduction block is seen. Nerve biopsies reveal focal thickenings, sequential demyelination, and remyelination. Point mutations in PMP22 and MPZ can also cause HNPP.

Other causes of autosomal dominant demyelinating CMT are mutations in the GJB1 (gap-junction B1) gene responsible for 8 to 10% of patients with nonsyndromic inherited neuropathies, MPZ (myelin protein zero) mutations identified in 3% of patients, and PMP22 mutations accounting for an additional 1.5% of patients. GJB1 is X linked so that affected women have a later onset and milder symptoms. In this variant, known as CMT1X, sensory loss may be more prominent than in other CMT1 subtypes. Other genes with mutations contributing to the autosomal dominant demyelinating class of neuropathies are L1TAF (liposaccharide-induced tumour necrosis factor-α‎) and EGR (early growth response-2).

The autosomal recessive demyelinating neuropathies are classified under CMT4. These are rare and more likely in populations with a high rate of consanguinity. They manifest in childhood and their nerve biopsies show redundant loops of myelin in onion bulb formations, hence the alternative label of Déjérine–Sottas neuropathy (DSN). CMT4D due to mutations in NDRG1 (N-myc downstream-regulated gene-1) is found in gypsies and is associated with hearing loss and dysmorphic features. Children with CMT4F due to mutations in PRX (periaxin) have marked slowing in motor NCVs and severe axonal loss.

The autosomal dominant axonal neuropathies are classified as CMT2 variants and may involve not only axonal loss but also primary nerve cell body abnormalities. A quarter of these patients have mutations in MFN2 which encodes mitofusin-2, a protein required for mitochondrial fusion. This is an early onset neuropathy and is sometimes accompanied by optic atrophy and/or sensorineural hearing loss.

Recurrent episodes of focal neuropathy of the brachial plexus are characteristic of hereditary neuralgic amyotrophy. The episode begins with a sharp, aching, or burning pain in the arm and is followed by weakness and sensory disturbances within days. Cranial and phrenic nerve involvement also occur. Although some recovery occurs, axonal loss in the affected muscles is seen on EMG. Mutations in SEPT9 are the cause.

Another class are the dominant intermediate CMTs (DI-CMTs) in which forearm nerve conduction velocities are between 30 and 40 m/s. The histological features are more typical of axonal loss than demyelination. Mutations in DMN2 encoding dynamin-2 and in YARS encoding tyrosyl-tRNA synthase can result in DI-CMT. Some mutations in GJB1, GDAP1, MPZ, and NEFL may also fit this criterion.

The hereditary sensory and autonomic neuropathies (HSANs) spare the motor neurons or axons. The onset of HSANI is in the second or third decade. It is associated with burning pain in the feet and plantar ulcers, and is slowly progressive. Autosomal dominant inheritance of either a SPTLC1 (long chain base subunit 1 of serine palmitoyl transferase) or RAB7 (Ras related in brain 7) mutation is responsible.

HSANII is manifested by sensory loss of all modalities and ulcers of the fingers and feet. It is caused by autosomal recessive mutations in the HSN2 gene.

HSANIII, also known as Riley–Day syndrome and familial dysautonomia, is caused by a recessive mutation in IKBKAP (inhibitor of κ‎ light polypeptide gene enhancer in B cells, kinase complex-associated protein). Almost all patients are of Ashkenazi Jewish ancestry. It is noted at birth with vomiting and swallowing difficulties, autonomic disturbances, and absence of fungiform papillae of the tongue. Areflexia, poor coordination, emotional lability, and kyphoscoliosis are other features. Autonomic crises are common and can lead to sudden death. There is a marked decrease in the number of unmyelinated fibres and the number of neurons in the autonomic and spinal ganglia are decreased.

HSANIV is associated with anhidrosis and congenital insensitivity to pain, leading to self-mutilation. Unmyelinated fibres are completely absent. This autosomal recessive disorder is due to mutations in NTRKA (neuron tyrosine kinase A).

