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Neurometabolic disorders 

Neurometabolic disorders
Neurometabolic disorders

Tony McShane

, Peter Clayton

, Michael Donaghy

, and Robert Surtees

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Subscriber: null; date: 18 August 2018

  1. 10.1 Introduction [link]

    1. 10.1.1 Introduction to neurometabolic disease [link]

    2. 10.1.2 When to suspect a neurometabolic disorder [link]

    3. 10.1.3 Investigation of possible neurometabolic disorder [link]

  2. 10.2 Leukodystrophies and brain dysmyelination [link]

    1. 10.2.1 Overview [link]

    2. 10.2.2 Metachromatic leukodystrophy [link]

    3. 10.2.3 Krabbe disease [link]

    4. 10.2.4 Adrenoleukodystrophy [link]

    5. 10.2.5 Vanishing white matter disease [link]

    6. 10.2.6 Megaloencephalic leukoencephalopathy with subcortical cysts [link]

    7. 10.2.7 Alexander disease [link]

    8. 10.2.8 L-2-hydroxyglutaric aciduria [link]

    9. 10.2.9 Canavan disease [link]

    10. 10.2.10 Pelizaeus–Merzbacher disease [link]

    11. 10.2.11 Aicardi–Goutiéres syndrome [link]

  3. 10.3 Primary grey matter degenerations of infancy and childhood [link]

    1. 10.3.1 Overview of grey matter degenerations [link]

    2. 10.3.2 The neuronal ceroid lipofuscinoses [link]

    3. 10.3.3 Lesch–Nyhan syndrome [link]

    4. 10.3.4 Infantile neuroaxonal dystrophy [link]

  4. 10.4 Lysosomal disorders affecting the brain [link]

    1. 10.4.1 Introduction to the neuronal storage diseases [link]

    2. 10.4.2 GM2 gangliosidosis or Tay Sachs disease [link]

    3. 10.4.3 GM1 gangliosidosis [link]

    4. 10.4.4 Niemann-Pick disease [link]

    5. 10.4.5 Mucopolysaccharidoses [link]

    6. 10.4.6 Gaucher’s disease [link]

  5. 10.5 Brain mitochondrial diseases [link]

    1. 10.5.1 Overview of the respiratory chain deficiencies [link]

    2. 10.5.2 Pearson syndrome [link]

    3. 10.5.3 Leigh’s syndrome [link]

    4. 10.5.4 Neuropathy, ataxia, retinitis pigmentosa syndrome [link]

    5. 10.5.5 Deficiencies of pyruvate dehydrogenase and co-enzyme CoQ10 [link]

    6. 10.5.6 Polymerase gamma mutations [link]

  6. 10.6 Brain peroxisomal disorders [link]

    1. 10.6.1 The range of peroxisomal disorders [link]

    2. 10.6.2 Zellweger syndrome [link]

    3. 10.6.3 Infantile Refsum disease [link]

    4. 10.6.4 Leukodystrophy [link]

    5. 10.6.5 Rhizomelic chondrodysplasia punctata [link]

    6. 10.6.6 Single peroxisomal enzyme or transporter disorders [link]

  7. 10.7 Other inborn errors of metabolism [link]

    1. 10.7.1 Metabolic causes of epileptic encephalopathy [link]

    2. 10.7.2 Congenital disorders of glycosylation [link]

10.1 Introduction

10.1.1 Introduction to neurometabolic disease

Various disorders result from genetically determined abnormalities of enzymes, the metabolic consequences of which affect the development or functioning of the nervous system. The range of metabolic disturbances is wide, as is the resultant range of clinical syndromes. Although most occur in children, some can present in adult life, and increasing numbers of affected children survive into adult life. In some, specific treatments are possible or are being developed. The last 20 years has seen a considerable expansion in our understanding of the genetic and metabolic basis for many neurological conditions. Particular clinical presentations of neurometabolic disorders include ataxias (Chapter 39), movement disorders (Chapter 40), childhood epilepsies (Chapter 30), or peripheral neuropathy (Chapter 21). Detailed coverage of the entire range of inherited metabolic diseases of the nervous system is available in other texts (Brett 1997; Scriver et al. 2001; Menkes et al. 2005). The range of neurometabolic disorders is summarized in Tables 10.1 and 10.2.

Table 10.1 Neurometabolic disorders without acute episodes of metabolic encephalopathy

  1. I. Amino acid disorders (p. 239)

  2. II. Organic acid disorders (p. 240)

  3. III. Mitochondrial disorders (p. 241)

  4. IV. Peroxisomal disorders (p. 242)

  5. V. Lysosomal enzymes (p. 243)

  6. VI. Congenital disorders of glycosylation (p. 246)

  7. VII. Purine and pyrimidines (p. 247)

  8. VIII. Metals (p. 248)

  9. IX. Vitamins (p. 248)

  10. X. Lipoproteins (p. 250)

  11. XI. Cholesterol metabolism (p. 250)

  12. XII. Neurotransmitter metabolism (p. 250)

  13. XIII. Creatine synthesis and transport (p. 251)

  14. XIV. Transport defects (p. 251)

  15. XV. Red cell glycolytic defects (p. 251)

  16. XVI. Pentose phosphate pathway disorder (p. 251)

  17. XVII. DNA repair defects (p. 252)

  18. XVIII. Classical white matter disorders (p. 252)

  19. XIX. Others (p. 252)


1. Hyperphenylalaninaemia syndromes:

a. Phenylketonuria (phenylalanine hydroxylase deficiency). Identified by neonatal screening, dietary treatment prevents classical phenotype of severe dementia, behaviour disorder and epilepsy. Nevertheless a significantly lowered intelligence quotient, behaviour difficulties and abnormalities of myelin on MRI present in treated young adults. Some adults develop a severe neurological disease if diet is stopped in late childhood. Severe teratogenic effects of untreated maternal phenylketonuria.

Screening tests:

plasma amino acids (raised phenylalanine, reduced tyrosine)phenylalanine and tetrahydrobiopterin loads.


liver phenylalanine hydroxylase activity, DNA.

b. Tetrahydrobiopterin (BH4) deficiencies.

BH4 is the cofactor for phenylalanine hydroxylase, tyrosine and tryptophan mono-oxygenases and nitric oxide synthase. Severe forms (usually recessive) present in infancy with hyperphenylalaninaemia and parkinsonism-dystonia (due to dopamine deficiency). Less severe forms (may be dominant) may present later in life with symptoms of dopamine deficiency alone (DOPA-responsive dystonia).

i. Dihydropteridine reductase and pterin-4a-carbinolamine dehydratase deficiencies prevent recycling of BH4.

ii. GTP-cyclohydrolase, 6-pyruvoyltetrahydropterin synthase and, in theory, sepiapterin reductase are defects of tetrahydrobiopterin synthesis.

Screening tests:

plasma amino acids, CSF or urine pterin analysis. CSF neurotransmitter amine metabolites.


red cell dihydropteridine reductase activity, white cell GTP-cyclohydrolase or 6-pyruvoyltetrahydropterin synthase activity.DNA.

2. Glutathione metabolism defects.

a. Oxoprolinuria (pyroglutamic aciduria). Learning difficulties, spasticity. Haemolysis and severe metabolic acidosis in new-born period.

Screening tests:

urine organic acids (increased oxoproline).


red cell glutathione synthetase activity low.

b. Glutamylcysteine synthetase deficiency. Adult spinocerebellar degeneration, haemolysis, peripheral neuropathy, myopathy, generalized aminoaciduria.

Screening tests:

urine amino acids (generalized aminoaciduria).


red cell glutamylcysteine synthetase low.

3. Hyperornithinaemia. Progressive choroidoretinitis (gyrate atrophy) and subcapsular cataract: night blindness in first 10 years, complete blindness in 5th decade. Mild proximal muscular weakness, late white matter degeneration.

Screening tests:

plasma amino acids (raised ornithine, modest decrease in glutamate, glutamine, lysine and creatinine).


fibroblast ornithine aminotransferase, DNA.

4. Homocystinuria.

a. Cystathionine ß-synthase deficiency. Learning difficulties, psychiatric illness, osteoporosis, lens dislocation, marfanoid features, vascular disease.

Screening tests:

plasma amino acids (raised methionine; homocystine and mixed disulphides present), plasma total homocysteine, urine amino acids, methionine load.


fibroblast cystathionine β-synthase activity.

b. Inborn errors of folate metabolism. Vide infra. The range of severity of these is great, from severely affected infants to asymptomatic adults. Dementia, motor disorders, seizures and psychiatric.

c. Some inborn errors of cobalamin metabolism. Vide infra. The range of severity of these is great, from severely affected infants to adults with a disorder mistaken for multiple sclerosis. Dementia, motor disorders, seizures and psychiatric.

5. Tyrosinaemia.

a. Type I (fumarylacetoacetase deficiency). Liver and renal tubular disease, peripheral neuropathy and porphyric crises.

b. Type II (tyrosine aminotransferase deficiency). Palmar-plantar keratosis, corneal erosions, mental retardation in 50% (Richner-Hanhart syndrome).

c. Type III (4-hydroxyphenylpyruvate dioxygenase deficiency). Mild developmental delay, seizures. Delayed maturation can cause benign transient neonatal tyrosinaemia.

Screening tests:

plasma amino acids (raised tyrosine), urinary succinylacetone (Type 1).


white cell or fibroblast FAA activity, liver TAT and 4HPPD activities, DNA.

6. Arginase deficiency. Progressive spastic paraparesis, seizures, learning difficulties, metabolic stroke. May have episodes of encephalopathy.

Screening tests:

plasma ammonia, amino acids (raised arginine).


red cell arginase activity.

7. Hyperlysinaemia. Commonest cause not associated with neurological disease. Rare form with progressive spastic quadriplegia and epilepsy.

8. Hyperprolinaemia. Type II. Developmental delay, seizures (pyridoxine-responsive).

Screening tests:

plasma amino acids (proline 10-15x normal).

Diagnostic Tests:

fibroblast/leukocyte delta-1-pyrroline 5-carboxylate dehydrogenase activity

DNA - P5CDH gene.

9. Serine synthesis disorders. Vide infra under epileptic encephalopathies. Diagnosed from low fasting plasma and CSF serine and glycine. Can result in dysmyelination. One low serine disorder causes peripheral neuropathy.


1. Canavan’s disease. Macrocephaly, dementia, optic atrophy, demyelination, death in early childhood. Milder variants (juvenile) exist.

Screening tests:

urine N-acetylaspartate.


fibroblast aspartoacylase activity, DNA.

2. L2-Hydroxyglutaric aciduria. Early onset ataxia and mild learning difficulties, later myoclonus, extrapyramidal movement disorder, dementia in teens, characteristic demyelination.

Screening tests:

urine L2-hydroxyglutaric acid, CSF lysine.



2a. D2-Hydroxyglutaric aciduria. Early onset intractable epilepsy, severe learning difficulties, cardiomyopathy. Later onset of a variety of neurological problems (ascertainment bias?).

Screening tests:

urine D2-hydroxyglutaric acid.



3. 4-Hydroxybutyric aciduria. Non-progressive ataxia, hypotonia with depressed reflexes, less commonly hyperkinesis, seizures and supranuclear ophthalmoplegia, psychiatric.

Screening tests:

urine 4-hydroxybutyric acid.


fibroblast succinate semialdehyde dehydrogenase activity, DNA.

4. 3-Methylglutaconic aciduria. Some evidence to suspect that, excepting hydratase deficiency, these syndromes may be secondary to mitochondrial oxidative phosphorylation defects.

a. Type I. Delayed speech and macrocephaly.

Screening tests:

urine 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids.


fibroblast 3-methylglutaconylCoA hydratase activity.

b. Type II (Barth’s X-linked cardiomyopathy and neutropaenia syndrome). Myopathy

Screening tests:

cholesterol (low), neutrophil count, urine 3-methylglutaconic, 3-methylglutaric acids.


analysis of fibroblast cardiolipins, DNA (TAZ gene).

c. Type III (Costeff’s optic atrophy). Early onset optic atrophy, later chorea, paraparesis, ataxia and nystagmus.

Screening tests:

urine 3-methylglutaconic and 3-methylglutaric acids.


DNA (OPA3 gene).

d. Type IV (unclassified).

5. Glutaric aciduria type 1. One of the more common metabolic diseases causing neurological disease, often misdiagnosed as cerebral palsy. One-third have gradual onset dystonia in infancy, less commonly seizures and learning difficulties.

Screening tests:

urine glutaric, 3-hydroxyglutaric and glutaconic acids, glutarylcarnitine and glutarylglycine. Reduced plasma free carnitine, increased plasma glutarylcarnitine.


fibroblast or white cell glutaryl-CoA dehydrogenase activity, DNA.

6. Mevalonic aciduria. Progressive multisystem disorder. Learning difficulties, progressive ataxia, progressive myopathy and cardiomyopathy, failure to thrive, dysmorphism. Clinical course punctuated by recurrent crises of fever, rash, arthralgia and diarrhoea and vomiting.

Screening tests:

urine mevalonic acid, plasma mevalonic acid, creatine kinase (raised) and ubiquinone-10 (reduced).


fibroblast or white cell mevalonate kinase activity. DNA.

7. 2-Methyl-3-hydroxybutyryl-CoA Dehydrogenase Deficiency. Delayed psychomotor development, progressive neurodegeneration with hypotonia, choreoathetosis seizures.

Screening tests:

urine organic acids—increased 2-methyl-3 hydroxybutyrate, tiglyglycine.


fibroblast MHBD activity, DNA (HSD17B10 gene).


1. Pyruvate carboxylase deficiency. Type A, learning difficulties and lactic acidosis. Type B, neonatal lactic acidosis, seizures, hypotonia, stridor, dystonia, dementia, liver failure and early death (less than three months).

Screening tests:

CSF and blood lactate, plasma alanine. Plasma ammonia, citrulline and lysine increased in type B.


Fibroblast pyruvate carboxylase activity, DNA.

2. Pyruvate dehydrogenase deficiency. Variable clinical features. Brain malformation syndromes, through lethal neonatal lactic acidosis, Leigh’s disease to carbohydrate-induced episodic ataxia in males.

Screening tests:

CSF and blood lactate, plasma alanine.


Fibroblast pyruvate dehydrogenase activity, DNA.

3. Citric acid cycle defects. Variable from neonatal lactic acidosis to Leigh-like presentation.

a. Succinyl-CoA ligase (ADP-forming subunit) disorders.

α subunit (SUCLA1/SUCLAG1 gene): Fatal infantile lactic acidosis

β subunit (SUCLA2 gene): Irritability, inconsolable crying. Severely retarded psychomotor development, muscle hypotonia, impaired hearing. seizures, dystonia. MRI suggestive of Leigh syndrome (with high signal T2 intensity in the putamen bilaterally) and cortical atrophy.

Screening test:

mildly elevated urine methylmalonic acid

blood C4-dicarboxylic carnitine

variable lactic acidosis

mtDNA depletion in muscle biopsy.


DNA (SUCLA2 gene).

b. Fumarase deficiency. Cutaneous leimyomata in parents. Hypotonia, developmental delay, seizures, microcephaly.

