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Publisher:: Oxford University Press

Print Publication Date:: May 2010

Print ISBN-13:: 9780199204854

Published to Oxford Medicine:: May 2010

DOI:: 10.1093/med/9780199204854.001.1

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Mitochondrial encephalomyopathies

Chapter:: Mitochondrial encephalomyopathies
Author(s):: P F Chinnery,
D M Turnbull

DOI:

10.1093/med/9780199204854.003.0242405

Essentials

Mitochondrial encephalomyopathies are caused by primary defects in the respiratory chain that lead to disturbed generation of ATP by aerobic metabolism, which characteristically impairs the function of high-demand tissues such as the brain, eye, cardiac and skeletal muscle, as well as endocrine organs. The numerous proteins involved in this chain are encoded by genes in mitochondrial or nuclear DNA, mutations in many of which can lead to clinical disorders.

Clinical features

The clinical presentations of mitochondrial encephalomyopathies are highly variable: the same clinical syndrome can be caused by different genetic defects, and the same genetic defect may present in a variety of different ways. Several characteristic syndromes are described, including those produced by the following:

Large-scale single deletions of mitochondrial genome—typically cause progressive ophthalmoplegia and ptosis, and limb muscles may be affected; can also cause an extended phenotype of cerebellar ataxia, pigmentary retinopathy, sensorineural deafness, diabetes mellitus and heart block (Kearns–Sayre syndrome).

Pearson’s syndrome—pancreatic exocrine failure and hypoplastic bone marrow with sideroblastic anaemia in infancy; survivors may develop features of Kearns–Saye syndrome. Point mutations in the mitochondrial genome—may be present in adult life and are the major cause of visual loss in young adult males (Leber’s hereditary optic neuropathy). Other syndromes include Leigh’s syndrome—subacute necrotizing encephalomyopathy, with characteristic lesions in basal ganglia, cerebellum, and brainstem.

Nuclear genetic mutations with autosomal recessive inheritance—typically present in infants and children.

Investigation and treatment

Investigation—aside from general investigations to characterize the pattern and nature of organ involvement, the diagnostic strategy depends on the clinical context: (1) Inherited cases—in many patients it is possible to identify a specific clinical syndrome with a clear maternal family history suggestive of a mitochondrially inherited disorder. Under these circumstances it is appropriate (after counselling) to proceed directly to molecular genetic testing. (2) Sporadic cases—the key investigation is muscle biopsy for biochemical studies of oxidative phosphorylation, leading on to targeted molecular analysis of suitable samples of mitochondrial and nuclear DNA.

Treatment—there is no definitive treatment for patients with mitochondrial disease, except for those with deficiency of coenzyme Q₁₀. Management is aimed at minimizing disability, preventing complications, and genetic counselling. Multidisciplinary expertise is needed to provide adequate nutrition and physiotherapy, and to address endocrinological, cardiac and ophthalmic complications.

Introduction

Mitochondria are ubiquitous intracellular organelles that are involved in many different metabolic pathways. Disorders of intermediary metabolism (such as fatty acid β-oxidation or tricarboxylic acid cycle defects) involve mitochondrial enzymes, but the term ‘mitochondrial encephalomyopathy’ usually means a disease which is due to an abnormality of the final common pathway of energy metabolism—the mitochondrial respiratory chain, which is linked to the production of ATP by oxidative phosphorylation (OXPHOS). The respiratory chain is essential for aerobic metabolism, and respiratory chain defects characteristically affect tissues and organs that are heavily dependent upon oxidative metabolism (such as the central nervous system, the eye, skeletal muscle, myocardium, and endocrine organs).

Recent studies have demonstrated the central role of the mitochondrion in the pathophysiology of well-established diseases such as Friedreich’s ataxia and Wilson’s disease, and mitochondrial abnormalities have been described in common sporadic disorders including idiopathic Parkinson’s disease, but these are not primarily disorders of the mitochondrial respiratory chain and are not considered further here.

Biochemistry and genetics of the respiratory chain

The intermediary metabolism of carbohydrates, amino acids, and fatty acids generates the reduced cofactors NADH, NADPH, and FADH₂. These cofactors transfer electrons to the mitochondrial respiratory chain. As the electrons are passed through complexes I to IV of the respiratory chain along the inner mitochondrial membrane, protons are pumped out of the mitochondrial matrix into the intermembrane space. This creates an electrochemical gradient that is harnessed by complex V (ATP synthase) to generate ATP from ADP. Each respiratory chain complex contains many polypeptide subunits, some of which are coded by genes within the nucleus and some of which are encoded by the mitochondrial genome. Although all of the polypeptides encoded in mitochondrial DNA (mtDNA) have been known for over two decades, many nuclear genes involved in mitochondrial biogenesis have yet to be characterized in detail.