HSANV—a rare congenital disorder—is manifested by a selective loss of pain sensation with other sensory modalities, motor strength and tendon reflexes remaining normal. Decreased sweating is also noted. Sensory nerve-evoked potentials are normal. The disease is caused by recessive mutations in the NGFB (nerve growth factor β‎) gene.

The hereditary motor neuropathies (HMNs) begin in childhood or early adulthood with distal weakness affecting the extensor muscles of the feet. Sensory responses are normal but there is reduced amplitude of the motor responses and denervation by needle EMG. Most of these disorders show autosomal dominant inheritance (see Table 24.17.6). Upper limb weakness is characteristic of HMNV and a vocal fold paralysis is a feature of HMNVII.

Inherited myopathies

(see also Chapter 24.24.4)

Hereditary forms of muscle disease may be classified according to age of onset, location of muscle weakness, and pathological mechanism. Thus, separate classes of muscle disease are recognized, namely congenital myopathies, proximal and distal myopathies, dystrinopathies, myotonic dystrophies, ion channels disorders, and inclusion body myopathies. In this section we describe degenerative muscular disease of the hereditary type. The more benign and relatively nonprogressive hereditary myopathies, such as central core, nemaline, and centronuclear myopathies, are considered to be a separate category due to their nondegenerative nature. Most congenital muscular dystrophies (CMDs), some limb-girdle muscular dystrophies (LGMDs), and Duchenne and Becker muscular dystrophies are caused by pathogenic mutations of proteins involved in the dystrophin–glycoprotein complex (DGC), which provides structural support to the muscle cell membrane and participates in signalling across the cell membrane. These proteins include dystrophin, syntrophin, neuronal nitric oxide synthase (nNOS), and dystrobrevin, which are associated with the cytoplasmic surface of the cell membrane; the sarcoglycans (α‎, β‎, γ‎, and δ‎) and β‎-dystroglycan, which span the membrane, and α‎-dystroglycan, which connects to the extracellular matrix. On a pathophysiological basis, muscular dystrophies may be viewed as a mismatch between muscle breakdown and muscle repair, leading to increased susceptibility of a muscle to injury and a cascade of events that lead to cell death. These disorders are characterized by proximal muscle weakness and markedly elevated creatine kinase (CK) values during the period of maximum muscle breakdown.

Duchenne and Becker muscular dystrophies

Duchenne muscular dystrophy (DMD) is the most common X-linked recessive lethal genetic disorder in children, affecting primarily skeletal and cardiac muscle. Approximately 1 in 3500 boys born is affected with DMD; approximately a third of cases arise from a new genetic mutation. In skeletal muscle, the DMD gene produces a large protein molecule of 427 kDa designated dystrophin, the central component of the DGC. This complex, which includes dystroglycans and sarcoglycans, spans the muscle sarcolemma, providing a linkage between the intracellular cytoskeleton and the extracellular matrix. Dystrophin localizes to the cytoplasmic surface of skeletal muscle membrane in a subsarcolemmal location. In DMD, all components of DGC are normally synthesized but not properly assembled or integrated into the sarcolemma. Boys with DMD have a progressive and predictable deterioration of skeletal and cardiac muscle function due to lack of dystrophin, which is critical for muscle membrane stability. Without dystrophin, muscle contraction leads to membrane damage and activation of the inflammatory cascade, progressing to muscle necrosis, fibrosis, and loss of function.

Becker muscular dystrophy (BMD) is a less severe form of dystrophinopathy. The pattern of muscle wasting closely resembles that seen in DMD but BMD patients walk beyond the age of 15 years. First symptoms usually develop between age 5 and 15 years, but onset may be delayed into the third or fourth decade.