Screening test:

Urine organic acids: fumarate, lactate, pyruvate.


Fibroblast fumarase activity, DNA (FH gene).

4. Respiratory chain defects. A complex group of disorders with both nuclear and mitochondrial inheritance. May have any, and combinations, of: dementia, seizures, spasticity, ataxia, dystonia, retinopathy, optic atrophy, ophthalmoplegia, deafness, peripheral neuropathy, extra-neural symptoms. “Any symptom, any organ, at any age”. Recognisable syndromes include Pearson’s marrow-pancreas syndrome, Leigh’s disease, Leber’s hereditary optic neuritis, Kearns-Sayre, MERRF, MELAS, NARP and MNGIE syndromes; considerable overlap occurs in childhood.

Screening tests:

evaluation for multi-organ involvement (e.g. blood count, echocardiogram, liver function tests, tubulopathy markers)

CSF and blood lactate and alanine, muscle histology and histochemistry

organic acid analysis.


muscle respiratory chain complex assays

mitochondrial and nuclear DNA.

a. Pearson’s syndrome. Sideroblastic anaemia and exocrine or endocrine pancreatic failure. Variable central nervous system involvement. Survivors may develop Kearns-Sayre syndrome later. Normally large deletion mitochondrial DNA.

b. Leigh’s disease. Originally, a post-mortem diagnosis where necrosis, gliosis and neovascularisation are seen in, predominantly, the basal ganglia and brainstem. In life, the disease may be suspected when there is the stuttering onset of brainstem or extrapyramidal symptoms, raised CSF lactate and neuroimaging findings of symmetrical basal ganglia or periaqueductal lesions. Usually nuclear DNA mutations, particularly SURF 1 mutations (when cytochrome oxidase activity is deficient in fibroblasts as well as in muscle). Some families have private mitochondrial DNA mutations.

c. Leber’s hereditary optic neuritis. Subacute onset optic neuritis in early adulthood with permanent visual impairment. Multiple or large scale deletions mitochondrial DNA.

d. Kearns-Sayre syndrome. Chronic progressive external ophthalmoplegia, cardiac conduction defects, short stature, myopathy and a variety of central nervous system defects. Most due to a large deletion or duplication mitochondrial DNA.

e. MERRF. Myoclonic epilepsy with ragged red fibres on muscle biopsy. Most due to a point mutation in mitochondrial DNA.

f. MELAS. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Most due to a point mutation in mitochondrial DNA.

g. MNGIE. Myoneural, gastrointestinal encephalopathy. Early-onset intestinal pseudo-obstruction followed by myopathy and encephalopathy in adulthood. Some cases are due to thymidine phosphorylase (TP) deficiency and have raised plasma and urine thymidine and reduced white cell TP activity.

h. Alper’s poliodystrophy. Developmental delay, sudden onset of seizures resistant to medication. progressive deterioration in liver function. Many of these cases have been shown to have mutations in the DNA polymerase -γ responsible for mitochondrial DNA replication.

5. Ubiquinone synthesis disorders.


Reduced activity of complexII+II in muscle biopsy, restored by addition of Coenzyme Q white cell ubiquinone.

a. Mevalonic aciduria. Vide supra.

b. Prenyl diphosphate synthase (subunit 1) deficiency. Early-onset deafness, developmental delay, obesity, livedo reticularis, mitral and aortic regurgitation, peripheral neuropathy.


DNA (PDSS1 gene)

c. Prenyl diphosphate synthase (subunit 2) deficiency. Leigh syndrome and nephrotic syndrome. Mutations in PDSS2 gene

d. Parahydroxybenzoate-polyprenyltransferase. Nephrotic syndrome, nystagmus, hypotonia, optic atrophy, psychomotor delay followed by regression, renal failure. Improvement in neurological symptoms with CoQ. Mutations in CoQ2 gene.

e. Ataxia, early-onset, with oculomotor apraxia and hypo-albuminemia. Secondary CoQ deficiency but may respond to treatment. Mutations in Aprataxin (APTX) gene.


A group of diseases with either absence of peroxisomes (at least 13 different types) or deficiencies of the oxidative or synthetic enzymes contained within.

1. Peroxisomal biogenesis disorders.

a. Zellweger’s syndrome. Craniofacial abnormalities (high forehead, upslanting palpebral fissures, hypoplastic supraorbital ridges & epicanthic folds), severe weakness and hypotonia, deafness, neonatal seizures, absent development, retinal pigmentation, optic nerve hypoplasia, cataract, corneal clouding, hepatomegaly, renal cysts. Neuroimaging may show polymicrogyria, pachygyria, neuronal migration defects and abnormal myelination. Reduced eletroretinogram.

Screening tests:

plasma very long chain fatty acids, red cell plasmalogens, plasma and urinary bile acids, X-ray patella/acetabulum (for stippling).


studies of peroxisomal function in fibroblasts


liver biopsy.

b. Neonatal adrenoleucodystrophy. Less severe Zellweger’s syndrome with mild adrenal hypofunction.

Screening tests:

As for Zellweger. No calcific stippling/renal cysts.

c. Infantile Refsum’s Disease. Soft dysmorphic features e.g. high forehead. Motor delay, deafness, pigmentary retinopathy, failure to thrive, liver dysfunction in infancy. May develop leukodystrophy later.

Screening tests:

plasma very long chain fatty acids, phytanate and pristanate, plasma bile acids.


studies of peroxisomal function in fibroblasts, DNA.

d. Childhood/Adult Onset Leukodystrophy. Deafness, developmental delay in infancy. Ataxia and progressive spastic quadraparesis in childhood.

Screening tests:

as for infantile Refsum’s.


as for infantile Refsum’s.

2. Disordered peroxisome enzyme import.

a. Rhizomelic chondrodysplasia punctata. Short proximal limbs, restriction of joint movements, microcephaly, developmental delay, ichthyosis, cataracts. Both phenotypic and genotypic variability.

Screening tests:

X-ray knees (metaphyseal splaying, calcific stippling), plasma phytanate, red cell plasmalogens.


platelet dihydroxyacetonephosphate acyltransferase

fibroblast studies of peroxisomal function


3. Defects of single peroxisomal enzymes.

a. Deficiencies of acyl-CoA oxidase/D-bifunctional protein (Pseudo-Zellweger syndrome/pseudo neonatal adrenoleukodystrophy). Clinical features similar to Zellweger/neonatal adrenoleukodystrophy.

Screening tests:

plasma very long chain fatty acids, pipecolic acid and bile acid intermediates increased but peroxisomes present on analysis of liver biopsy/fibroblasts. Plasmalogens normal.


fibroblast acyl-CoA oxidase and bifunctional enzyme activities, DNA.

b. X-linked Adrenoleucodystrophy. Severe childhood cerebral form dementia, seizures, motor disorder, adrenal dysfunction; neuroimaging shows a leucodystrophy. Adrenomyeloneuropathy form progressive paraparesis with sphincter involvement, adrenal dysfunction in 60%.

Screening tests:

plasma very long chain fatty acids, synacthen test.



c. Refsum’s disease. Tetrad of retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and increased CSF protein, may have neural deafness, anosmia and ichthyosis.

Screening tests:

plasma phytanic acid.


fibroblast phytanate α-oxidase, DNA.

d. Alpha-methyl-acyl-CoA Racemase Deficiency. Developmental delay in childhood, sensorimotor neuropathy in adult life.

Screening tests:

plasma very long chain fatty acids (normal), phytanate (mildly raised) and pristanate (more raised)plasma bile acids (elevated THCA, DHCA, C29-acid).


tests of peroxisomal function in fibroblasts, DNA.

e. Dihydroxyacetonephosphate acyltransferase deficiency (Glyceronephosphate O-acyl transferase deficiency). Identical presentation to rhizomelic chondrodysplasia punctata in infancy with severe developmental delay or mild developmental delay and chondrodysplasia punctata

f. Alkyl-dihydroxyacetone phosphate synthase deficiency. Identical presentation to rhizomelic chondrodysplasia punctata in infancy


1. Mucopolysaccharidoses.

All develop some features of Hurler syndrome, excrete glycosaminoglycans in urine, and may have white cell inclusions. The clinical features of Hurler’s disease include hepatosplenomegaly, characteristic bony features of brachymetacarpal dwarfism, stiff joints, coarse facies, mental deterioration and corneal cloudiness. Behaviour problems are frequent and early.

Screening tests

skeletal survey, vacuolated lymphocytes, urine glycosaminoglycans.


white cell enzyme (below)DNA.

a. MPS I H: Hurler disease (α-L-iduronidase deficiency).

b. MPS I S: Scheie disease (α-L-iduronidase deficiency). Normal central nervous system. Carpal tunnel syndrome.

c. MPS I H/S (α-L-iduronidase deficiency).

d. MPS II XR: Severe Hunter disease (Iduronate sulphate sulphatase deficiency). No corneal clouding.

e. MPS II XR: Mild Hunter disease (Iduronate sulphate sulphatase deficiency). Normal intelligence quotient.

f. MPS III A: Sanfilippo disease (Heparan N-sulphatase deficiency). Progressive dementia with only mild mucopolysaccharidosis features.

g. MPS III B: (N-acetyl-α-D-glucosaminidase deficiency).

h. MPS III C: (Acetyl-CoA:α-glucosaminide N-acetyl-transferase deficiency).

i. MPS III D: (Acetyl-CoA:α-glucosaminide 6-sulphatase deficiency).

j. MPS IV A: Morquio disease (Galactosamine 6-sulphate sulphatase deficiency). Skeletal and corneal involvement, normal inkuigence quotient but atlanto-axial dislocation. Some central nervous system, including meningeal, involvement.

k. MPS IV B (ß-galactosidase deficiency). No central nervous system involvement.

l. MPS VI: Severe Maroteaux-Lamy disease (Arylsulphatase B deficiency). Mainly skeletal with risk of cervical cord compression.

m. MPS VI: Intermediate Maroteaux-Lamy disease (Arylsulphatase B deficiency).

n. MPS VI: Mild Maroteaux-Lamy disease (Arylsulphatase B deficiency).

o. MPS VII: Sly disease (ß-glucuronidase deficiency). Very variable phenotype.

2. Pompé disease. Infantile progressive proximal muscle weakness, anterior horn cell disease, cardiomyopathy and early death. Later onset progressive proximal muscular weakness.

Screening tests:

vacuolated white cells, muscle histology.


white cell or muscle acid α-glucosidase, DNA.

3. Abnormal lysosomal enzyme phosphorylation. Prevents normal trafficking of enzymes to lysosomes. Hurler-like features with variable time of onset.

Screening tests:

vacuolated white cells, plasma lysosomal enzymes (10–20 fold increase in β-hexosaminidase, arylsulphatase A and iduronate sulphatase), urine glycosaminoglycans (normal).


fibroblast UDP-GlcNAc: lysosomal enzyme precursor GlcNAc1-phosphotransferase activity, DNA (GNPTAB gene).

a. I-cell disease (Mucolipidosis II).

b. Pseudo-Hurler syndrome (Mucolipidosis III).

4. Schindler disease. Severe: onset in second year hypotonia, dementia, upper and lower motor neuropathy, brainstem disease. Mild: mild learning difficulties, angiokeratoma.

Screening tests:

skin nerve electron microscopy (axonal spheroids).

white cell α-N-acetylgalactosaminidase.


white cell α-N-acetylgalactosaminidase, DNA.

5. Abnormal glycoprotein degradation.

a. α-Mannosidosis. Hurler features, dementia, angiokeratoma.

Screening tests:

vacuolated white cells, urinary oligosaccharides.


white cell α-mannosidase A & B.

b. β-Mannosidosis. Hurler features, deafness, variable neurological phenotype.

Screening tests:

vacuolated white cells, urine oligosaccharides.


white cell β-mannosidase.

c. Fucosidosis. Mild Hurler features, dementia and seizures, retinopathy.

Screening tests:

vacuolated white cells, urine oligosaccharides.


white cell α-fucosidase activity.

d. Sialic Acid Storage Disorders (Salla disease, Sialic acid lysosomal transport deficiency). Dementia, extrapyramidal and cerebellar signs. Infantile and later onset.

Screening tests:

vacuolated white cells, urine sialic acid.


white cell sialic acid.

e. Sialidosis (ML I). Infantile onset and juvenile onset. i. Normosomic. Cherry-red spot, action myoclonus, seizures, ataxia, normal facies and bones; burning feet; often no vacuolated lymphocytes. ii. Dysmorphic (may be associated with partial ß-galactosidase deficiency). Cherry-red spot, myoclonus, mild MR, coarse Hurler-like facies, bony changes, ataxia.

Screening tests:

vacuolated white cells and foam cells, urine oligosaccharides.


white cell neuraminidase activity.

f. Aspartylglucosaminuria. Mild Hurler features, learning difficulties.

Screening tests:

urine aspartylglucosamine, vacuolated white cells.


white cell aspartylglucosaminidase activity.

6. Wolman’s disease. Hepatosplenomegaly; severe gastrointestinal illness; neurological deterioration; calcification of adrenals.

Screening tests:

vacuolated lymphocytes and lipid inclusions in bone marrow cells.

abdominal ultrasound.


white cell acid lipase activity.

7. Farber’s disease. Infantile onset swollen, very painful joints, joint and tendon nodules; laryngeal involvement; anterior horn cell disease, myopathy, foveal grey spot.


white cell ceramidase activity.

8. Niemann-Pick disease A & B. A: hepatosplenomegaly, hypotonia, dementia, foveal grey or cherry red spot. B: hepatosplenomegaly with no central nervous system involvement or mild ataxia alone.

Screening tests:

vacuolated white cells, bone marrow foamy histiocytes.


white cell acid sphingomyelinase, DNA.

9. Niemann-Pick disease C. Progressive vertical supranuclear ophthalmoplegia, ataxia, dystonia and dementia. Variable early hepatosplenomegaly and failure to thrive. Neonatal hepatitis in 60%.

Screening tests:

plasma chitotriosidase, foam cells in marrow, white cell sphingomyelinase activity (normal).


fibroblast lysosomal cholesterol accumulation, DNA.

10. Gaucher’s disease.

a. Type 1. Chronic non-neuronopathic form. Can present from infancy to adult life; early splenomegaly; hypersplenism and bone pain; late neurological problems in some.

b. Type 2. Acute neuronopathic form. First year; hepatosplenomegaly; trismus, strabismus, retroflexion of head, progressive spasticity and dementia.

c. Type 3. Subacute neuronopathic form. Half have onset in first 10 years, dementia, spasticity, ataxia, movement disorder, supranuclear horizontal ophthalmoplegia; splenomegaly.

Screening tests:

raised plasma chitotriosidase, non-tartrate inhibitable acid phosphatase (types 1 and 2), bone marrow for Gaucher cells.


white cell glucocerebrosidase activity.

11. Krabbe’s disease (globoid cell leukodystrophy).

a. Infantile. Early irritability, opisthotonus, dementia, peripheral neuropathy, optic atrophy, pyramidal signs, raised CSF protein.

b. Juvenile. Cortical blindness; spasticity or extrapyramidal signs.