The mitochondrial genome encodes seven complex I subunits (NADH-ubiquinone oxidoreductase), one of the complex III subunits (ubiquinol-cytochrome c oxidoreductase), three of the complex IV (cytochrome c oxidase) subunits, and the ATPase 6 and ATPase 8 subunits of complex V. Interspaced between the protein-encoding genes are two ribosomal RNA genes (12S and 16S rRNA), and 22 transfer RNA genes that provide the necessary RNA components for the mitochondrial translation machinery. The remaining polypeptides, including all of the complex II subunits, are synthesized from nuclear gene transcripts within the cytosol. These are subsequently imported into the mitochondria through the inner and outer membrane translocation complexes. There are many additional proteins that are essential for the normal assembly and function of the mitochondrial respiratory chain. As a result, mitochondrial respiratory chain disorders can be due to mutations affecting both nuclear and mitochondrial genes.

The classification and investigation of mitochondrial respiratory chain disorders has been revolutionized by the recent advances in our understanding of the underlying genetic defects affecting both mtDNA and nuclear DNA (Table 24.24.5.1).

Table 24.24.5.1 Genetic basis of mitochondrial encephalomyopathies

Nuclear DNA defects
Nuclear genetic disorders of the mitochondrial respiratory chain, mutations in structural subunits
	Leigh’s syndrome (complex I deficiency—mutations in NDUFS1, NDUFS4, NDUFS7, NDUFS8, NDUFV1. Complex II deficiency, SDHA)
	Cardiomyopathy and encephalopathy (complex I deficiency, mutations in NDUFS2)
	Optic atrophy and ataxia (complex II deficiency—mutations in SDHA)
	Hypokalaemia and lactic acidosis (complex III, mutations in UQCRB)
Nuclear genetic disorders of the mitochondrial respiratory chain, mutations in assembly factors:
	Leigh’s syndrome (mutations in SURF I and LRPPRC)
	Hepatopathy and ketoacidosis (mutations in SCO1)
	Cardiomyopathy and encephalopathy (mutations in SCO2)
	Leucodystrophy and renal tubulopathy (mutations in COX10)
	Hypertrophic cardiomyopathy (mutations in COX15)
	Encephalopathy, liver failure, renal tubulopathy (with complex III deficiency, mutations in BCS1L)
	Encephalopathy (with complex V deficiency, mutations in ATP12)
Nuclear genetic disorders of the mitochondrial respiratory chain, mutations in translation factors:
	Leigh’s syndrome, Liver failure and lactic acidosis (mutations in EFG1)
	Lactic acidosis, developmental failure and dysmophism (mutations in MRPS16)
	Myopathy and sideroblastic anemia (mutations in PUS1)
	Leukodystrophy and polymicrogyria (mutations in EFTu)
Nuclear genetic disorders associated with multiple mtDNA deletions or mtDNA depletion:
	Autosomal progressive external ophthalmoplegia (mutations in POLG, POLG2, PEO1 and SLC25A4)
	Mitochondrial neurogastrointestinal encephalomyopathy (thymidine phosphorylase deficiency—mutations in TP)
	Alpers-Huttenlocher syndrome (mutations in POLG and MPV)
Disorders of the lipid mileu
Co-enzyme Q₁₀ deficiency (mutations in COQ2)—new genetic defects now described from Hirano et al.
Barth syndrome (mutations in TAZ)
Mitochondrial DNA defects
Rearrangements (deletions and duplications):
	Chronic progressive external ophthalmoplegia
	Kearns–Sayre syndrome
	Diabetes and deafness
Point mutations:^a
Protein-encoding genes	Leber’s hereditary optic neuropathy (G11778A, T14484C, G3460A)
Protein-encoding genes	Neurogenic weakness with ataxia and retinitis pigmentosa/Leigh’s syndrome (T8993G/C)
tRNA genes	MELAS (A3243G, T3271C, A3251G)
	MERRF (A8344G, T8356C)
	Chronic progressive external ophthalmoplegia (A3243G, T4274C)
	Myopathy (T14709C, A12320G)
	Cardiomyopathy (A3243G, A4269G)
	Diabetes and deafness (A3243G, C12258A)
	Encephalomyopathy (G1606A, T10010C)
rRNA genes	Non-syndromic sensorineural deafness (A7445G)
rRNA genes	Aminoglycoside-induced non-syndromic deafness (A1555G)

* mtDNA nucleotide positions refer to the l-chain. Many different pathogenic point mutations of the mitochondrial genome have been identified with only the most common or best characterized mentioned here.