Supportive measures for DMD include physical therapy and night splints to prevent contractures, and segmental spinal stabilization in later stages when scoliosis occurs. Prednisone and deflazacort have both been shown to increase muscle strength, pulmonary function, and functional ability in double-blind randomized controlled trials, providing long-term benefits of prolonged independence. Gene therapy using adenoviral vectors raised much hope in the past, but was unsuccessful because of their tendency to immunogenicity and their large size, which limited diffusion in the muscle tissue. A phase I clinical trial of myoblast transplantation into dystrophic muscle, which will give rise to dystrophin-expressing myofibres, has been completed. Limitations of this therapy include poor survival and migration of myoblasts and also possibly an immune response to donor myoblasts. Exon skipping of dystrophin gene exons, which contain a mutation using antisense oligonucleotides to splice out selected exons from the pre-mRNA, at or next to the mutation site, is a promising potential therapy for DMD and other recessive muscular dystrophies. Skipping specific exons is expected to restore the reading frame and result in the production of internally deleted, but essentially functional, dystrophin as observed in the milder BMD, thus providing significant functional improvement of DMD.

Emery–Dreifuss muscular dystrophy

Emery–Dreifuss muscular dystrophy (EDMD) is an X-linked, autosomal dominant and, more rarely, autosomal recessive condition. The gene responsible for X-linked EDMD, EMD, encodes a ubiquitous transmembrane protein of the nuclear envelope inner membrane, emerin. The gene mutated in autosomal dominant and recessive forms of EDMD is LMNA, and located on chromosome 1, encoding two major somatic cell polypeptides, lamins A and C, which are intermediate filament proteins associated with the nuclear envelope inner membrane. Mutations in LMNA have been shown to cause several very different human diseases (laminopathies) other than muscular dystrophies such as partial lipodystrophy syndromes, a peripheral neuropathy, and accelerated ageing disorders such as Hutchinson–Gilford progeria syndrome. Even though these proteins are rather ubiquitously expressed, the reason for relative tissue specificity of EDMD, affecting cardiac muscle and certain skeletal muscles and tendons, is not clear.

The clinical triad of EDMD consists of: (1) slowly progressive muscle weakness and wasting in a scapulohumeroperoneal distribution; (2) early contractures of the elbows, ankles, and posterior neck; and (3) cardiac conduction defects, cardiomyopathy, or both. Contractures affecting the elbows, neck extensor muscles, and Achilles tendons are followed by slowly progressive muscle weakness and wasting in a humeroperoneal distribution (biceps, triceps, and peroneal), usually at the end of the second decade of life. Cardiac disease starting at the end of the second decade occurs in virtually all cases of EDMD and bears no direct relationship to the severity of the skeletal muscle involvement. Over time, dilated cardiomyopathy develops, complicated by ventricular tachydysrhythmias, which may cause sudden cardiac death. Timely insertion of an implantable defibrillator can be a lifesaving measure.

Fascioscapulohumeral muscular dystrophy

Fascioscapulohumeral dystrophy (FSHD) is autosomal dominant with 10 to 30% of cases being sporadic; it is the third most common form of inherited muscular dystrophy after Duchenne dystrophy and myotonic dystrophy. The FSHD locus, mapped to the subtelomeric portion of chromosome 4 (4q35), is composed mainly of a polymorphic repeat structure consisting of 3.3-kilobase repeat elements designated D4Z4. The number of repeat units varies from 11 to more than 100 in the general population, whereas in patients with FSHD there is a deletion of an integral number of these units, so that they exhibit an allele containing 10 or fewer repeat units.