Screening tests:



white cell galactocerebrosidase activity.

12. Metachromatic leukodystrophy (Sulphatide lipidosis). Variable time of onset and features; 5 subtypes recognized although only 3 given for simplicity. Occasional rare case of metachromatic leukodystrophy without Arylsulfatase A deficiency. Pseudodeficiency gene is common.

a. Infantile. Ataxia, dementia, pyramidal tract signs and demyelinating peripheral neuropathy.

b. Juvenile. 3–20 years; psychosis, dementia, pyramidal tract signs and dystonia.

c. Adult. Like juvenile, or pure dystonia.

Screening tests:

neuroimaging, urinary sulphatide excretion, metachromatic inclusions in fresh urinary sediment.


white cell arylsulphatase A activity, pseudodeficiency gene, fibroblast sulphatide load, sphingolipid activating protein.

13. Fabry’s disease. X-linked recessive. Angiokeratoma corporis diffusum; limb pains; retinopathy, variable neurology, stroke; severe renal disease, ischaemic heart disease.


white cell α-galactosidase A activity.

14. GM1 gangliosidosis

a. GM1 type I. Hepatosplenomegaly, Hurler features, dementia, cherry red spot.

Screening tests:

vacuolated white cells. Bone marrow foam cells.


white cell ß-galactosidase activity.

b. GM1 type II—Morquio B. Later onset; mild bony involvement, ataxia, dementia; spasticity.

Screening tests:

Vacuolated white cells. Bone marrow foam cells.


white cell ß-galactosidase activity.

15. GM2 gangliosidosis.

a. GM2 type I—Tay-Sachs disease.

i. Early onset. Hyperacusis; visual failure, cherry red spot; dementia; hypotonia and pyramidal tract signs.

ii. Juvenile. Dystonic stammer, ataxia, extrapyramidal disease, anterior horn cell disease, dementia.


white cell hexosaminidase A activity.

b. Sandhoff disease. Clinically like Tay-Sachs disease.


white cell hexosaminidase A & B activity.

16. Batten’s disease (ceroid lipofuscinosis).

a. Infantile (Santavuori). Early onset (8 to 12 months); knitting hyperkinesia, extrapyramidal and pyramidal signs, dementia, epilepsy, retinal degeneration, progressive reduction in EEG activity.

Screening tests:

EEG and electroretinogram/visual evoked potentials.


white cell electron microscopy, neural histopathology on rectal (full thickness) or skin biopsy

Fibroblast or white cell palmitoyl-protein thioesterase activity. DNA.

b. Late infantile (Jansky-Bielschowsky). Myoclonic epilepsy and other seizures; ataxia; dementia; visual failure is a late feature.

Screening tests:

loss of electroretinogram with large visual evoked

potentials to slow rates of flicker.


neural histopathology on rectal (full thickness) biopsy

White cell tripeptidyl peptidase I activity (not the variant forms) DNA (not the variant forms).

c. Juvenile (Spielmeyer-Vogt). Rapidly progressive retinitis pigmentosa, then disintegrative psychosis and dementia; seizures; late pyramidal and extrapyramidal movement disorder.

Screening tests:

vacuolated white cells. Electroretinogram/visual

evoked potentials.


neural histopathology on rectal (full thickness) biopsy, DNA.

d. Adult (Kufs). May exhibit seizures, psychiatric and extrapyramidal features.


neural histopathology on rectal (full thickness) biopsy.


1. Defects of N-Glycosylation of Proteins.

Syndromes defined by the isoelectric focusing pattern of transferrin.

Type 1

Screening tests:

Transferrrin isoelectric focussing (type I pattern)

Plasma albumin, thyroid binding globulin, haptoglobin, specific coagulation factors, proteins C and S, antithrombin III (reduced). Plasma aspartyl-glucosaminidase (increased).

Differential diagnosis:

Specific enzyme assays; phosphomannomutase activity (type 1a),

Fibroblast lipid-linked oligosaccharide (LLO) profiles, DNA.

i. Type 1a. Infantile onset: learning difficulties, squint and supranuclear ophthalmoplegia, hypotonia; abnormal fat distribution, inverted nipples; hepatomegaly, cardiomyopathy, pericardial effusions; cerebellar hypoplasia. Later onset: learning difficulties, ataxia, peripheral neuropathy, strokes, epilepsy; thoracic deformity, hypogonadism; cerebellar hypoplasia.

ii. Type 1c. Axial hypotonia, developmental delay, areflexia, strabismus, seizures, ataxia

iii. Type 1d. Dysmorphic features incl. arthrogryposis. Microcephaly, severe, developmental delay, seizures (with hypsarrhytmia), hypertonia, cerebral atrophy, severe visual impairment with reduced electroretinogram.

iv. Type 1e. Microcephaly, dysmorphia, severe global developmental delay, hypotonia, no visual fixation, seizures, hepatosplenomegaly.

v. Type 1f. Severe encephalopathy with scaly erythematous skin rash.

vi. Type 1g. Facial dysmorphia, hypotonia, developmental delay, progressive microcephaly.

vii. Type 1h. Dysmorphia ± macrocephaly. Diarrhoea, liver and renal dysfunction, oedema, ascites, seizures, progressive hypotonia, head growth deceleration.

viii. Type 1i. Infantile spasms with hypsarrhythmia. dysmyelination on MRI, severe developmental delay, brisk reflexes.

ix. Type 1j. Microcephaly, dysmorphia, hypotonia, developmental delay, infantile spasms, intractable epilepsy.

x. Type 1k. Recurrent refractory seizures, rapidly developing microcephaly, coagulopathy. Early death.

xi. Type 1l. Macrocephaly, central hypotonia, developmental delay seizures. Delayed myelination. Hepatomegaly

xii. Type 1m. Seizures, hypotonia, progressive tetraplegia, acquired microcephaly, hypoglycaemia, ichthyosis, dilated cardiomyopathy.

Type 2. Severe learning difficulties and hypotonia.

Screening tests:

Transferrin isoelectric focussing (type 2 pattern)

Specific coagulation factors.

Urine oligosaccharides.

Differential diag:

Glycan analysis

Test for combined N-glycosylation and O-glycosylation defect (apolipoprotein C isoelectric focussing).



i. Type 2a. Developmental delay, epilepsy, stereotyped behaviour, dysmorphia, raised AST, normal ALT

ii. Type 2b. Dysmorphia, hypotonia, epilepsy. Abnormal urinary oligosaccharide, transferrin ief normal

iii. Type 2c. Craniofacial dysmorphia, severe psychomotor and growth retardation, recurrent bacterial infections, leucocytosis, leukocyte adhesion defect, transferrin ief normal

iv. Type 2d. Developmental delay, Dandy Walker malformation and myopathy

v. Type 2e (COG7 deficiency)*. Perinatal asphyxia, dysmorphia, loose, wrinkled skin, hypotonia, hepatosplenomegaly, jaundice, severe epilepsy.

vi. Type 2g (COG1 deficiency)*. Hypotonia, mild developmental delay, progressive microcephaly, mild hepatosplenomegaly

vii. Type 2h (COG8 deficiency)*. Hypotonia, developmental delay, axonal neuropathy, acute encephalopathy with loss of skills. Ataxia. Cerebellar and brain stem atrophy.

* Combined defect of N-glycosylation and O-glycosylation of proteins

2. Defects of O-Glycosylation of Proteins: Congenital muscular dystrophies with neuronal migration defects in the brain and ocular abnormalities.


Abnormalities of O-glycosylation detected on muscle biopsy (α-dystroglycan staining).

Walker-Warburg syndrome: Severe muscle weakness, absent psychomotor development, ocular abnormalities, death in infancy. Cobblestone lissencephaly, agenesis of corpus callosum, cerebellar hypoplasia, hydrocephalus.


DNA (POMT1, POMT2, fukutin, and fukutin related protein genes).

Limb Girdle Muscular Dystrophy: Can be caused by milder POMT1 mutations

Muscle-eye-brain disease: Severe muscle weakness, psychomotor retardation, epilepsy, ocular abnormalities


DNA (POMGnT1 gene).

3. Defects of Lipid Glycosylation:

Amish Infantile Onset Epilepsy Syndrome. Irritability, poor feeding, seizures, developmental stagnation, regression. MRI brain showing diffuse atrophy


Plasma glycosphingolipid analysis.


DNA (SIAT9 [=GM3 synthase gene]).

Glycosylphosphatidylinositol Deficiency. Portal and hepatic vein thromboses, recurrent absence seizures.


Thromophilia screen, positive HAMM test.


DNA (PIGM gene).


1. Purine defects.

a. Lesch-Nyhan syndrome. X-linked. Learning difficulties, hypotonia and chorea in the 1st year, self-mutilation, dystonia and spasticity at some stage in childhood.

Screening tests:

plasma urate, urine urate to creatinine ratio (both increased; urine test more sensitive because of high renal urate clearance).


red cell hypoxanthine-guanine phosphoribosyl-transferase activity, DNA.

b. Phosphoribosylpyrophosphate synthetase superactivity. X-linked. Variable neurology. Learning difficulties, deafness.

Screening tests:

plasma urate, urine urate to creatinine ratio (both increased; urine test more sensitive because of high renal urate clearance).


red cell phosphoribosylpyrophosphate synthetase activity.

c. Adenylosuccinase deficiency. Severe learning difficulties with autism, later epilepsy. Milder variants occur related to degree enzyme deficiency.

Screening tests:

plasma succinyladenosine and succinylaminoimidazole carboxamide riboside.


red cell adenylosuccinase activity, DNA.

d. Adenosine deaminase deficiency. Combined immunodeficiency; spasticity and ataxia.

Screening tests:

white cell count, serum immunoglobulins. Plasma adenosine and deoxyadenosine (both increased), red cell deoxyadenosine triphosphate (increased) and S-adenosylhomocysteine hydrolase activity (decreased).


red cell ADA activity


e. Purine nucleoside phosphorylase deficiency. Combined (mostly cellular) immunodeficiency; spasticity (diplegia), learning difficulties, ataxia and tremor.

Screening tests:

white cell count, serum immunoglobulins. Plasma urate and urine urate to creatinine ratio (both decreased).


red cell PNP activity.


2. Pyrimidine defects.

a. Dihydropyrimidine dehydrogenase deficiency. No consistent neurological consequences. Epilepsy, learning difficulties and microcephaly.

Screening tests:

urine thymine, 5-hydroxymethyluracil and uracil (increased).


fibroblast or white cell dihydropyrimidine dehydrogenase activity.

b. Dihydropyrimidinase deficiency. No consistent neurological consequences. Epilepsy, learning difficulties and microcephaly.

Screening tests:

urine dihydrothymine, dihydrouracil (increased) and 5-hydroxymethyluracil (not detected).


liver dihydropyrimidinase activity.

c. Ureidopropionase (β-alanine synthase) deficiency. Learning difficulties, hypotonia and dystonia.

Screening tests:

urine dihydrothymine, dihydrouracil, ureidopropionate, ureidoisobutyrate (increased) and 5-hydroxymethyluracil (not detected).


liver ureidopropionase activity.


d. Hyper-ß-alaninaemia. Seizures and dementia.

Screening tests:

plasma and urine amino acids.


liver β-alanine-α-ketoglutarate aminotransferase.


1. Copper metabolism.

a. Wilson’s disease. Onset over 4 years, usually 2nd/3rd decade. Liver disease; progressive dystonia and other involuntary movements, Kayser Fleischer rings.

Screening tests:

plasma copper (total) and caeruloplasmin (reduced), urine copper (increased), penicillamine load.


liver copper (increased)


b. Menke’s syndrome. X-linked. Steely or kinky hair; hypothermia; osteoporosis with flared epiphyses, fractures; haemorrhages; seizures, dementia, early death.

Screening tests:

plasma copper and caeruloplasmin (reduced).


fibroblast copper uptake


Milder form: Occipital horn syndrome

2. Molybdenum metabolism.

Molybdenum cofactor deficiency. Combined sulphite oxidase and xanthine oxidase deficiency, symptoms caused by sulphite oxidase deficiency which may exist as an isolated defect. Neonatal-onset feeding difficulties and seizures, dementia, lens dislocation, pyramidal tract signs.

Screening tests:

plasma urate (reduced), urine sulphite.


fibroblast sulphite oxidase activity.

DNA (3 genes).

3. Magnesium Transport.

Primary hypomagnesaemia (with secondary hypocalcaemia). Defect of intestinal magnesium uptake. Onset before 4 months, irritability, feeding difficulties, tetany, seizures.

Screening tests:

plasma magnesium and calcium (reduced),

urine magnesium (reduced).


DNA (TRPM6 gene).

Renal hypomagnesaemia. Defect affecting renal transport of magnesium. Convulsions and tetany in infancy

Screening tests:

plasma magnesium and calcium (reduced)

urine magnesium (increased).


DNA (paracellin-1 [=CLDN16] gene)

dominant form FXYD2 gene.

Gitelman syndrome. Muscle weakness, cramps, tetany, paraethesiae, convulsions. Polyuria, failure to thrive, alkalosis

Screening tests:

plasma magnesium and potassium (reduced)

urine magnesium, potassium (increased).


DNA (SLC12A3 gene).


1. Tetrahydrofolate (Vitamin B9) metabolism.

a. Congenital folate malabsorption. Infantile onset severe megaloblastic anaemia, learning difficulties, later dementia, pyramidal and extrapyramidal motor disorder, intracranial calcification, demyelination.

Screening tests:

plasma total homocysteine. Serum, red cell and CSF 5-methyltetrahydrofolate, oral folate load.

small bowel folate transporter activity.



b. 5,10-Methylenetetrahydrofolate reductase deficiency. Variable severity of symptoms from severely affected infants to asymptomatic adults. Dementia, motor disorders, demyelination, seizures and psychiatric; vascular; no megaloblastic anaemia.

Screening tests:

plasma total homocysteine. Serum, red cell and CSF 5-methyltetrahydrofolate.


fibroblast 5,10-methylenetetrahydrofolate reductase



c. Forminoglutamic aciduria. Variable neurological picture and uncertain whether causes disease. i. Type 1: learning difficulties and hypotonia. ii. Type 2: mild speech delay.

Screening tests:

serum and red cell folate (raised), histidine load.

2. Cobalamin (vitamin B12) metabolism. Very variable symptoms depending upon site and severity of the metabolic block.

a. Defects in absorption and transport.

i. Intrinsic factor deficiency. Onset 2nd to 5th year of life, failure to thrive, irritability, muscular weakness, drowsiness, megaloblastic anaemia.

ii. Immerslund-Gräsbeck syndrome. Onset after 2nd year, gastrointestinal symptoms and developmental delay, proteinuria.

iii. Transcobalamin 2 deficiency. Onset 1st year, failure to thrive, weakness, megaloblastic anaemia, developmental stagnation.

iv. R-binder deficiency. Of uncertain disease-causing status, demyelination in adulthood.