Basic mitochondrial genetics

There are two main differences between nuclear DNA and mtDNA that are important for the expression and transmission of mitochondrial genetic disease, as follows.

Heteroplasmy and the threshold effect

Each mammalian cell contains over 1000 copies of the small (16.5 kb) mitochondrial genome. Individuals with mtDNA disease often harbour a mixture of mutated and wild-type (normal) mtDNA—a situation known as heteroplasmy. Single cells only express a respiratory chain defect when the proportion of mutated mtDNA exceeds a critical threshold with low levels of wild type mtDNA. Different organs, and even adjacent cells within the same organ, may contain different amounts of mutated mtDNA. This variability, coupled with tissue-specific differences in the threshold and the varied dependence of different organs on oxidative metabolism, explains in part why certain tissues are preferentially affected in patients with mtDNA disease. In general, postmitotic (nondividing) tissues such as neurons, skeletal and cardiac muscle, and endocrine organs harbour much higher levels of mutated mtDNA and are often clinically involved. In contrast, rapidly dividing tissues such as the bone marrow are only rarely clinically affected (one example is Pearson’s syndrome—see below).

Maternal inheritance and the transmission of heteroplasmy

After fertilization of the oocyte, sperm mtDNA is actively degraded. As a consequence, mtDNA is transmitted exclusively down the maternal line. This means that affected males with mtDNA disease cannot transmit the genetic defect. Deleted molecules are rarely, if ever, transmitted from clinically affected females to their offspring. By contrast, a female harbouring a heteroplasmic mtDNA point mutation, or mtDNA duplications, may transmit a variable amount of mutated mtDNA to her children. Early during development of the female germ line, the number of mtDNA molecules within each oocyte is reduced before being subsequently amplified to reach a final number of more than 100 000 in each mature oocyte. This restriction and amplification (also called the mitochondrial ‘genetic bottleneck’) contributes to the variability between individual oocytes, and the different levels of mutant mtDNA seen in the offspring of a single female.

Clinical presentation of respiratory chain disorders

Mitochondrial encephalomyopathies are highly variable both clinically and at the genetic level. The same clinical syndrome can be caused by different genetic defects (which may be within nuclear or mitochondrial genes), but the same genetic defect may present in a variety of different ways. In general, adults who present with mitochondrial disease are often found to have a defect of mtDNA. Children often present with different clinical features and are more likely to have a nuclear genetic defect. It is often possible to identify well-defined clinical syndromes, but many patients present with a collection of clinical features that are highly suggestive of respiratory chain disease but do not fit into a discrete clinical category.

Defined clinical syndromes (Table 24.24.5.2)

Large-scale deletions can cause chronic progressive external ophthalmoplegia and bilateral ptosis (PEO). Some of these patients have limited limb muscle involvement. In contrast, similar deletions may also cause chronic progressive external ophthalmoplegia with bilateral sensorineural deafness, cerebellar ataxia, pigmentary retinopathy, diabetes mellitus, and cardiac conduction defects leading to complete heart block. When this begins in teenage years and is associated with a raised cerebrospinal fluid protein, it is called the Kearns–Sayre syndrome (KSS), which is a progressive neurological disorder associated with severe disability. Hypoparathyroidism and hypothyroidism are well-recognized features of KSS. The vast majority of cases of chronic PEO and KSS. These two syndromes are the extremes of a spectrum of disease and many individuals lie somewhere between the pure extraocular muscle and severe central neurological phenotypes.

Pearson’s syndrome of exocrine pancreatic failure, sideroblastic anaemia, and marrow panhypoplasia is usually due to a mtDNA deletion. Pearson’s syndrome also presents in infancy and a number of individuals who have survived into later childhood subsequently developed the Kearns–Sayre phenotype.