Limb-girdle muscular dystrophies

Twenty-one molecularly characterized forms of limb-girdle muscular dystrophy (LGMD) have been described thus far, comprising a clinically and genetically widely heterogeneous grouping. The subclassification of the classic groups of autosomal dominant LGMD (AD-LGMD or LGMD1) and autosomal recessive LGMD (AR-LGMD or LGMD2) is based on the involved proteins and the underlying genetic defects. The dominantly inherited disorders are phenotypically milder than the recessively inherited forms. Although proximal muscle weakness is considered a clinical hallmark of LGMD, presentation with distal myopathy or myofibrillar myopathy is being increasingly recognized. Cranial, ocular, and bulbar muscles, as well as the heart and brain, are generally spared. Patients usually present in adolescence or young adulthood, but childhood-onset disorders mimicking BMD are also known. The incidence of different LGMDs is dependent on ethnicity and geographical location. Molecular diagnosis is complex because mutations have been described in a large number of genes, very few of which are recurrent mutations, with the exception of LGMD2D. Overlap in clinical presentation with allelic disorders, such as LGMD1B, and autosomal dominant forms with LGMD2B and Miyoshi’s distal myopathy further complicates molecular analysis. Western blot or immunohistochemistry of muscle biopsy specimens for protein analysis is helpful in delineating the precise diagnosis. However, missense mutations may not lead to complete absence of proteins, e.g. missense mutations in myotilin (LGMD1A), and absence of a protein may be secondary to mutations in a related protein, as seen in the sarcoglycanopathies (LGMD2C-F). See Tables 24.17.7 and 24.17.8 for molecular classification and clinical features of AD and AR LGMDs respectively.

Table 24.17.7 Molecular classification and clinical features of autosomal dominant limb-girdle muscular dystrophy (LGMD)

Disease name

Locus name

Gene symbol

Chromosomal locus

Protein product

Onset (years) (average)

Presentation

Late findings

Symptoms

Signs

LGMD1A (myotilinopathy)

LGMD1A

TTID

5q31

Myotilin

18–35 (27)

Proximal weakness

  • Tight Achilles tendons

  • Nasal, dysarthric speech (50%)

Distal weakness

LGMD1B

LGMD1B

LMNA

1q21.2

Lamin A/C

Birth to adulthood; about half with childhood onset

Proximal lower limb weakness

  • Mild contractures of elbows

  • Arrhythmia and other cardiac complications (25–45 years)

  • Sudden death

Caveolinopathy

LGMD1C

CAV3

3p25

Caveolin-3

About 5

  • Cramping

  • Mild-to-moderate proximal weakness

  • Rippling muscle disease

Calf hypertrophy

LGMD1D

CMD1F

Unknown

6q23

Unknown

< 25

  • Dilated cardiomyopathy Cardiac conduction defect

  • Proximal muscle weakness

All individuals remain ambulatory

LGMD1E

LGMD1E

Unknown

7q

Unknown

9–49

Proximal lower and upper limb weakness

Pelger–Huet anomaly

  • Contractures

  • Dysphagia

LGMD1F

LGMD1F

Unknown

7q31.1-q32.2

Unknown

1–58

Proximal lower and upper limb weakness

Serum creatine kinase (normal to 20 × normal)

Distal weakness

LGMD1G

LGMD1G

Unknown

4q21

Unknown

30–47

Proximal lower limb weakness

Progressive limitation of finger and toe flexion

Proximal upper limb weakness

Table 24.17.8 Molecular classification and clinical features of autosomal recessive limb-girdle muscular dystrophy (LGMD)

Disease

Protein

Gene

Relative prevalence/founder mutations

Creatine kinase levels (IU/litre)

Age of onset (years)

Respiratory involvement

Cardiac involvement

Clinical clues

LGMD2A

Calpain3

CAPN3

One of the most common forms of AR-LGMD worldwide; founder mutations in Basques (2362_2363delinsTCATCT) and in eastern Europeans (550delA)

Normal to 50 ×

1st to 2nd decades (2–40 years)

Preferential involvement of posterior thigh muscles; ankle contractures; scapular winging

LGMD2B

Dysferlin

DYSF

More common in southern than northern Europe; founder mutations in several populations

10–100 ×

2nd to 3rd decades (10–73)

±

Distal weakness and wasting; muscle pain and/or swelling; good athletic performance in childhood; inflammatory cells in muscle biopsy

LGMD2C

γ‎-Sarcoglycan

SGCG

Present worldwide; founder mutations in North Africans (521delT) and gypsies (848G> A)

10–100 ×

1st decade (3–20)