Screening tests:

blood count, serum cobalamin, plasma total homocysteine, urinary methylmalonate, double isotope Schilling test.


serum transcobalamin 2 activity, fibroblast transcobalamin 2 production.

b. Defects in intracellular processing.

i. MethylmalonylCoA mutase defects alone (cblA and cblB). Neonatal or late onset forms. Failure to thrive, developmental delay, acute encephalopathy.

ii. Methionine synthase defects alone (cblE and cblG). Onset usually in 1st year, failure to thrive, megaloblastic anaemia, learning difficulties, seizures.

iii. Combined defects (cblC, cblD and cblF). Infantile and late-onset forms. Infantile: microcephaly, failure to thrive, megaloblastic anaemia, learning difficulties, seizures, retinopathy, demyelination, severe systemic vasculitis. Late onset: anorexia, irritability, dementia, myelopathy, psychiatric.

Screening tests:

blood count, serum cobalamin, plasma total homocysteine, urinary methylmalonate.


fibroblast complementation studies.

3. Biotin (vitamin B7) metabolism.

a. Biotinidase deficiency. Seizures, ataxia, hyperventilation or stridor, dementia, deafness, optic atrophy, rash and alopecia.

Screening tests:

urine lactate, methylcitrate, propionylglycine, 3-hydroxypropionate, 3-methylcrotonylglycine, 3-hydroxyisovalerate may only be apparent late in the course of the disorder. Plasma lactate and alanine. CSF lactate.


plasma biotinidase activity.

b. Holocarboxylase synthetase deficiency. Neonatal onset, apnoea, hypotonia, seizures, coma.

Screening tests:

blood acidosis and hyperammonaemia, urine lactate, methylcitrate, propionylglycine, 3-hydroxypropionate, 3-methylcrotonylglycine, 3-hydroxyisovalerate and tiglylglycine.


fibroblast carboxylase activities.

c. Biotin transporter defect.

4. Vitamin B6 metabolism.

Vide infra under epileptic encephalopathies.

a. Pyridoxine dependency. Antiquitin deficiency, actually a disorder of valine catabolism. Intractable neonatal seizures, CNS malformations. Untreated can be fatal or associated with severe developmental delay. Milder variants with later onset of treatable seizures may be more common.

b. Pyridoxal phosphate dependency. Pyridox(am)ine phosphate oxidase deficiency. Progressive neurological dysfunction can occur in untreated patients. Variable neurological problems in treated patients including dystonia and breakthrough seizures.

5. Nicotinamide (vitamin B3) deficiency. No enzymatic diagnoses made, but patients present with a photosensitive rash (pellagra-like), learning difficulties and ataxia.

Screening tests:

urine kynurenine pathway metabolites.

6. Thiamine (vitamin B1) metabolism.

Amish lethal microcephaly (MCPHA). Defect of mitochondrial transport of thiamine pyrophosphate. Severe microcephaly, death before 6 mo.

Screening tests:

Urine organic acids (2-oxoglutarate).



7. Pantothenate (vitamin B5) Metabolism.

Hallervorden-Spatz disease. Pantothenate kinase deficiency. Progressive dystonia, retinopathy and dementia in some.

Screening tests:

neuroimaging, electroretinogram, acanthocytes, lipoprotein electrophoresis.


DNA (PANK2 gene).

8. Riboflavin (vitamin B2 metabolism).

Vide infra—glutaric aciduria type II. Severe form is associated with brain malformation—warty cerebral dysplasia

9. Isolated Vitamin E Deficiency.

Neurologic abnormalities similar to those of vitamin E deficiency (retinopathy, neuropathy, ataxia) but no evidence of fat malabsorption.

(contrast abetalipoproteinaemia)

Screening tests:

Low vitamin E.


DNA (TTPA gene).


1. Abetalipoproteinaemia. Malabsorption; vitamin E deficiency causing retinopathy; peripheral neuropathy; ataxia.

Screening tests:

acanthocytes on wet blood film, decreased serum cholesterol, triglycerides and Vitamin E.


absent apolipoprotein B


2. Tangier disease. Tonsil abnormality; corneal opacification; hepatosplenomegaly; mononeuritis multiplex in adults.

Screening tests:

decreased serum cholesterol, normal or raised triglycerides.


absent apolipoprotein A-I.


1. Cerebrotendinous xanthomatosis (CTX): Neonatal hepatitis. Developmental delay. Late childhood/adult onset dementia/motor dysfunction/psychiatric presentation, tendon xanthomata, atherosclerosis.

Screening tests:

urine bile alcohols,

plasma bile acid precursors,

plasma cholestanol.



2. Peroxisomal disorders: (vide supra)

3. Disorders of cholesterol synthesis (pathway from lanosterol to cholesterol): Multiple malformations, dysmorphic features, developmental delay, behaviour problems.

Screening tests:

plasma sterol profile.

a. Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency). Variable severity. Microcephaly, ptosis, anteverted nares, micrognathia, 2-3 syndactyly of toes, hypospadias. Developmental delay, hypotonia in infancy, hypertonia in childhood, autistic features, abnormal sleep pattern, self injury, aggression.

Screening tests::

increased 7-dehydrocholesterol and 8-dehydrocholesterol.


DNA (DHCR7 gene).

b. Conradi-Hunermann syndrome Δ8-Δ7sterol isomerase deficiency. X-linked dominant. Girls: Ichthyosis, alopecia, cataracts, asymmetric limb shortening, chondrodysplasia punctata. May have mild-moderate mental retardation, Dandy-Walker malformation, ventriculomegaly. Boys (mosaics can survive) show severe developmental delay

Screening tests:

increased 8-dehydrocholesterol and 8(9)-cholestenol.


DNA (EBP gene).

c. Desmosterolosis. Lethal form with multiple formations. Milder form with multiple congenital anomalies, microcephaly, and profound developmental delay.

Screening tests:

increased tissue/plasma desmosterol.


DNA (DHCR24 gene).

d. Lathosterolosis. Sterol C5-desaturase deficiency. Microcephaly, dysmorphia including anteverted nares, poly/syndactyly, intrahepatic cholestasis. Hypotonia, developmental delay.

Screening tests:

increased plasma lathosterol


fibroblast 3-beta-hydroxysteroid-delta-5-desaturase

DNA (SC5DL gene)

e. CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. X-linked dominant. NSDHL mutations. Unilateral hypoplasia can include cranial nerves, pons, medulla and spinal cord.


1. Tyrosine hydroxylase deficiency. Infantile parkinsonism/Segawa syndrome (L-Dopa responsive)

Screening tests:

CSF neurotransmitter amine metabolites

Low HVA normal 5HIAA and pterins

Serum prolactin (raised).



2. Aromatic amino acid decarboxylase deficiency. Trunkal hypotonia, hypokinesia, oculogyric crises, ptosis

Screening tests:

CSF neurotransmitter amine metabolites

Low HVA and 5HIAA, raised 3-methoxytyrosine

Serum prolactin (raised).


Plasma AADC activity


3. Succinic semialdehyde dehydrogenase deficiency (4-Hydroxybutyric aciduria) Vide supra (organic acid disorders)


1. Guanidinoacetate methyltransferase (GAMT) deficiency: Hypotonia, developmental stagnation, intractable seizures, dystonia. Low plasma creatinine, increased urine guanidinoacetate, absent creatine plus creatine phosphate peak on proton magnetic resonance spectroscopy. White cell guanidinoacetate methyltransferase activity and DNA.

2. Arginine: glycine amidinotransferase (AGAT) deficiency: Hypotonia, developmental delay, progressive extrapyramidal movement disorder, ataxia, intractable seizures.

3. Creatine transporter deficiency: X-linked. Developmental delay, seizures.


1. Lysosomal transport.

a. Sialic acid storage disorders.

i. Infantile free sialic acid storage disease. Severe Hurler-like phenotype.

ii. Salla disease. Infantile onset learning difficulties and ataxia.

Screening tests:

vacuolated white cells, urine sialic acid.


white cell sialic acid.

b. Cystinosis. Renal failure mid-childhood. Surviving adults may develop myopathy, anterior horn cell disease and central demyelination.

Screening tests:

corneal crystals on slit-lamp examination.


increased fibroblast or polymorphonucleocyte cystine


2. Lowe’s syndrome. X-linked. Prenatal cataract and other ocular abnormalities, hypotonia with absent tendon reflexes, learning difficulties.

Screening tests:

renal Fanconi syndrome (bicarbonaturia, renal tubular acidosis, aminoaciduria, phosphaturia, tubular proteinuria, impaired urine concentration).



3. Lysinuric protein intolerance. Can have encephalopathic episodes (vide infra) but protein avoidance more usual; hepatosplenomegaly; sparse hair; hypotonia, psychiatric disturbance.

Screening tests:

decreased plasma lysine, ornithine and arginine; increased plasma ammonia, glutamate, alanine, serine, proline, citrulline and glycine. Massive urine lysine excretion.


fibroblast cationic amino acid transporter activity


4. Hartnup disease. Around 10% develop intermittent symptoms of pellagra (photosensitive rash, ataxia).

Screening tests:

neutral aminoaciduria, but not proline, cystine, lysine and ornithine.


1. Triose phosphate isomerase deficiency. Haemolytic anaemia; cardiomyopathy and early death; jerky dystonia, pyramidal tract, anterior horn cell disease.


red cell triose phosphate isomerase activity.

2. Phosphoglycerate kinase deficiency. X-linked. Haemolytic anaemia; variable neurology—learning difficulties, dystonia, psychiatric.


red cell phosphoglycerate kinase activity.


1. Ribose-5-phosphate isomerase deficiency. Developmental delay in infancy, epilepsy, regression in childhood with cerebellar ataxia, spasticity, optic atrophy, neuropathy.

Screening tests:

urine polyols

pentose phosphate pathway intermediates in blood spots

proton MR spectroscopy of brain.


fibroblast ribose-5-phosphate isomerase activity



1. DNA excision repair defects.

Screening tests:

fibroblast chromosome ultraviolet sensitivity.


DNA (in some).

a. Cockayne syndrome. Sun sensitivity, short stature, dysmorphism; microcephaly, demyelination, intracerebral calcification, retinitis pigmentosa, dementia, neuropathy. Milder variant recognised, three complementation groups.

b. Xeroderma pigmentosa. Sun sensitivity and neoplasia; dementia, deafness, ataxia, neuropathy. Seven complementation groups.

c. Trichothiodystrophy. Sulphur-deficient, brittle hair, short stature, learning difficulties, late movement disorder.

2. Ataxia telangiectasia. Ataxia, dystonia, supranuclear ophthalmoplegia; immunodeficiency; neoplasia.

Screening tests:

serum α-fetoprotein

immunoglobulins and IgG subclasses.


white cell chromosome radiation sensitivity



Diagnosis requires expert neuroradiology and magnetic resonance imaging in addition to biochemical and other investigations.

1. Leukodystrophies.

a. Metachromatic leukodystrophy. Vide supra.

b. Krabbe leukodystrophy. Vide supra.

c. Adrenoleukodystrophy. Vide supra.

d. Canavan’s disease. Vide supra.

e. Alexander’s disease. Failure to thrive; dementia, leukodystrophy, megalencephaly.

f. Aicardi-Goutiere syndrome. Microcephaly, intracranial calcification, demyelination, CSF pleocytosis, raised CSF α-interferon. DNA.

g. Cockayne syndrome. Vide supra.

h. Megalencephalic cystic leukoencephalopathy (van der Knaap leukodystrophy). Macrocephaly in 1st year, motor disorder by 5th year, seizures and dementia in teens.

i. Cerebellar ataxia central hypomyelination/vanishing white matter disease. Encephalopathy followed by spastic/ataxic motor disorder, late bulbar involvement and optic atrophy.

j. Peroxisomal leukodystrophies. Vide supra

2. Brain dysmyelinating disorders. Excluding disorders affecting amino acids/B12/folate)

a. Pelizaeus-Merzbacher disease. X-linked. Onset in 1st year nystagmus, spastic paraparesis, movement disorder.

b. Merosin-deficient congenital muscular dystrophy. Weakness and contractures at birth. No central nervous system symptoms.


1. Rett syndrome. Females. From 6 months—2 years; hand stereotypes and loss of hand function, dementia, acquired microcephaly, seizures; later pyramidal tract signs and neuropathy. MECP2 mutations. Can also occur with STK9 (CDKL5) mutations.

2. Progressive neuronal degeneration of childhood (Alpers’ disease). Early onset dementia, myoclonus and seizures; rapid deterioration, late liver involvement. Brain or liver biopsy may show characteristic changes. Some cases due to mitochondrial respiratory chain defects (vide supra). Particularly mutations in the mitochondrial DNA polymerase γ gene (POLG)

3. Infantile neuroaxonal dystrophy (Seitelberger’s disease). Onset at end of 1st year; profound hypotonia, dementia, pyramidal signs, anterior horn cell disease, optic atrophy and squint. Atypical cases include a juvenile variant with progressive myoclonic epilepsy and sometimes retinopathy. Axonal spheroids found on electron microscopy of brain, nerve, conjunctival or skin biopsy. Schindler’s disease is a variant (vide supra).

4. Unvericht-Lundborg disease. Onset 8 to 13 years; progressive myoclonic epilepsy, action myoclonus, dementia.

5. Lafora-Body disease. Onset 11 to 18 years; myoclonic seizures, focal occipital seizures, dementia. Lafora bodies in apocrine sweat glands.

6. Idiopathic torsion dystonias. Childhood onset progressive dystonia, usually sparing orobulbar musculature. DYT 1 gene accounts for some dominantly inherited forms, recessive inheritance also occurs.

7. Hereditary spastic paraplegias. Childhood onset progressive spastic paraparesis. Usually dominantly inherited with variable penetrance.

8. Friedreich’s ataxia. Late childhood onset ataxia, axonal neuropathy and cardiomyopathy. DNA.

9. Sjögren-Larssen syndrome. Ichthyosis at birth; spastic diplegia and mental retardation developing before 3 years; macular changes. Skin alcohol dehydrogenase activity reduced. DNA.

10. Chediak-Higashi syndrome. Partial albinism, hepatosplenomegaly, lymphadenopathy; learning difficulties, cerebellar degeneration, nystagmus, peripheral neuropathy.

Table 10.2 Neurometabolic disorders with episodes of acute metabolic encephalopathy

  1. I. Carbohydrate disorders (p. 253)

  2. II. Amino acid disorders (p. 253)

  3. III. Organic acid disorders (p. 254)

  4. IV. Mitochondrial fat oxidation defects (p. 254)

  5. V. Epileptic encephalopathies (p. 255)

  6. VI. Mitochondrial respiratory chain/PDH/PC disorders (p. 256)

  7. VII. Peroxisomal disorders (p. 256)

  8. VIII. Congenital disorders of Glycosylation (p. 256)

  9. IX. Others (p. 256)


1. Neuroglycopenia. Episodes of impaired supply of glucose to the brain cause acute encephalopathy and can cause permanent damage

a. Hypoglycaemia. Comprehensive list of causes not possible here but includes hyperinsulinism, disorders of gluconeogenesis (e.g. fructose-1,6-bisphosphatase deficiency), glycogen storage diseases, disorders of fatty acid oxidation (vide infra), ketone body synthesis and utilisation, ketotic hypoglycaemia etc.

b. Glut1 glucose transporter deficiency. Early onset epilepsy, motor delay with hypotonia/ataxia/dystonia, speech delay. CSF glucose 1.4–2.0 mM when blood sugar normal. Confirmation from DNA analysis.