Although many patients with PEO and KSS are sporadic cases, PEO can also be inherited as either an autosomal dominant (adPEO) or recessive (arPEO) trait. A high incidence of psychiatric disease, a parkinsonian syndrome, and primary gonadal failure have also been documented in some families. Some cases have a profound peripheral neuropathy and ataxia (referred to as SANDO, sensory ataxic neuropathy with dysarthria and ophthalmoparesis), and some family members present with adult-onset ataxia without ophthalmoplegia (also called mitochondrial recessive ataxia syndrome, MIRAS) which is common in Scandinavia. Mutations in the gene encoding the mitochondrial polymerase (polγ, encoded by the nuclear gene POLG) are a major cause of adPEO and arPEO. adPEO can also be caused by mutations in PEO1 (which codes for the mtDNA helicase Twinkle), SLC25A4 (which codes for the adenine nucleotide translocase ANT1), and POLG2 (which codes for the accessory subunit of polγ).

Pathogenic point mutations of mtDNA are more common than rearrangements. This is partly because mtDNA deletions cause sporadic disease, whereas many mtDNA point mutations are transmitted down the maternal line. The m.3243A>G mutation in the leucine (UUR) tRNA gene was first described in a patient with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Different families harbouring the same genetic defect may have different phenotypes. For example, some families harbouring m.3243A>G have predominantly diabetes and deafness, some have chronic progressive external ophthalmoplegia, and some present with hypertrophic cardiomyopathy. It is currently not known why this is the case but it is likely that additional nuclear genetic factors play an important role in modifying the expression of the primary mtDNA defect. This single mutation is important since it has been estimated that between 0.5 and 1.5% of cases of diabetes mellitus in the general population are associated with the m.3243A>G mutation.

Patients may present with myoclonic epilepsy, ataxia, optic atrophy, and have ragged-red fibres in skeletal muscle (MERRF) and this may also be due to a point mutation of mtDNA (e.g. A8344G).

mtDNA mutations are the major cause of visual loss in young adult males. About one-half of all males who harbour one of three point mutations of mtDNA (m.11778G>A, m.14484T>C, m.3460G>A) develop bilateral sequential visual loss in the second or third decade—a disorder known as Leber hereditary optic neuropathy (LHON). The majority of individuals with these mutations are homoplasmic, harbouring only mutated mtDNA. It is not clear why the disease only affects approximately one-half of the males and 10% of females who inherit the primary mtDNA defect. Environmental factors, such as alcohol and tobacco, may explain the variable penetrance of this disorder; however, additional, as yet unknown, nuclear genetic factors may also be important in modulating the phenotype.

Leigh’s syndrome (subacute necrotizing encephalomyopathy) is a relapsing encephalopathy with prominent cerebellar and brainstem signs that usually presents in childhood and is associated with characteristic neuroimaging abnormalities involving the basal ganglia. Leigh’s syndrome can be due to an X-linked pyruvate dehydrogenase deficiency or a defect of the mitochondrial respiratory chain. Complex I deficiency or cytochrome c oxidase deficiency are common findings in Leigh’s syndrome. In these patients it may be possible to identify recessive mutations in nuclear complex I genes, or genes involved in the assembly of the respiratory chain complexes (for example SURF1). Point mutations at position m.8993 in the ATPase 6 gene of mtDNA may cause neurogenic weakness with ataxia and retinitis pigmentosa. These particular mutations are also associated with some forms of childhood Leigh’s syndrome.

Alpers–Huttenlocher syndrome is a severe autosomal recessive hepatoencephalopathy with intractable seizures and visual failure which presents in early childhood and is associated with depletion (loss) of mtDNA in affected tissues. Mutations in POLG are a major cause of Alpers–Huttenlocher syndrome, and mutations in MPV also cause liver disease. Other causes of mtDNA depletion include mutations in TK2 (encoding thymine kinase) which presents with a progressive childhood myopathy or spinal muscular atrophy, DGUOK (encoding dexyguanosine kinase) which presents in childhood with a myopathy and liver failure, and SUCLA2 (coding for ADP-forming succinyl-CoA synthase) which presents in early childhood with an encephalomyopathy.

Cytochrome c oxidase deficiency may also present in childhood with an infantile myopathy and a severe lactic acidosis, which may also be associated with a cardiomyopathy and the Toni–Fanconi–Debre syndrome. Despite maximal supportive intervention, this is usually a fatal disorder and a severe depletion of mtDNA occurs in a proportion of these cases. It is important to recognize that isolated myopathy and lactic acidosis may be self-limiting, often with a significant improvement by 1 year of age and complete resolution by the age of 3 years.