+

+

Calf hypertrophy; scapular winging

LGMD2D

α‎-Sarcoglycan

SGCA

Present worldwide; most frequent sarcoglycan form in all populations; common mutation (229C>T), especially in northern Europe

10–100 ×

1st decade (3–40)

+

Rare

Calf hypertrophy; scapular winging

LGMD2E

β‎-Sarcoglycan

SGCB

Common in northern and southern Indiana Amish

10–100 ×

1st decade (3–20)

+

+

Calf hypertrophy; scapular winging

LGMD2F

δ‎-Sarcoglycan

SGCD

Rare all over the world; common mutation (del656C) in African–Brazilian

10–100 ×

1st decade (3–20)

+

+

Calf hypertrophy

LGMD2G

Telethonin

TCAP

Rarely reported outside Brazil

Normal to 30 ×

2nd decade (9–15)

±

Calf hypertrophy or hypotrophy distal leg weakness

LGMD2H

TRIM32

TRIM32

Only recently reported outside Hutterite population of Canada

Normal to 20 ×

2nd decade (1–44)

±

Possible mild facial weakness; small vacuoles in muscle fibres

LGMD2I

Fukutin-related protein

FKRP

Relatively frequent in northern Europe; founder mutation in northern Europeans (826C>A)

10–100 ×

1st to 2nd decade (2–40)

+

+

Calf hypertrophy; myoglobinuria; muscle pain

LGMD2J

Titin

TTN

Reported only in Finland

Normal to 25 ×

1st decade (5–20)

Distal weakness described; proximal–distal myopathy with associated cardiomyopathy recently described

LGMD2K

O-Mannosyl transferase-1

POMT1

Few reported LGMD cases (Turkish and English families)

10–50 ×

Birth–6 years

+

Microcephaly and cognitive impairment; muscle hypertrophy (thigh and calf)

LGMD2La

Fukutin

FKTN

Few reported LGMD cases

5–100 ×

<1 years

?

Motor function deterioration during infections

LGMD2Ma

O-Mannose β‎-1,2-N-acetylglucosaminyl transferase

POMGn1

Only one reported LGMD case

20–60 ×

12 years

?

?

Rapidly progressive

LGMD2Na

O-Mannosyl transferases-2

POMT2

Few reported LGMD cases

15 ×

< 2 years

?

–/?

Calf hypertrophy; possible cognitive impairment

LGMD?a

?

11p13

Reported in French Canadian families

Normal to 30 ×

3rd decade (11–50)

?

Quadriceps atrophy

a No international agreement has been reached for the nomenclature of this LGMD.

Limb–girdle muscular dystrophies. Curr Opin Neurol, Oct; 21(5), 576–584.

Myotonic dystrophies

Myotonic dystrophies (DMs) types I and II are, in general, late-onset autosomal dominant multisystem disorders characterized by myotonia, muscular dystrophy, posterior iridescent cataracts, endocrine, and heart involvement. DM type I (DM1) is caused by an expanded CTG repeat in the 3′‎-untranslated region of the dystrophia myotonica–protein kinase (DMPK) gene, which is mapped to 19q13. It has an incidence of about 13 in 100 000. The expansion size varies from 80 to 4000 in affected patients, while clinically normal individuals have 50 to 100 repeats. Intergenerational instability, especially with maternal transmission, may cause expansion of several thousand repeats in a single generation. Phenotypic correlation with age of onset exists with the expansion size up to 400 CTG repeats, but not for longer repeats. In DM type II (DM2), a CCTG expansion was identified in intron 1 of the zinc finger protein 9 (ZNF9) gene, mapped to 3q21. The incidence of DM2 is estimated at 1 in 1000. The underlying pathogenic mechanism in DM is disruption of mRNA metabolism and dominant negative effects of RNA containing the CUG and CCUG expansions, leading to accumulation of ribonuclear inclusions in the nuclei of DM cells.