2. Galactosaemia. Neonatal liver failure with hepatomegaly; cerebral oedema; cataracts. Later dyspraxia, variable learning difficulties, later still dystonia.

Screening tests:

urine galactose, red cell galactose-1-phosphate.


red cell galactose-1-phosphate-uridyl transferase or UDP-glucose epimerase activity.

3. Hereditary fructose intolerance. Drowsiness, apathy; liver disease.

Liver failure with encephalopathy if large amounts of fructose given.


liver fructose-1-phosphate-aldolase deficiency.



1. Maple Syrup Urine Disease. Accumulating keto-acids have an aroma of maple syrup or fenugreek seeds.

a. Classical. Acute new-born presentation with severe ketoacidosis.

b. Intermittent. Ketoacidosis; ataxia, lethargy, slurred speech during attack; neurological handicap varies.

c. Intermediate. Learning difficulties without ketoacidosis.

d. Thiamine responsive. Learning difficulties.

e. E3 deficient form. Progressive encephalopathy in first year.

Screening tests:

raised plasma branched chain amino acids (leucine, isoleucine and valine)branched chain 2-oxoacids e.g. 2-oxo-isocaproic acid in urine


fibroblast leucine oxidation or branched chain keto-acid decarboxylase activity.

2. Non-ketotic hyperglycinaemia. Neonatal encephalopathy with apnoea and myoclonus. Later intractable seizures, pyramidal and extrapyramidal movement disorder; developmental stagnation.

Screening tests:

raised plasma, urine, and CSF glycine and raised CSF/plasma glycine. (>0.09).


liver glycine cleavage enzyme activityDNA.

3. Urea Cycle Disorders. Ataxia, lethargy and coma, especially during decompensation, seizures. May present as Reye-like illness, stroke and intermittent ataxia.

Screening tests:

plasma ammonia and amino acids,urine aminoacids, orotic acid.


enzyme activity (red cells/fibroblasts/liver)DNA.

a. N-acetylglutamate synthetase deficiency. Very severe.

b. Carbamoylphosphate synthetase deficiency. Suspected by normal citrulline, arginosuccinic acid and arginine. No orotic acid in urine.

c. Ornithine carbamoyl transferase deficiency. X-linked, with manifesting carriers; liver disease. Orotic aciduria, low plasma arginine.

d. Arginosuccinate synthetase deficiency (citrullinaemia). Can be mild.Citrulline high, orotic aciduria, no arginosuccinic acid

e. Arginosuccinate lyase (argininosuccinic aciduria). Metabolic acidosis, hepatomegaly; trichorrhexis nodosa and ataxia. Arginosuccinate in urine. Orotic aciduria.

f. Arginase deficiency (argininaemia). Vide supra.

4. Other Amino Acid Disorders with Encephalopathy and Hyperammonaemia

a. Hyperornithinaemia, Hyperammonaemia, Homocitrullinaemia. Ataxia, growth failure, learning difficulties.

b. Ornithine aminotransferase deficiency. Hyperammonaemia with low plasma ornithine in infancy. Progressive choroidoretinitis (gyrate atrophy) etc. with high plasma ornithine in childhood/adulthood (Vide supra Table 10.1 I 3).

c. Citrullinaemia type II. Neonatal cholestatic liver disease. Episodes of encephalopathy starting in 2nd/3rd decade. Symptoms include enuresis, delayed menarche, insomnia, sleep reversal, nocturnal sweats and terrors, recurrent vomiting (especially at night), diarrhea, tremors, episodes of confusion after meals, lethargy, convulsions, delusions, hallucinations, and brief episodes of coma. Avoidance of foods high in carbohydrate.


plasma ammonia and citrulline elevated.


DNA (SLC25A13 gene).


1. Propionic acidaemia. Severe acidosis, osteoporosis, neutropaenia, thrombocytopaenia, hyperglycinaemia. Neurological deficits acquired in acute attacks, and as late onset chorea.

Screening tests:

blood count and gases, raised plasma glycine, raised urine methylcitrate, propionylglycineincreased propionylcarnitine in blood.


white cell propionylCoA carboxylase activity.

2. Methylmalonic aciduria. Severe acidosis, neutropaenia, thrombocytopaenia, hyperglycinaemia. Severe extrapyramidal disorder with low attenuation in globus pallidus following acute decompensation. Cobalamin responsive forms (cblA and cblB, vide supra) do better.

Screening tests:

blood count and gases, raised plasma glycine and methylmalonate, raised urine methylmalonate.increased propionylcarnitine in blood.


fibroblast methylmalonylCoA mutase activity.

3. Isovaleric acidaemia. Acquired neurological deficits; sweaty feet smell.

Screening tests:

urine N-isovalerylglycine and 3-hydroxyisovaleric acidincreased isovalerylcarnitine in blood.


white cell or fibroblast isovalerylCoA dehydrogenase.

4. Glutaric aciduria type I. Vide supra. Approximately two thirds present with an encephalopathic crisis and on recovery have dystonia and chorea; macrocephaly.

Screening tests:

urine glutaric, 3-hydroxyglutaric and glutaconic acids, glutarylcarnitine and glutarylglycine. Reduced plasma free carnitine, increased glutarylcarnitine.


fibroblast or white cell glutarylCoA dehydrogenase activityDNA.

5. Glutaric aciduria type II (multiple acylCoA dehydrogenase deficiency). Dysmorphic features, coma, hypoglycaemia (acidosis, hyperammonaemia); renal cysts; sweaty feet smell. Classically with early death, but milder variants.

Screening tests:

urine lactate, ethylmalonic, glutaric, adipic, 2-hydroxyglutaric, suberic and sebacic acidsabnormal carnitine profile with variable increases in isolvaleryl, medium chain and long chain.


fibroblast electron transfer flavoprotein or ETF-ubiquinone oxidoreductase activity.

6. 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency. Hypotonia, progressive dystonia with episodes of ketosis and encephalopathy.

Screening tests:

blood hydroxy-C4 carnitine.


fibroblast HIBCH activityDNA.

7. 2-Methyl-3-hydroxybutyryl-CoA Dehydrogenase Deficiency. See above. Developmental delay and regression may be associated with episodes of acute metabolic decompensation with hypoglycaemia and/or lactic acidosis.

8. Other organic acidaemias. Acute encephalopathy and neurological damage can also occur in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, 3-oxoacyl-CoA thiolase deficiency etc.


1. Carnitine transporter defect. Early onset: hypoglycaemia (hypoketotic, hyperammonaemia), myopathy and cardiomyopathy. Late onset: progressive myopathy and cardiomyopathy.

Screening tests:

decreased plasma carnitineincreased urine carnitine.


white cell or fibroblast carnitine transporter activity.

2. Carnitine palmitoyltransferase I deficiency. Encephalopathy, seizures; hepatomegaly; hypoglycaemia.

Screening tests:

normal or raised plasma carnitine, no abnormal urinary metabolites.


white cell or fibroblast CPT I activity.

3. Carnitine palmitoyltransferase II deficiency. Early onset: myopathy and cardiomyopathy. Adult: episodic myoglobinuria.

Screening tests:

elevation of long chain acyl carnitines (C16, C18:1)increased C16/C2 and C18:1/C2 ratio.


muscle, white cell or fibroblast CPT II activity.

4. Carnitine/acylcarnitine translocase deficiency. Hypoglycaemia (hyperammonaemia); myopathy and cardiomyopathy.

Screening tests:

plasma carnitine low (neonatal presentation)long chain acyl carnitines elevated.


fibroblast CAT activity.

5. Medium chain acylCoA dehydrogenase deficiency. Fasting induced encephalopathy, Reye’s-like illness, no myopathy; hypoglycaemia (hyperammonaemia).

Screening tests:

acylcarnitine profile (increased C8, C6, C10:1, low free carnitine,urine organic acids: hexanoylglycine, C6–12 dicarboxylic acids.


DNA (common mutation in N Europe)fibroblast MCAD activity.

6. Very long chain acylCoA dehydrogenase deficiency. Fasting induced encephalopathy, hypoglycaemia, lethargy, muscle weakness, cardiomyopathy.

Screening tests:

blood carnitine species profile - increased C14:1raised plasma urate,urine C6–10 dicarboxylic acids.


fibroblast VLCAD activity


7. Short chain acylCoA dehydrogenase deficiency. Variable failure to thrive, myopathy. May be asymptomatic.

Screening tests:

urine ethylmalonate and methylsuccinateblood butyrylcarnitine.


fibroblast SCAD activityDNA (common mutation).

8. Long chain 3-hydroxyacylCoA dehydrogenase deficiency. Fasting encephalopathy, myopathy, cardiomyopathy, retinitis pigmentosa, neuropathy.

Screening tests:

blood carnitine profile hydroxy-C16 and hydroxy-C18:1 carnitine speciesurine C6–14 hydroxydicarboxylic acids.


fibroblast LCHAD activityDNA.

9. Short chain 3-hydroxyacylCoA dehydrogenase deficiency. Most cases have presented with hypoglycaemia due, at least in part, to hyper-insulinism, and responsive to diazoxide. Reye-like presentation also reported.

Screening tests:

blood hydroxy-C4 carnitine (elevated)urine organic acids: 3-hydroxyglutaric acid increased.


DNA (SCHAD [=HADH] gene).


Mostly neonatal onset. Severe developmental delay and may be fatal if untreated or untreatable. Variable learning difficulties in patients whose seizures respond well to treatment.

1. Pyridoxal phosphate dependency. (Pyridox(am)ine phosphate oxidase [PNPO] deficiency)

Screening tests:

Urine organic acids (vanillactic acid)CSF amino acids and neurotransmitter amine metabolitesCSF pyridoxal phosphateTrial of pyridoxal phosphate treatment.


DNA (PNPO gene).

2. Pyridoxine dependency. (α-Aminoadipic semialdehyde dehydrogenase [antiquitin] deficiency)

Screening tests:

Urine (or plasma or CSF) α-aminoadipic semialdehydePlasma or CSF pipecolic acidTrial of pyridoxine.


DNA (antiquitin [ALDH7A1] gene).

3. Sulphite oxidase deficiency. Vide supra. Often presents with neonatal onset feeding difficulties and seizures which can be difficult to control.

Screening tests:

Urine sulphite (dip stick test)Urine sulphocysteine.


Fibroblast sulph]ite oxidase activityDNA (SUOX gene).

4. Molybdenum cofactor deficiency. Vide supra

5. Nonketotic hyperglycinaemia. (Vide supra) May present with neonatal epileptic encephalopathy with burst suppression on EEG.

6. Adenylosuccinate lyase deficiency .(Vide supra) Intractable seizures can occur in early infancy.

7. Defect of mitochondrial glutamate transporter. Neonatal hypotonia, early onset myoclonic seizures with EEG showing burst suppression. Mutations in SLC25A22 gene.

8. X-Linked EIEE /West syndrome. Early-onset epileptic encephalopathy with burst suppression on EEG followed by infantile spasms with hypsarrhythmia, and developmental arrest can be caused by mutations in the ARX and STK9 (CDKL5) genes (see also early onset encephalopathic variant of Rett syndrome below).

9. Peroxisomal disorders: Intractable seizures and profound hypotonia in a neonate may be presenting features. Dysmorphic features, ocular abnormalities (especially reduced ERG), epiphysial stippling etc. may be present

10. Disorders of serine synthesis.

Screening tests:

fasting plasma and CSF serine and glycine (low).




a. Phosphoglycerate dehydrogenase deficiency. Congenital microcephaly, psychomotor retardation, and seizures

b. Phosphoserine aminotransferase deficiency. Intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation

11. Disorders of creatine synthesis and transport. Vide supra. Can cause intractable seizures.

12. Causes of hypoglycaemia/hypocalcaemia/hypomagnesaemia etc.

Vide supra for hypoglycaemia and hypomanganesaemia. Causes of hypocalcaemia include hypoparathyroidism e.g. DiGeorge syndrome, mutations in the calcium-sensing receptor, hypomagnesaemia, vitamin D disorders, bile acid synthesis defects.

13. Glut1 Deficiency. Vide supra. Can cause anticonvulsant resistant epileptic encephalopathy

14. Biotinidase deficiency. Vide supra. Can cause neonatal epileptic encephalopathy although later presentation is more common

15. D2-hydroxyglutaric aciduria. Vide supra. Can present with early onset intractable epilepsy.

16. Congenital Disorders of Glycosylation. Vide supra. Intractable seizures can be a presenting feature of some congenital disorders of glycosylation.


Acute encephalopathy with lactic acidosis in infancy.

Strokes in MELAS.


Eplieptic encephalopathy in infancy—vide supra.

Acute encephalopathy in childhood is a rare presentation of peroxisomal disorders (e.g. α-methylacyl-CoA racemase deficiency).


The following may occur: epileptic encephalopathy (see above), stroke like episodes (CDG 1a), acute encephalopathy with loss of psychomotor abilities (CDG 2h).


1. Glycerol kinase deficiency. X-linked.

Screening tests:

urine glycerol.


white cell or fibroblast GK activity.

a. Juvenile onset. Encephalopathy, vomiting, acidosis.

b. Adult. Benign (artefactual hypertriglyceridaemia).

c. Complex. Contiguous gene defect involving Xpter-adrenal hypoplasia-glycerol kinase-Duchenne muscular dystrophy-cen.

2. The porphyrias. Intermittent neuropathic symptoms in 10%, triggered by drug, hormonal, nutritional or unknown factors. Abdominal pain and vomiting; neuropathic pain and neuropathy (motor, sensory, cranial or autonomic), psychiatric.

a. δ-aminolevulinic acid dehydratase porphyria. Recessive.

Screening tests:

increased urine δ-aminolevulinic acid, normal porphobilinogen.


red cell δ-aminolevulinic acid dehydratase activity.

b. Acute intermittent porphyria. Dominant.

Screening tests: increased urine δ-aminolevulinic acid and porphobilinogen.


red cell porphobilinogen deaminase activity.

c. Hereditary coproporphyria. Dominant, photosensitivity in 30%.

Screening tests:

increased urine and faecal coproporphyrinogen III.


hepatic coproporphyrinogen oxidase activity.

d. Variegate porphyria. Dominant, photosensitivity.

Screening tests:

faecal protoporphyrinogen IX and coproporphyrinogen III.


hepatic protoporphyrinogen oxidase activity.

3. Bilirubin encephalopathy (Kernicterus). In an infant with bilirubin >350μM: Hypotonia, hyporeflexia, athetosis, opisthotonus. May be fatal. Long-term sequelae include hearing loss, cranial nerve palsy, movement disorder, developmental delay.