Coenzyme Q₁₀ deficiency can present in childhood with recurrent myoglobinuria, myopathy and seizures. In some families it presents with an infantile encephalomyopathy with renal tubular defects. Finally, it may also present with ataxia and variable involvement of other regions of the central nervous system, peripheral nerve, and muscle. Mutations in genes coding for enzymes involved in the biosynthesis of coenzyme Q₁₀ have been found in some families.

Nonspecific clinical presentations

The foregoing diseases and numerous other syndromes may strongly suggest a mitochondrial aetiology (Fig. 24.24.5.1 and Table 24.24.5.2), many patients do not present with a characteristic phenotype. Children may present in the neonatal period with a metabolic encephalopathy and systemic lactic acidosis, often associated with hepatic and cardiac failure. This may be associated with depletion in the total amount of mtDNA within affected tissues (see above). This syndrome may be fatal, and in some the liver failure is precipitated by exposure to Sodium Valproate, but it may also be a self-limiting disorder. Childhood presentations may be even less specific, with neonatal hypotonia, feeding and respiratory difficulties, and failure to thrive. A respiratory chain defect should be considered in any patient who has a disease with multiple organ involvement, particularly if there are central neurological features (such as seizures and dementia), a myopathy, cardiomyopathy, and endocrine abnormalities such as diabetes mellitus (Fig. 24.24.5.1). Bilateral sensorineural deafness and ocular features (retinopathy, optic atrophy, ptosis, and ophthalmoparesis) are common. Renal tubular defects, gastrointestinal hypomotility, cervical lipomatosis, and psychiatric features are also well described in patients with respiratory chain disease.

Fig. 24.24.5.1

The clinical features and biochemical and molecular genetic basis of mitochondrial encephalomyopathies.

Table 24.24.5.2 Clinical syndromes

Disorder	Primary features	Additional features
Alpers–Huttenlocher syndrome	Encephalopathy with seizures	Developmental delay
Alpers–Huttenlocher syndrome	Liver failure	Hypotonia
Chronic progressive external ophthalmoplegia	External ophthalmoplegia and bilateral ptosis	Proximal myopathy
Kearns–Sayre syndrome	Progressive external ophthalmoplegia onset before age 20 with pigmentary retinopathy, plus one of the following: Cerebrospinal fluid protein >1 g/litre, cerebellar ataxia, or heart block	Bilateral deafness Myopathy Dysphagia Diabetes mellitus Hypoparathyroidism Dementia
Pearson’s syndrome	Sideroblastic anaemia of childhood Pancytopenia Exocrine pancreatic failure	Renal tubular defects
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)	Stroke-like episodes before age 40 years Seizures and/or dementia Lactic acidosis Myopathy	Diabetes mellitus Cardiomyopathy (hypertrophic leading to dilated) Bilateral deafness Cerebellar ataxia
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)	Gastrointestinal pseudo-obstruction Myopathy Leukoencephalopathy Peripheral neuropathy
Myoclonic epilepsy with ragged-red fibres (MERRF)	Myoclonus Seizures Cerebellar ataxia Myopathy	Dementia Optic atrophy Bilateral deafness Peripheral neuropathy Spasticity Multiple lipomas
Leber’s hereditary optic neuropathy	Subacute bilateral visual failure Males:females approximately 4:1 Median age of onset 24 years	Dystonia Cardiac pre-excitation syndromes
Leigh’s syndrome	Subacute relapsing encephalopathy with cerebellar and brainstem signs	Basal ganglia lucencies
Infantile myopathy and lactic acidosis (fatal and nonfatal forms)	Hypotonia in the first year of life Feeding and respiratory difficulties	Fatal form may be associated with a cardiomyopathy and/or the Toni–Fanconi–Debre syndrome

Investigation of respiratory chain disease

The investigation of patients with a suspected mitochondrial encephalomyopathy involves the careful assimilation of clinical and laboratory data. In a significant proportion of cases (such as Leber’s hereditary optic neuropathy), it is possible to identify a specific clinical syndrome with a clear maternal family history. Under these circumstances it is appropriate to carry out a molecular genetic test on a blood sample. In many situations, particularly in sporadic cases, this is not appropriate because the clinical features overlap with those of many other disorders. Even if the patient has a mitochondrial disorder, numerous different genetic defects may be responsible, some of which will not be detectable by analysis of blood samples.