DM1 may present at any age from the pre-/postnatal period to adulthood with the largest number of CTG repeats (more than 1500) identified in congenital myotonic dystrophy. Infants present with hypotonia, talipes equinovarus, other contractures, and immobility; there may be a history of hydrops fetalis or polyhydramnios with reduced fetal movements. Bilateral weakness of facial, jaw, and palatal muscles causing an open mouth, tent-formed upper lip, and a high arched palate, along with a weak cry, poor suck, and feeding difficulties, are commonly present. Tendon reflexes are absent. Mechanical ventilation may be necessary due to respiratory insufficiency. Later complications include aspiration, delayed speech and motor development, and psychomotor impairment. Unlike in myotonia congenita, clinical and electrophysiological myotonia is seldom evident. EMG analysis and clinical examination of the mother may be more informative. In the childhood-onset form, speech and learning disabilities with or without distal weakness, cardiological problems, and myotonia are the presenting features. The classic adult-onset form presents with bilateral facial weakness, mild ptosis, and weakness of neck flexors, followed by wasting of sternocleidomastoid and temporal muscles. Distal weakness includes weakness of finger flexors and ankle dorsiflexors. Grip and percussion myotonia are commonly seen. Myotonia of bulbar, tongue, and facial muscles can lead to speech, mastication, and swallowing difficulty. The spectrum of cardiac involvement varies from conduction abnormalities with arrhythmia and conduction block to sudden cardiac death. Cognitive decline as well as psychological dysfunction are often present. Posterior capsular cataracts are well described but retinal degeneration is also known. Endocrine abnormalities include hypotestosteronism with testicular atrophy as well as insulin resistance with diabetes. Significant disability ensues by the fifth or sixth decade compounded by diaphragmatic weakness, leading to aspiration, chest infections, and respiratory failure. A cardiac pacemaker may be lifesaving in preventing sudden cardiac death.

A congenital form of DM2 is not described. The clinical presentation of DM2 in childhood- and adult-onset forms is similar to DM1, except that patients experience exercise-induced fatigue. In DM2, weakness of the iliopsoas muscle causes difficulty rising from a chair or squatting position and difficulty climbing stairs is more prominent. In general, the phenotype is considered milder in DM2 with fewer frequent respiratory and cardiac complications.

The management of patients with myotonic dystrophies involves symptomatic therapy for motor and mental impairment, psychiatric treatment for behavioural problems, cataract surgery, cardiac evaluation, regular follow-up, pacemaker implantation, monitoring of respiratory function, prevention of aspiration, and prompt treatment of pneumonia. Appropriate attention should be given to endocrine abnormalities and physical therapy should be employed diligently. Drugs known to reduce myotonia, such as mexiletine, phenytoin, and carbamazepine, may be tried.

Congenital muscular dystrophy

The congenital muscular dystrophies (CMDs) comprise a group of autosomal recessive disorders presenting at birth or in early infancy with significant muscular weakness, hypotonia, respiratory insufficiency, bulbar dysfunction, and arthrogryposis. Muscle biopsy shows typical dystrophic changes such as variability in fibre size, endomysial and perimysial connective tissue proliferation, and fat infiltration in areas of muscle fibre loss with varying degrees of necrosis and regeneration. Immunohistochemistry is useful in delineating a particular subtype based on the absence of merosin staining (merosin negative CMD, MDC1A), or the presence of normal merosin staining and expression of β‎-dystroglycan but absent or reduced glycosylated α‎-dystroglycan, with preservation of core α‎-dystroglycan staining (dystroglycanopathies). CMDs are classified based on the underlying genetic defect, namely mutations in genes affecting extracellular matrix proteins, in genes affecting membrane receptors, and in the gene for an endoplasmic reticular protein. Ultimately, all gene defects lead to an abnormal connection between the extracellular matrix and the DGC.