Crigler-Najjar syndrome. (Bilirubin UDP glucuronyltransferase deficiency)

Neonatal haemolytic jaundice. (e.g. glucose-6-phosphate dehydrogenase deficiency)

4. Early onset encephalopathic variant of Rett syndrome. Severe infantile encephalopathy due to MECP2 and CDKL5 (STK9) mutations.Onset of symptoms in girls with Rett syndrome is usually after the age of 6 months. Boys with an MECP2 mutation on their X chromosome can have severe neonatal onset severe encephalopathy with profound hypotonia, apnoea/respiratory insufficiency, seizures. Later stereotypic movements, limb rigidity, movement disorder, lack of purposeful movements occur. Similar features can result from CDKL5 mutations.

Treatment is possible for some metabolic diseases. For instance, the devastating neurological effects of phenylketonuria (Table 10.1, I 1a) have been recognized for many years. Neonatal screening for this disorder and dietary modification in the developed world has removed phenylketonuria from the list of important causes of serious neurological disability in children. This success has lead to new challenges in the management of the adult with phenylketonuria and unexpected and devastating effect of the disorder on the unborn child of an untreated Phenylketonuria mother. More recently Biotinidase deficiency (Table 10.1, IX 3a) has been recognized as an important and easily treatable cause of serious neurological disease usually presenting with early onset drug resistant seizures. This and some other neurometabolic diseases can be identified on neonatal blood screening although a full range of screening is not yet routine in the United Kingdom. More disorders are likely to be picked up at an earlier asymptomatic stage as the sophistication of screening tests increases (Wilcken et al. 2003; Bodamer et al. 2007).

Although individual metabolic disorders are rare, collectively such disorders are relatively common. In reality most clinicians will see an individual condition only rarely in a career. Furthermore, patients with certain rare conditions are often concentrated in specialist referral centres, further reducing the exposure of general and paediatric neurologists to these disorders. A recent study into progressive intellectual and neurological deterioration, PIND, gives some information about the relative frequency and distribution of some childhood neurodegenerative diseases in the United Kingdom (Verity et al. 2000; Devereux et al. 2004). Although primarily designed to identify any childhood cases of variant Creutzfeldt-Jakob disease (Section 42.8.9), the study also provided much information about the distribution of neurometabolic disease in children in the United Kingdom. The commonest five causes of progressive intellectual and neurological deterioration over 5 years were Sanfilippo syndrome, 41 cases, adrenoleukodystrophy, 32 cases, late infantile neuronal ceroid lipofuschinosis, 32 cases, mitochondrial cytopathy, 30 cases, and Rett syndrome, 29 cases. Notably, geographical foci of these disorders were also found and correlate with high rate of consanguinity in some local populations (Fig. 10.1). (Text continues on page 257.)

Fig. 10.1 Total progressive intellectual and neurological deterioration, PIND, in the United Kingdom between May 1997 and September 2002 in children aged up to 16 years (from Devereux et al. 2004). (A) The five most frequent diagnoses encountered. Neuronal ceroid lipouscinoses. (B) Map of the United Kingdom showing Public Health Laboratory Service districts. The five highlighted districts are those in which the largest numbers of progressive intellectual and neurological deterioration cases resided and may reflect high rates of consanguinity.

Fig. 10.1
Total progressive intellectual and neurological deterioration, PIND, in the United Kingdom between May 1997 and September 2002 in children aged up to 16 years (from Devereux et al. 2004). (A) The five most frequent diagnoses encountered. Neuronal ceroid lipouscinoses. (B) Map of the United Kingdom showing Public Health Laboratory Service districts. The five highlighted districts are those in which the largest numbers of progressive intellectual and neurological deterioration cases resided and may reflect high rates of consanguinity.

10.1.2 When to suspect a neurometabolic disorder

The child with a neurometabolic disease can present in a number of ways. These children typically have a normal birth history and normal early development. Later on development slows, plateaus, and then declines with increasing disability and eventual death. The age at onset and rate of progression depends on the particular disorder. In children this interface between the effects of the disease and the normal developmental process often makes it difficult to recognize the serious underlying nature of the disorder, especially early on. Thus the clinical course of a child with a neurometabolic disorder may, in the early stages, be difficult to distinguish from the child with a relatively ’static’ neurodevelopmental disorder, such as Rett syndrome or Autism, or from the child with an epileptic encephalopathy. The term ’static’ is used loosely here whilst acknowledging that ‘progression’ or clinical evolution, either negative or positive, is seen in conditions like Rett syndrome and Autism. This early difficulty in recognizing that a condition is progressive has probably led to underreporting of some disorders, such as juvenile neuronal ceroid lipofuscinosis, in the progressive intellectual and neurological deterioration study.

A neurometabolic disorder should be particularly suspected in an infant or child presenting with neurological symptoms and any of the following:

  1. A progressively deteriorating neurological or developmental disorder.

  2. Evidence of diffuse neurological involvement, for instance a combined disorder of the brain and peripheral nerves.

  3. Parental consanguinity or a known family history.

  4. Evidence of leukodystrophy or other symmetric abnormalities on initial brain MRI.

  5. Dysmorphic features (Table 10.3).

  6. Spinal deformity raises the question of mucopolysaccharidoses (Section 10.4.5) or the newly described congenital disorders of glycosylation (Table 10.1, VI).

  7. Dysfunction of other organs, for instance the liver in Wilson’s disease, or the heart in Pompé disease.

Table 10.3 Clinical clues to the diagnosis of metabolic diseases of the nervous system (modified from Menkes et al. 2005)



Cutaneous abnormalities

Increased pigmentation

Telangiectases (conjunctiva, ears, popliteal areas)

Perioral eruption

Abnormal fat distribution

Angiokeratoma (red macules or maculopapules) of hips, buttocks, scrotum

Oculocutaneous albinism


Subcutaneous nodules


Inverted nipples

Mongolian spots



Multiple carboxylase deficiency

Congenital disorders of glycosylation

Fabry disease, sialidosis, fucosidosis type II

Chédiak–Higashi syndrome

Cerebrotendinous xanthomatosis

Ceramidosis (Farber disease)

Sjögren–Larsson syndrome (spasticity, seizures)

Refsum disease (neuropathy, ataxia, phtylanic acid)

Dorfman-Chanarin syndrome (lipid storage in muscle, granulocytes)

Congenital disorders of glycosylation

GM1 gangliosides

Abnormal urinary or body odour


Maple syrup or caramel

Sweaty feet or ripe cheese

Sweaty feet

Cat urine


Maple syrup urine disease

Isovaleric acidemia

Glutaric academia type II

3-methylcrotonyl-CoA carboxylase deficiency

Multiple carboxylase deficiency

Hair abnormalities


Kinky hair

Multiple carboxylase deficiency

Menke’s kinky hair disease

Argininosuccinic aciduria

Multiple carboxylase deficiency

Giant axonal neuropathy

Trichothiodystrophy (Pollitt syndrome; mental retardation, seizures)

Unusual facies


Slight coarsening (compared to other family members)

High nasal bridge, prominent jaw, large pinnae

Mucopolysaccharidoses (Hunter–Hurler syndrome)

I-cell disease (mucolipidosis II)

GM1 gangliosidosis (infantile)

Sanfilippo syndrome

Mucolipidosis III (pseudo-Hurler dystrophy)

Fucosidosis II


Sialidosis II


Congenital disorders of glycosylation

Ocular abnormalities


Corneal clouding

Cherry-red spot


Cerebrotendinous xanthomatosis


Hurler syndrome

Hunter syndrome (late in severe cases)

Morquio syndrome

Maroteaux–Lamy syndrome

Tay–Sachs, Sandhoff diseases (GM2 gangliosidosis)

GM1 gangliosidosis (infantile)

Niemann–Pick disease (types A and C)

Infantile Gaucher disease (type II)


In addition, neurometabolic disorders enter into the differential diagnosis in children with:

  1. Progressive ataxias of childhood (Table 10.4).

  2. Dystonias and other movement disorders (Table 10.5).

  3. Childhood epilepsies, especially if myoclonic (Table 10.2, V) (Table 30.1).

  4. Presentation with cognitive decline (Table 10.6).

Table 10.4 The range of childhood ataxias

Neurometabolic disorders

DNA repair defects (Section 39.7)

Ataxia-telangiectasia (Sections 11.5 and 39.7.1)

Metabolic ataxias (Section 39.5)

Leukoencephalopathies (Section 10.2)

Mitochondrial disorders (Sections 10.5 and 39.6)

Coenzyme Q deficiency (Sections 10.5.5 and 39.6)

Pyruvate dehydrogenase deficiency (Sections 10.5.5 and 39.5.1)

Leigh’s syndrome (Sections 10.5.3 and 39.6)

Hereditary degenerative disorders (Sections 39.3 and 39.4)

Pontocerebellar hypoplasia types I and II (Section 39.3.1)

Congenital early onset ataxias (Section 39.3)

Early onset hereditary degenerative ataxias including Friedreich’s ataxia (Section 39.4)

Acquired in childhood (Section 39.8)

Opsoclonus-myoclonus syndrome (Section 38.4.5)

Post-infectious acute cerebellar ataxia (Section 42.3.3)

Toxins (Section 39.11.1)

Gluten sensitivity or coeliac ataxia (39.11.9)

Posterior fossa structural disorders

Table 10.5 Dystonias and other movement disorders in children

Primary torsion dystonias (Section 40.4.2)

Dopa responsive dystonia (Section 40.4.4) and Tetrahydrobiopterin deficiency (Table 10.1, I1b)

Rapid onset dystonia-parkinsonism (Section 40.4.6)

Paroxysmal kinesigenic choreoathetosis (Section 40.4.7)

Paroxysmal dystonic choreoathetosis (Section 40.4.7)

Dyskinetic athetoid cerebral palsy and Kernicterus (Section 40.4.8)

Deafness-dystonia, Mohr Tranebjaerg syndrome (Section 40.4.14)

Ataxia-telangiectasia (Sections 11.5; 39.7.1; 40.4.15)

Huntington’s disease, juvenile Westphal variant (Section 40.5.2)

Benign hereditary chorea (Section 40.5.5)

Sydenham’s chorea (Section 40.5.7)

Other post-streptococcal movement disorders (Section 40.10)

Gilles de la Tourette’s syndrome (Section 40.6.3)

Hereditary hyperekplexia (Section 40.11.11)

Mirror movements (Section 40.11.12)

Wilson’s disease (Section 40.8)

Metabolic disorders

Organic acidurias:

3-methylgutaconic aciduria Type III, Costeff’s optic atrophy (Table 10.1, II 4c)

Glutaric aciduria type I (Table 10.1, II 5)

Other (Table 10.2, III)

L2-hydroxyglutaric aciduria (Table 10.1, II 2; Section 10.2.8)

2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (Table 10.1, II 7)

Mitochondrial disorders (Table 10.1, III 1,3,4)

Lysosomal disorders

Sialic acid storage disorders (Table 10.1 V5d)

Niemann–Pick disease type C (Table 10.1 V9)

Gaucher’s disease type 3 (Table 10.1, V 10c)

GM2 gangliosidosis (Table 10.1, V 15)

Neuronal ceroid lipofuscinosis, or Batten’s disease (Table 10.1, V 16)

Lesch–Nyan syndrome (Table 10.1, VII 1a; Section 10.3.3)

Ureidopropionase deficiency (Table 10.1, VII 2c)

Caeruloplasmin deficiency (Table 10.1, VIII 1a; Section 40.8)

Congenital folate malabsorption (Table 10.1, IX 1a)

Rett syndrome (Table 10.2, IX 4; Sections 9.6.2; 40.4.15)

Creatine synthesis and transport abnormalities (Table 10.1, XIII)

Red cell glycolytic defects (Table 10.1, XV)

Carbohydrate disorders (Table 10.2, I)

Nonketotic hyperglycinaemia (Table 10.2, II 2)

Pantothenase kinase deficiency (Section 40.4.12)

Neuroferritinopathy (Section 40.5.4)

Table 10.6 Some neurometabolic and developmental, conditions which can present with cognitive deterioration

Neurodevelopmental disorders

Hydrocephalus (Section 9.3.2)

Rett syndrome (Sections 9.6.2; 10.7.2)

Autism and childhood disintegrative disorder (Section 9.6.4)


Metachromatic leukodystrophies (Section 10.2.2)

Krabbe disease (Section 10.2.3)

Adrenoleukodystrophies (Section 10.2.4)

Vanishing white matter leukoencephalopathy (Section 10.2.5)

Primary grey matter degenerations

Neuronal ceroid lipofuscinoses (Section 10.3.2)

Mitochondrial disorders

Some (Table 10.1, III.4)

Lysosomal disorders

GM1 gangliosidoses types 2 and 3 (Table 10.1, V.14; Section 10.4.3)

GM2 gangliosidosis; Tay Sachs disease (Section 10.4.2)

Niemann Pick disease Type C (Section 10.4.4)

Sanfillippo disease; mucopolysaccharidosis Type III (Section 10.4.5)

Schindler disease (Table 10.1, V.4)

Abnormalities of glycoprotein degradation (Table 10.1, V.5)

Aminoacid disorders

Phenylketonuria (Table 10.1, I.1a)

Homocystinuria (Table 10.1 I, 4b.c)


Huntington’s disease, juvenile Westphal variant (Section 40.5.2)

Wilson’s disease (Section 40.8)

Cerebrotendinous xanthomatosis (Table 10.1, XI.1; Section 21.8.9)

Xeroderma pigmentosum (Table 10.1, XVII.1b; Section 11.6.7)

Methylenetetrahydrofolate reductase deficiency (Table 10.1 IX, 1b)

Neurometabolic disorders can be categorized also into those which are associated with episodes of acute encephalopathy (Table 10.2) and those which are not associated with acute encephalopathy (Table 10.1).

10.1.3 Investigation of a possible neurometabolic disorder

A number of variables need to be considered when planning the investigation of a child with a possible neurometabolic disease. Age is of most importance, closely followed by the details of the history and examination. Although some advocate a blanket screen of investigations to consider in any child presenting with specific symptoms there is a need to try and rationalize the approach by undertaking relevant investigations in a logical sequence. Inevitably there is a tension between the desire to reach a timely and accurate diagnosis and to detect important diagnoses with potential genetic and treatment implications, whilst avoiding subjecting the child to a variety of unpleasant, expensive, and potentially unnecessary tests. The approach to investigation will vary between individuals, and is ever changing with the growth of knowledge and the availability of new investigations.

Brain MRI

This is the single investigation that has most helped the practising paediatric neurologist in the past 20 years. It is essential early in the diagnostic process. CT can also be enormously helpful particularly in the infant presenting with an acute encephalopathy, with its more obvious demonstration of calcification and acute haemorrhage. Brain imaging will help to distinguish some of the neurodegenerative diseases and is particularly important in revealing a leukodystrophy (Table 10.7). It is important to remember that the appearance of an MR brain scan changes significantly in the normal child with increasing age. This is mainly due to the process of myelination, of which there is little evidence at birth before an almost normal adult pattern is reached by 5 years. Most of this developmental change in myelination occurs in the first 2 years.