Investigations fall into two main groups: clinical investigations used to characterize the pattern and nature of the different organs involved, and specific investigations to identify the biochemical or genetic abnormality.

General clinical investigations

It is essential to search for the more common features of respiratory chain disease, especially those which are potentially treatable. This includes cardiac assessment (ECG and echocardiography) and endocrine assessment (oral glucose tolerance test, thyroid function tests, alkaline phosphatase, fasting calcium, and parathyroid hormone levels). The organic and amino acids in urine may be abnormal even in the absence of overt tubular disease. Measuring blood and cerebrospinal fluid lactate levels is more helpful in the investigation of children than adults. These measurements must be interpreted with caution because there are many causes of blood and cerebrospinal fluid lactic acidosis, including fever, sepsis, dehydration, seizures, and stroke. The cerebrospinal fluid protein may be elevated. The serum creatine kinase level may be raised but is often normal. Neurophysiological studies may identify a myopathy or neuropathy. Electroencephalography may reveal diffuse slow-wave activity consistent with a subacute encephalopathy, or evidence of seizure activity. Cerebral imaging may be abnormal, showing lesions of the basal ganglia, high signal in the white matter on MRI, or generalized cerebral atrophy.

Specific investigations

A skeletal muscle biopsy is invaluable in the investigation of respiratory chain disease. Histochemical and biochemical investigations, in conjunction with the clinical assessment, often indicate where the underlying genetic abnormality must lie.

Histochemistry and biochemistry

Histochemical analysis may reveal subsarcolemmal accumulation of mitochondria (so-called ‘ragged red’ fibres), or cytochrome c oxidase deficiency. A mosaic of cytochrome c oxidase-positive and cytochrome c oxidase-negative muscle fibres suggests an underlying primary mtDNA defect or a secondary defect of mtDNA as seen in patients with POLG mutations. Patients who have cytochrome c oxidase deficiency due to a nuclear genetic defect usually have a global deficiency of this enzyme affecting all muscle fibres. Electron microscopy may identify paracrystalline inclusions in the intermembrane space, but these are non-specific and may be seen in other nonmitochondrial disorders. Respiratory chain complex assays can be carried out on various tissues. Skeletal muscle or affected tissue is preferable, but cultured fibroblasts are useful in the investigation of childhood mitochondrial disease. Measurement of the individual respiratory chain complexes determines whether an individual has multiple complex defects that would suggest an underlying mtDNA defect, involving either a tRNA gene or a large deletion. Isolated complex defects may be due to mutations in either mitochondrial or nuclear genes. Co-enzyme Q₁₀ can be measured directly in affected tissues.

Molecular genetic investigations

Under certain circumstances, the clinical and biochemical features may point towards a specific genetic defect, and it may be possible to detect this abnormality in a blood sample. Children presenting with Leigh’s syndrome and who have an isolated deficiency of one of the respiratory chain subunits may have a point mutation within the nuclear-encoded respiratory chain subunit or assembly genes. These have been identified by direct sequencing of the appropriate exons.

For some mtDNA defects (particularly mtDNA deletions) the abnormality is not detectable in a DNA sample extracted from blood, and the analysis of DNA extracted from muscle is essential to establish the diagnosis. The first stage is to look for mtDNA rearrangements or mtDNA depletion by long-range polymerase chain reaction (PCR) or real-time PCR. This is followed by PCR and restriction fragment length polymorphism (RFLP) analysis for common point mutations. Many patients with mitochondrial disease have a previously unrecognized mtDNA defect and it is necessary to sequence directly the mitochondrial genome. Interpretation of the sequence data can be extremely difficult. mtDNA is highly polymorphic and any two normal individuals may differ by up to 60 base pairs. In the strictest sense, a mutation can only be considered to be pathogenic if it has arisen independently several times in the population, it is not seen in controls, and it is associated with a potential disease mechanism. These stringent criteria depend upon a good knowledge of polymorphic sites in the background population. If a novel base change is heteroplasmic, this suggests that it is of relatively recent onset. Family, tissue segregation, and single cell studies may show that higher levels of the mutation are associated with mitochondrial dysfunction and disease, which strongly suggests that the mutation is causing the disease. Specific nuclear genes (e.g. POLG) are usually sequenced after initial mtDNA analysis identifies a secondary defect of mtDNA (multiple deletions or depletion). Although there may be a corresponding histochemical or biochemical defect, this may not be detectable in readily available tissues.