Muscular weakness in CMD is static or slowly progressive. Muscle hypertrophy of tongue and calf may be seen. Clinically, CMDs may be classified based on the presence or absence of brain malformation. Most patients with the common form of CMD, MDC1A, caused by laminin α‎2 or merosin deficiency, are mentally normal but T2-weighted imaging on brain MRI consistently shows the presence of widespread cerebral white matter abnormalities, often most marked in the periventricular and frontal U-fibres after the age of 6 months. A sensorimotor peripheral neuropathy is also present. Patients with CMD with fukutin-related protein are described as having mild learning disabilities and cerebellar cysts. Patients with CMD with rigid spine disease and Ullrich’s myopathy, as well as its later onset milder allelic form, Bethlem myopathy, have normal mental capacity as well as a normal brain MRI.

The unifying feature of complex CMD is a disorder of neuronal migration referred to as cobblestone cortex, which results in lissencephaly in the most severe form. Walker–Warburg syndrome (WWS), the most severe of the dystroglycanopathies, presents at birth. Patients lack spontaneous movements, and have marked hypotonia and microcephaly. Hydrocephalus secondary to aqueductal stenosis represents a serious complication. Patients are blind and several ocular abnormalities are described, including microphthalmia, cataracts, iris malformations, glaucoma, retinal dysplasia with or without retinal detachment, colobomas of the retina, and hypoplastic optic nerves. Fukuyama’s congenital muscular dystrophy (FCMD) and muscle–eye–brain (MEB) disease are more common in Japan and Finland, respectively. MEB disease has a more severe phenotype with persistent bedridden state and death during the first year of life. FCMD is associated with severe intellectual impairment, cardiomyopathy, seizures, and ocular abnormalities, but not blindness. Characteristic brain malformations found include polymicrogyria, pachygyria, and agyria of the cerebrum and cerebellum (type II lissencephaly). The cerebral cortex is highly disorganized, showing no recognizable lamination and neuronal overmigration into the leptomeninges.

Further reading

Kolanczyk M, et al. (2007). Multiple roles for neurofibromin in skeletal development and growth. Hum Mol Genet, 16, 874–86.Find this resource:

    Lyon G, Kolodny EH, Pastores GM (2006). Neurology of Hereditary Metabolic Diseases of Children. McGraw-Hill, New York.Find this resource:

      Pandolfo M (2011). Genetics of epilepsy. Semin Neurol, 31, 506–18.Find this resource:

        Paulson HL, Igo I (2011). Genetics of dementia. Semin Neurol, 31, 449–60.Find this resource:

          Rosenberg RN, DiMauro S, Paulson HL, Ptacek L, Nestler EJ (eds.) (2008). The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 4th edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA.Find this resource:

            Tidball JG, Spencer MJ (2003). Skipping to new gene therapies for muscular dystrophy. Nat Med, 9, 997–8.Find this resource:

              Van Haren K, et al. (2004). The life and death of oligodendrocytes in vanishing white matter disease. J Neuropathol Exp Neurol, 63, 618–30.Find this resource:

                Websites

                The tables are a guide to the established disease genes but are not comprehensive because new discoveries in neurogenetics occur at a rapid pace. For further listings, the reader should consult the websites below.

                Human Genome Variation Society. Mutation database of inherited peripheral neuropathies. http://www.molgen.ua.ac.be/CMTMutations

                Institute of Medical Genetics in Cardiff. Human gene mutation database. http://www.hgmd.cf.ac.uk/ac/index.php

                National Center for Biotechnology Information. Gene tests. http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests

                Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/omim/

                Patient support and information

                Alzheimer Foundation http://alzfnd.org

                Charcot-Marie-Tooth Association http://www.cmtfoundation.org

                Children’s Tumor Foundation. http://www.ctf.org

                Climb (Children living with inherited metabolic diseases http://www.climb.org.uk

                Genetic Alliance http://geneticalliance.org

                Muscular Dystrophy Association http://wwwmdausa.org

                National Organization for Rare Disorders (NORD) http://www.rarediseases.org/info/contact.html

                National Tay-Sachs and Allied Diseases Association http://www.ntsad.org

                Neurofibromatosis, Inc. http://www.nfinc.org

                Tuberous Sclerosis Alliance. http://www.tsalliance.org/