Table 10.7 MRI evidence of leukodystrophy in childhood


Metachromatic leukodystrophy (Sections 10.2.2; 21.8.2 ; 37.7.3)

Krabbe disease (Sections 10.2.3; 21.8.3; 37.7.1)

Adrenoleukodystrophy (Sections 10.2.4; 21.8.4; 37.7.2)

Vanishing white matter disease (Sections 10.2.5; 37.7.6)

Cree leukoencephalopathy (Section 10.2.5)

Ovarioleukodystrophy syndrome (Section 10.2.5)

Megaloencephalic leukoencephalopathy with subcortical cyst (Section 10.2.6)

Alexander disease (Section 10.2.7)

L-2-hydroxyglutaric aciduria (Section 10.2.8)

Canavan disease (Section 10.2.9)

Pelizaeus–Merzbacher disease (Section 10.2.10)

Peroxisomal biosynthesis disorders (Section 10.6)

Developmental disorders

Cockayne’s syndrome (Section 11.6.8)

Some mitochondrial disorders (Section 10.5)


Acute disseminated encephalomyelitis (Section 37.4.1)


The EEG is particularly important in the child with seizures and developmental regression. It can give diagnostic and other specific information concerning Hypsarrhythmia (Section 30.4.2), subacute sclerosing panencephalitis (Section 42.3.7), Battens disease or neuronal lipoid cerdjuscinosis (Section 30.3.4), and Alper’s disease (Section 30.3.4). In general, it should be noted that the EEG is of most value in children with the epileptic encephalopathies which occur more commonly than epilepsies due to neurometabolic disease (Section 30.5.2).


The lumbar puncture remains essential in the differential diagnosis of children with serious neurological disease. The CSF examination should routinely include cell count and culture, with protein, glucose, and lactate. A low CSF glucose might suggest glucose transporter deficiency, a condition with an expanding phenotype (Klepper and Leiendecker 2007). A high lactate suggests a mitochondrial disorder; the CSF lactate is often considered more informative than the blood lactate. CSF amino acid estimations are diagnostically helpful in the infant presenting with an early onset epileptic encephalopathy; with high CSF glycine in non-ketotic hyperglycinemia and low serine in the newly described serine deficiency syndromes (Section 10.7.1). The CSF can be examined for neurotransmitter metabolites, abnormal in Segawa syndrome and other dystonias, and for pterins and folate metabolites (Garcia-Cazorla et al. 2007; Pearl et al. 2007). In addition to the search for clues to a neurometabolic disorder the CSF can be examined for evidence of a wide range of infectious agents; for instance subacute sclerosing panencephalitis remains an important cause of degenerative neurological disease worldwide (Section 42.3.7). Inflammatory neurological disease is relatively common in children, such as acute disseminated encephalomyelitis (Section 37.4.1) and occasionally multiple sclerosis (Section 37.5), although the diagnostic utility of CSF oligoclonal bands is limited (Section 3.6.8).

Blood tests

A large range of possible blood tests can be undertaken for suspected neurometabolic disorders. Liver function and coagulation are deranged in many metabolic conditions and the blood glucose and lactate should be available for comparison with CSF values. The glucose, ammonia, pH, and lactate should be measured in any child with encephalopathy. Blood amino acids should be routinely checked in all children with unexplained encephalopathy. Some amino acid disorders can mimic other neurological disease, for instance arginase deficiency can mimic cerebral palsy (Prasad et al. 1997) and the polyneuropathy of tyrosinaemia can resemble Guillain Barré syndrome (Noble-Jamieson et al. 1994). Biotinidase deficiency should be considered in any child with seizures but can present with other progressive neurology (Rahman et al. 1997).

The range of further testing depends on the diagnostic possibilities. An exhaustive listing of the huge number of metabolic diseases that can present in children and adults summarizes the diagnostic tests for each (Tables 10.1 and 10.2). Observation of vacuolated lymphocytes on routine blood film raises the possibility of various inherited metabolic disorders, particularly juvenile forms of neuronal ceroid lipofuscinosis or GM1 gangliosidosis (Fig. 10.2).

Fig. 10.2Vacuolated lymphocytes. (A) Low power image of a blood film, illustrating the correct area in which to look for the presence of vacuolated lymphocytes (arrow), and (inset) high power photomicrograph demonstrating a small vacuolated lymphocyte and monocyte (May–Grunwald–Giemsa staining; original magnification, 400). ( A.)

Fig. 10.2
Vacuolated lymphocytes. (A) Low power image of a blood film, illustrating the correct area in which to look for the presence of vacuolated lymphocytes (arrow), and (inset) high power photomicrograph demonstrating a small vacuolated lymphocyte and monocyte (May–Grunwald–Giemsa staining; original magnification, 400). ( A.)

Any request for ‘leukocyte enzymes’ needs to be accompanied by awareness of the diagnostic possibilities to guide the range of conditions for which the laboratory will test. Not all laboratories do the same tests, some offering screens which vary depending on the clinical details which were provided. Often proper targeting of testing is compromised by provision of insufficient clinical information when the tests are requested by an inexperienced clinician. Good communication between the clinician and the laboratory will help ensure appropriate and prompt investigation.

The recent elucidation of the genetics and metabolic causes of pyridoxine-dependent epilepsy will improve identification of this rare but important treatable disorder. All infants with refractory epilepsy should have measurement of pipecolic acid in blood and CSF (Willemsen et al. 2005; Bok et al. 2007) or α-aminoadipic semialdehyde in urine (Mills et al. 2006). Indeed whilst awaiting these results a therapeutic trial with pyridoxine, biotin, and folinic acid should be considered in any infant with an unresponsive epilepsy (Been et al. 2005).

Disorders of glycosylation are suggested by the association of dysmorphic features including inverted nipples and subcutaneous fat pads, micro- or macrocephaly, or spinal deformity with a neurological disorder in children aged less than 5 years. These should be investigated by electrophoretic separation of transferrin isoforms, and other blood glycoproteins, and with other investigations (Table 10.1, VI; Section 10.7.2).


Urine sampling is important in any child presenting with possible neurometabolic disease and should be sent routinely for organic acid estimation. Urine metabolic screening tests are also important particularly in the sick neonate. Urine amino acid screening is not usually necessary in the child without encephalopathy provided blood amino acids and urine organic acids have been checked. The range of possible screening investigations in urine is large. Screening for the mucopolysaccharidoses is essential in all infants with developmental slowing. Other screening tests include urine sulphite in infants with early onset difficult epilepsy. Sulphite oxidase deficiency can mimic hypoxic ischaemic encephalopathy (Hobson et al. 2005). Urine screening is now available for a number of disorders of purine and pyrimidine metabolism and should be considered in the child with severe learning disability with autism, who might have adenylosuccinase deficiency and dystonia, and with possible Lesch–Nyan syndrome. Urine can also be examined for creatine and guanidinoacetate so as to detect recently described disorders of creatine biosynthesis and transport (Table 10.1, XIII). Such disorders present with hypotonia, developmental standstill, and seizures.

10.2 Leukodystrophies and brain dysmyelination

10.2.1 Overview

Leukodystrophies are generally diagnosed on the basis of abnormal white matter on brain MRI (Table 10.7) in children or adults under investigation for developmental delay, cognitive impairment, or demyelinating peripheral neuropathy, often in varying combinations.

Neuropathology can distinguish between:

  1. Demyelination: destruction of normally formed myelin;

  2. Hypomyelination; too little myelin;

  3. Dysmyelination: formation of abnormal myelin; and

  4. Delayed myelination: immature pattern of myelination.

It is more difficult to be sure about these pathological categorizations from MR images. Nevertheless, demyelination is suggested by high signal from the white matter on T2-weighted images with low signal on T1-weighted images; dysmyelination or hypomyelination by high signal from the white matter on T2-weighted images with normal signal on T1-weighted images; and delayed myelination by the pattern of normal myelin signal on T2- and T1-weighted images with respect to age (Fig. 10.3).

Fig. 10.3 MRI features of white matter pathology. (A) Demyelination. Late infantile Krabbe disease. High signal from posterior white matter on T2-weighted axial image on the left, low signal from parietal white matter on T1-weighted coronal image on the right. (B) Dysmyelination or hypomyelination. Pelizaeus-Merzbacher disease. High signal from hemispheric white matter on T2-weighted axial image on the left, normal signal from hemispheric white matter on T1-weighted axial image on the right. (C) Delayed myelination. Delayed development of unknown aetiology in a 9-month-old infant. The only normal myelin signal is seen in the anterior and posterior limbs of the internal capsule representing an age equivalent to 2–3 months.

Fig. 10.3
MRI features of white matter pathology. (A) Demyelination. Late infantile Krabbe disease. High signal from posterior white matter on T2-weighted axial image on the left, low signal from parietal white matter on T1-weighted coronal image on the right. (B) Dysmyelination or hypomyelination. Pelizaeus-Merzbacher disease. High signal from hemispheric white matter on T2-weighted axial image on the left, normal signal from hemispheric white matter on T1-weighted axial image on the right. (C) Delayed myelination. Delayed development of unknown aetiology in a 9-month-old infant. The only normal myelin signal is seen in the anterior and posterior limbs of the internal capsule representing an age equivalent to 2–3 months.

10.2.2 Metachromatic leukodystrophy

Metachromatic leukodystrophy is named because of the appearance of accumulation of the sulphatide galactosylceramide-3-O-sulphate in neural tissue. This appears metachromatic using specific histological stains. This disorder is recessively inherited and caused by deficiency of arylsulphatase A.

Traditionally clinical subgroups have been defined based on the age of onset: late infantile, juvenile, and adult (Table 10.1, V 12) (Section 37.7.3). More recent studies have correlated genotype with phenotype, addressing whether mutations result in absence of arylsulphatase A activity or whether some residual activity remains. These suggest that the late infantile form of the disease shows little phenotypic variability but that the juvenile and adult forms form a continuum, alternatively described as late onset metachromatic leukodystrophy.

Infantile forms

By far the commonest presentation, occurring in approximately half, is the late infantile form of metachromatic leucodystrophy. Here, first symptoms start towards the end of the first year of life or during the second year. The first manifestation is a gait disturbance due either to the polyneuropathy, as evidenced by hypotonia and absent tendon reflexes (Section 21.8.2), or to cerebral white matter degeneration, manifesting as hypertonia, pathologically brisk reflexes, and extensor plantar responses. These symptoms progress over a few months with the loss of motor skills. At this stage, dementia becomes apparent with loss of language and other cognitive skills. The motor disorder also progresses with the development of ataxia and progressive involvement of the pyramidal system and the child becomes bedridden. The children then become blind and may develop epilepsy. Finally, they become decerebrate (Hagberg 1963). Most children will die within 5 years of disease onset.

Late onset forms

First symptoms of the late onset forms usually occur between 3 to 60 years of age and the disease shows marked clinical heterogeneity in both its presentation and its course. Both juvenile onset, usually between ages of 3 and 10 years, and adult onset, usually after the age of 15 years, are described. There are two common presentations: behavioural and motor and MRI shows leukodystrophy (Fig. 10.4A). The presenting behavioural changes may be a change in personality, loss of social inhibition, dementia, or frank psychosis. These may remain isolated for many years, but gradually an ataxic-pyramidal tract motor disorder and a slowly progressive blindness caused by optic atrophy emerge. Those presenting with a motor disturbance usually have a slowly progressive pyramidal paraparesis or a progressive cerebellar ataxia. Dementia, blindness, and sometimes epilepsy emerge later. With both presentations a demyelinating peripheral neuropathy is found on nerve conduction studies, but is rarely symptomatic or detectable clinically (Section 21.8.2). The course of the disease is also variable. Some patients have a disorder which evolves rapidly and die within 5 years. In others the course is more protracted course and evolves over a decade or so (Baumann et al. 1991; Rauschka et al. 2006).

Fig. 10.4Late onset metachromatic leukodystrophy. T2-weighted MRI (A) axial and (B) coronal showing diffusely altered cerebral white matter signal. (Courtesy of Dr P. Anslow). (C) Urinary deposit stained with toluidine blue showing a shed epithelial cell containing brown metachromatic material. (Courtesy Dr W. Squier.) ( C.)

Fig. 10.4
Late onset metachromatic leukodystrophy. T2-weighted MRI (A) axial and (B) coronal showing diffusely altered cerebral white matter signal. (Courtesy of Dr P. Anslow). (C) Urinary deposit stained with toluidine blue showing a shed epithelial cell containing brown metachromatic material. (Courtesy Dr W. Squier.) ( C.)


MRI of the brain shows features of demyelination, but the pattern of involvement is entirely non-specific. In late infantile onset metachromatic leukodystrophy, the MRI initially shows involvement of the posterior cerebral white matter later spreading to the entire hemispheric white matter, dentate nucleus, and the brain stem. In late onset metachromatic leukodystrophy it is often the frontal lobe white matter that is initially involved.

In late infantile metachromatic leukodystrophy there is almost invariably a motor sensory demyelinating polyneuropathy with abnormal nerve conduction studies. These nerve conduction abnormalities can precede symptoms.

The diagnosis is made by demonstrating deficient activity of arylsulphatase A in peripheral blood leukocytes or cultured skin fibroblasts. However, this may not be straight-forward because there are two pseudodeficiency alleles present in up to 10 per cent of most populations, which, when combined, can reduce arylsulphatase A activity to approximately 8 per cent of normal. Ancillary methods to help diagnosis are the presence of metachromatic staining cells in a sample of fresh urine (Fig. 10.4C) and urinary sulphatide excretion. Rarely, metachromatic leukodystrophy can be caused by deficiency of saposin B, a sulphatide activating protein.


Currently, there is no effective treatment to cure or arrest late-infantile metachromatic leukodystrophy. Haematopoietic stem cell therapy may improve selected patients with late onset metachromatic leukodystrophy (Sevin et al. 2007a).

10.2.3 Krabbe disease

Krabbe disease is named after the author of the first clinical and neuropathological description. It is also called globoid cell leukodystrophy because the presence of multinucleated giant macrophages, containing galactocerebroside, in the perivascular spaces of white matter is the histological hallmark of the disorder. It is recessively inherited and caused by deficiency of galactocerebroside β-galactosidase.

Based on age of onset, there are two clinical subgroups: early infantile and juvenile (Table 10.1, V11 (Section 37.7.1)). Early infantile Krabbe disease makes up approximately 90 per cent of cases and symptoms start at 3–4 months of age. Late onset Krabbe disease usually becomes symptomatic before the age of 6 years, but cases presenting in adulthood are increasingly recognized.

Early infantile Krabbe disease

This has a relentlessly progressive course. Affected infants are usually normal for the first 3–4 months of life. Then they become miserable and hypersensitive to tactile and auditory stimuli. Such irritability should alert the clinician to this diagnostic possibility and it may mask or predate the neurological decline. They may develop a fever of central origin and difficulties with feeding causing faltering growth. This period is followed by rapid intellectual and motor deterioration with the development of opisthotonus and marked pyramidal tract signs. Virtually all patients with early infantile Krabbe disease have peripheral nerve involvement and deep tendon reflexes may be absent (Section 21.8.3). The infants become blind with optic atrophy and may develop seizures. The deterioration continues and the infants become decerebrate towards the end of the first year of life and death usually occurs before the age of two (Hagberg et al. 1963).