Management

There is currently no definitive treatment for patients with mitochondrial disease, except for patients with deficiency of coenzyme Q₁₀. Management is aimed at minimizing disability, preventing complications, and genetic counselling.

Supportive care and surveillance

Many patients with mitochondrial disorders require follow-up over many decades. An integrated approach is essential involving the primary physician, other specialist physicians (ophthalmology, diabetes, and cardiology), specialist nurses, physiotherapists, and speech therapists. Vigilant clinical monitoring over many years can prevent the development of complications, such as those secondary to cardiac and endocrine involvement. Specific procedures may be indicated at various stages of disease. These include cardiac pacing, ptosis correction, cataract surgery, and percutaneous gastrostomy.

Genetic counselling

The detailed investigation of patients with respiratory chain disease usually leads to a specific molecular genetic diagnosis, particularly in adults. This has profound implications on the counselling given to patients and their families. Most children with respiratory chain disease are compound heterozygotes with recessive nuclear gene mutations. Some adults have a recessive disorder, or adPEO. If it is possible to identify the causative mutations in both the offspring and parents, then this will allow confident genetic counselling for the whole family. If, as in many cases, it is not possible to identify the underlying gene defect, or the genetic defect in the affected child cannot be traced back to the parents, then counselling is less straightforward. The clinical penetrance of many recently identified nuclear gene defects has yet to be established, generating considerable uncertainty when counselling families

If a causative primary mtDNA defect is identified, then the implications for counselling are distinctly different. Males cannot transmit pathogenic mtDNA defects. Patients who carry mtDNA deletions rarely have a family history suggestive of mtDNA disease, and there is no significant risk that they will transmit the mtDNA defect to any offspring. There are a few rare exceptions to this rule where the propensity to develop mtDNA deletions is transmitted as an autosomal dominant or autosomal recessive trait. By contrast, women harbouring pathogenic mtDNA point mutations may transmit the genetic defect to their offspring. The mitochondrial genetic ‘bottleneck’ leads to a variation in the proportion of mutated mtDNA that is transmitted to any offspring (see above). It is therefore possible for a female to have mildly affected as well as severely affected children. The risk of having affected offspring varies from mutation to mutation, and although there does appear to be a relationship between the level of mutated mtDNA in the mother and the risk of affected offspring, there are insufficient data from prospective studies to allow accurate risk prediction.

Prognosis

In general the prognosis depends upon the extent of central neurological involvement. Patients with Leber’s hereditary optic neuropathy rarely have significant central neurological features and have a normal lifespan. The prospect for visual recovery varies. After the initial nadir, individuals harbouring the m.11778G > A mutation are the least likely to regain functional vision, whilst those harbouring the m.14484T > C mutation are the most likely to regain their sight.

Children presenting with an encephalopathy have a poor prognosis. Although residual neurological deficits are common after repeated childhood encephalopathic episodes, the disease may enter a more stable ‘chronic’ phase during teenage years and adulthood. A similar course may be seen in adults presenting with a relapsing encephalopathy. In contrast, a large proportion of adults with mtDNA defects and chronic progressive external ophthalmoplegia have very mild disease that may remain limited to the extraocular muscles for many decades. For specific mtDNA mutations, there also appears to be a relationship between the proportion of mutated mtDNA in skeletal muscle and the severity of the disease. Although the proportion of mutated mtDNA in muscle may give some guide to prognosis, there is insufficient information available to allow accurate prognostic counselling based upon these determinations. A significant proportion of patients have distinct phenotypes associated with unique genetic defects and the prognosis must be guarded in these families. There is limited natural history data for nuclear genetic disorders based on retrospective notes review (e.g. for specific POLG mutations).

Pharmacological treatments and novel approaches under development

Standard doses of vitamin C and K, thiamine, riboflavin, and ubiquinone (coenzyme Q₁₀) may be of some benefit, particularly in patients with isolated Q₁₀ deficiency. These treatments have no significant side effects and are relatively cheap, but their efficacy is largely based on anecdotal reports. Dichloracetate can be used to reduce lactic acid levels but may cause an irreversible toxic neuropathy and is therefore not favoured. Exercise is important for patients with mtDNA disease, and isometric muscle contraction may lead to an improvement in muscle strength. Finally, several centres are investigating methods for correcting the underlying mtDNA defect by gene therapy.

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