Late onset Krabbe disease

This has a more protracted course with an initially rapid development of a pyramidal hemiplegia or quadriplegia, visual loss, ataxia, and dementia, followed by a more gradual progression of symptoms (Kolodny et al. 1991; Lyon et al. 1991). Survival is variable, depending upon age of onset, but can be prolonged over decades. Cases presenting in adulthood often have symptoms initially suggestive of a progressive spastic paraparesis or motor neurone disease.


MRI of the brain in early infantile Krabbe disease shows signal abnormalities in the cerebellar white matter and dentate nuclei, the basal ganglia, thalamus, and the pyramidal tracts (Fig. 10.3A). There is often prominent atrophy of both grey and white matter structures. By contrast, patients with late onset Krabbe disease have involvement of the pyramidal tracts, parietóoccipital white matter, and corpus callosum (Loes et al. 1999). Early infantile Krabbe disease also causes a demyelinating peripheral neuropathy and virtually all cases have early abnormalities of nerve conduction (Siddiqi et al. 2006) (Section 21.8.3). CSF protein concentration is raised in symptomatic early infantile Krabbe disease.

The diagnosis is made by demonstrating deficient activity of galactocerebroside β-galactosidase in peripheral blood leukocytes or cultured skin fibroblasts. Very rarely, Krabbe disease can be caused by deficiency of saposin A, a galactocerebroside β-galactosidase activating protein.


Advances in haematopoietic stem cell treatment have led to this becoming the treatment of choice in late onset Krabbe disease in which it can reverse some neurological symptoms. Haematopoietic stem cell treatment is used also in presymptomatic Krabbe disease, most of whom would develop early infantile Krabbe disease, where it greatly ameliorates development of symptoms (Krivit et al. 1998; Escolar et al. 2005). Unfortunately, symptomatic early infantile Krabbe disease is untreatable.

10.2.4 Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked disorder that is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane ABC half transporter named adrenoleukodystrophy protein (Table 10.1, IV 3b). Mutant adrenoleukodystrophy protein causes many different phenotypes:

  1. acute cerebral forms of childhood, adolescent and adult onset;

  2. adrenomyeloneuropathy with or without cerebral involvement in hemizygotes; cerebellar in hemizygotes or heterozygotes;

  3. adrenal failure alone; and

  4. asymptomatic in hemizygotes or heterozygotes (Moser et al. 2005a).

Acute childhood cerebral adrenoleukodystrophy

This is the commonest manifestation. It presents between three and ten years of age with behavioural changes of attention difficulties and emotional lability. This is followed by increasing difficulties with auditory processing and vision. Affected boys then develop a progressive pyramidal and cerebellar motor disorder, dementia and often epilepsy. The disease rapidly progresses and the children become decerebrate over one to two years. Adolescent and adult onset acute cerebral forms are much rarer but have a similar rapidly progressive course (Section 37.7.2). Approximately 90 per cent of males with acute cerebral adrenoleukodystrophy also have adrenal insufficiency at presentation.

MRI of the brain shows demyelination in the parieto-occipital white matter (Fig. 10.5). There is contrast enhancement at the leading edge of the demyelination. Computed tomography of the brain shows similar white matter lesions and may show calcification within these areas.

Fig. 10.5 Adrenoleukodystrophy. T2-weighted axial MRI showing predominantly posterior white matter high signal change. (Courtesy of Dr P. Anslow.)

Fig. 10.5
Adrenoleukodystrophy. T2-weighted axial MRI showing predominantly posterior white matter high signal change. (Courtesy of Dr P. Anslow.)


This is the second most common manifestation. It presents in the second or third decade with a progressive spastic paraparesis. Additionally there may be bladder sphincter involvement, impotence, and signs of a mild sensory axonal peripheral neuropathy (Section 21.8.4). After around 10 years of symptoms, a fifth of males will develop the acute cerebral form. Around 70 per cent of males with adrenomyeloneuropathy have adrenal insufficiency. Rarely, adrenomyeloneuropathy can present with a progressive ataxia. It is estimated that approximately half of female heterozygotes will develop adrenomyeloneuropathy; but this is of later onset, does not progress to an acute cerebral form and is not associated with adrenal insufficiency.

MRI of the spinal cord usually shows atrophy only but there may be signal changes in the pyramidal tracts. Nerve conduction studies show a mild axonal polyneuropathy.


Diagnosis is made in the index patient by demonstrating raised plasma concentrations of the saturated, unbranched very long chain fatty acids, VLCFA. The most usual VLCFA measured is hexacosanoic acid, C26:0; both its absolute concentration and its ratios to docosanoic C22:0 and tetracosanoic C24:0 acids need to be examined. The diagnosis should be confirmed by mutation analysis of the ABCD1 gene. This is necessary because female heterozygotes may have normal plasma concentrations of VLCFA.


There has been consideration of many approaches to the treatment of adrenoleukodystrophy and trials in animal models and humans (Hudspeth and Raymond 2007; Kemp and Wanders 2007). This has led to some limited successes in the management of selected patients with childhood acute cerebral and presymptomatic adrenomyeloneuropathy. The associated adrenal insufficiency responds well to steroid replacement therapy.

There is good evidence that boys with pauci-symptomatic acute cerebral adrenomyeloneuropathy and limited demyelination on magnetic resonance imaging of the brain respond to haematopoietic stem cell therapy (Peters et al. 2004), although the mechanism by which this helps is not known. Because of the risks of the procedure and because half of the patients will develop adrenomyeloneuropathy rather than the acute cerebral form, prophylactic haematopoietic stem cell therapy is not recommended. There is also good evidence that treatment of presymptomatic boys with normal brain MRI with Lorenzo’s oil, a 4:1 mixture of glyceryltrioleate and glyceryltrierucate, reduces the risk of developing MRI abnormalities (Moser et al. 2005b). Current practice is to treat presymptomatic boys, identified through family screening or who have isolated adrenal insufficiency, with Lorenzo’s oil and to survey them for neurological symptoms, adrenal insufficiency and MRI abnormalities every 6 months. This allows early haematopoietic stem cell therapy at the time of development of symptoms or MRI abnormalities.

10.2.5 Vanishing white matter disease

The eIF2B-related disorders are a group of leukoencephalopathies that are caused by mutations in the genes encoding the five subunits that comprise eukaryocytic initiation factor 2B, eIF2B. Recognized discreet disorders are vanishing white matter leukoencephalopathy, Cree leukoencephalopathy, and ovarioleukodystrophy syndrome. They are recessively inherited.

Vanishing white matter leukoencephalopathy

This has also been called childhood ataxia with central nervous system hypomyelination. Classically it presents between 18 months and 5 years of age; earlier developmental milestones being normal or with minor delays (van der Knapp et al. 1997). It is characterized by episodic encephalopathy precipitated by intercurrent illnesses or minor head trauma, or even by fright (Vermeulen et al. 2005). This results in a progressive ataxia with progressive pyramidal tract signs. Intellect is said to be intact in the early years of the disorder. Later, optic atrophy and occasionally epilepsy can complicate the disease. Children with vanishing white matter leukoencephalopathy typically become wheel-chair dependent by their teenage years and die in the second and third decades. However, the age of presentation and the evolution of symptoms are very variable. Adolescent and adult onsets are well described with a milder course (van der Knapp et al. 1998; Biancheri et al. 2003; Ohtake et al. 2004) (Section 37.7.6). There are also infantile-onset cases with a rapidly progressive course and death before 2 years of age Francalanci et al. 2001), and indeed prenatal onset with multiple organ involvement (van der Knapp et al. 2003).

MRI of the brain is very characteristic in vanishing white matter leukoencephalopathy. There is diffuse, symmetrical signal abnormality throughout the cerebral hemisphere white matter and part of the white matter has the signal intensity of cerebrospinal fluid; there is also signal abnormality and atrophy of the dentate nucleus (Fig. 10.6). The diagnosis is made by demonstrating mutations in one of the genes for the five subunits of eIF2B. Treatment of vanishing white matter leukoencephalopathy is symptomatic.

Fig. 10.6 Vanishing white matter leukoencephalopathy. (A) Coronal flair and (B) Axial T2-weighted MRI showing white matter volume loss with intense high signal indicative of demyelination. (Courtesy of Drs R. Jefferson, S. Jayawant, and P. Anslow.)

Fig. 10.6
Vanishing white matter leukoencephalopathy. (A) Coronal flair and (B) Axial T2-weighted MRI showing white matter volume loss with intense high signal indicative of demyelination. (Courtesy of Drs R. Jefferson, S. Jayawant, and P. Anslow.)

Cree leukoencephalopathy

This is a disease of Cree and Chippewayan North American Indians. Affected infants often have hypotonia and motor delay prior to the onset of an encephalopathy. The encephalopathy occurs around 6 months of age and is precipitated by an incidental infection. The sudden onset of encephalopathy with seizures and pyramidal tract signs is followed by dementia, blindness, increasing pyramidal tract signs, dysautonomia, and stalled brain growth. The infants become decerebrate and die at around 1 year of age (Black et al. 1988; Fogli et al. 2002).

MRI of the brain shows a diffuse, symmetrical signal abnormality throughout the cerebral hemisphere white matter, and signal abnormalities in the globi pallida and often the thalamus. The diagnosis is made by demonstrating a mutation in the gene encoding ε-eIF2B (Fogli et al. 2002). Treatment of Cree leukoencephalopathy is symptomatic.

Ovarioleukodystrophy syndrome

This is a disorder of young women combining primary ovarian failure with a leukodystrophy. Menarche may be normal, delayed, or absent. There may be a history of learning difficulties in secondary education. Onset of neurological symptoms is in the second or third decade of life, with a slow dementia, pyramidal tract signs, and sometimes optic atrophy (Schiffmann et al. 1997; Fogli et al. 2003).

MRI of the brain shows a diffuse, symmetrical signal abnormality throughout the cerebral hemisphere white matter which is more prominent frontally and there may be some white matter volume loss posteriorly.

The diagnosis is made by demonstrating mutations in one of the genes for the β-, δ-, or ε-subunits of eIF2B. Treatment of ovarioleukodystrophy syndrome is symptomatic.

10.2.6 Megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts is the preferred terminology for this disorder which previously has been called megalencephalic cystic leukoencephalopathy and van der Knaap disease. It is inherited recessively, and approximately 80 per cent of cases are caused by mutations in the MLC1 gene.

In infants affected by megalencephalic leukoencephalopathy with subcortical cysts, macrocephaly is evident at birth or within the first 3 months of life. At this stage, neuroimaging already shows a diffuse leukoencephalopathy affecting cerebral white matter, often with temporal and parietal cysts. There may also be mild delay in developmental milestones. The first symptoms of the leukoencephalopathy develop usually between 18 months and 10 years of age. These consist of slowly progressive ataxia and pyramidal tract signs. Cognitive involvement is ’discrepantly mild’ at this stage. Some children can develop seizures and even coma after mild head injury. Children with megalencephalic leukoencephalopathy with subcortical cysts become wheelchair dependent usually in their teenage years and at this time a slow dementia develops, as can epilepsy. Death usually occurs in the second or third decade. However, the clinical course can be very variable even between affected members of the same family (van der Knapp et al. 1995; Singhal et al. 1996; Topcu et al. 1998).

MRI of the brain shows very distinctive findings (Fig. 10.7). The entire cerebral white matter has a diffuse signal abnormality with subcortical swelling and subcortical cyst formation in the temporal lobes and often the fronto-parietal lobes in addition. In some cases there are signal abnormalities from the cerebellar white matter. With time, the cysts become more extensive and cerebral atrophy develops (van der Knapp et al. 1995; Singhal et al. 1996; Topcu et al. 1998).

Fig. 10.7 Megalencephalic leukoencephalopathy with subcortical cysts. Coronal flair (A) and Axial T2-weighted (B) MRI showing multiple cysts, calcification and diffuse white matter loss. (Courtesy of Drs R. Jefferson, S. Jayawant, and P. Anslow.)

Fig. 10.7
Megalencephalic leukoencephalopathy with subcortical cysts. Coronal flair (A) and Axial T2-weighted (B) MRI showing multiple cysts, calcification and diffuse white matter loss. (Courtesy of Drs R. Jefferson, S. Jayawant, and P. Anslow.)

The diagnosis is made by detecting mutations in the MLC1 gene. However 20 to 30 per cent of patients with clinically and radiologically typical megalencephalic leukoencephalopathy with subcortical cysts do not have mutations in MLC1 and do not link to the MLC1 region of chromosome 22q. Patients with a similar clinical and neuroimaging picture, but without macrocephaly ‘normocephalic leukoencephalopathy with subcortical cysts’, also do not link to chromosome 22q.

Treatment of megalencephalic leukoencephalopathy with subcortical cysts is symptomatic.

10.2.7 Alexander disease

Alexander disease is named after the author who first described the clinical and neuropathological findings. It is mostly a sporadic disorder caused by de novo dominant mutations in the glial fibrillary acidic protein gene, GFAP, although dominant transmission of the adult form is well recognized.

Depending upon the age of onset of symptoms, there are three clinical subgroups:

  1. infantile with onset before 3 years, approximately 65 per cent of cases;

  2. juvenile with onset between 3 and 12 years, in approximately 25 per cent; and

  3. adult with onset after 12 years, in approximately 10 per cent.

Infantile Alexander disease

This presents towards the end of the first year and beginning of the second year of life, usually with seizures. Classically, thereafter the infants develop a rapidly progressive disorder with dementia, macrocephaly, epilepsy, cerebellar ataxia and pyramidal tract signs. Such affected infants survive a few months or years. However, infantile Alexander disease can evolve more slowly with early ataxia and pyramidal tract signs but dementia and macrocephaly occurring in mid-childhood and survival into teenage years (Rodriguez et al. 2001).

Juvenile Alexander disease

This commonly presents between 4 and 10 years with a worsening behaviour disorder, bulbar difficulties affecting speech and swallowing or a gait disorder. The disease slowly progresses with increasing bulbar difficulties, breathing problems, ataxia, pyramidal tract signs, and dementia. Survival is variable, with death occurring before 40 years (Gorospe et al. 2002; Li et al. 2005).

Adult Alexander disease

This is the most variable form clinically. Patients can present with the bulbar symptoms of palatal myoclonus, dysphonia, dysarthria or dysphagia, as well as with pyramidal tract disturbance, cerebellar ataxia, dysautonomia, or sleep apnoea. Symptoms gradually worsen over the years and decades, but, unlike the infantile and juvenile sub-groups, there appears to be no cognitive involvement, macrocephaly or epilepsy (Namekawa et al. 2002; Li et al. 2005).

MRI of the brain in infantile Alexander disease is often characteristic. There are diffuse symmetrical signal abnormalities in the hemispheric white matter, more extensive in the frontal regions, signal abnormalities in the basal ganglia, thalamus or brain stem, and contrast enhancement in these areas. MRI in adult Alexander disease often shows no hemispheric white matter involvement, instead showing signal change and later atrophy of the medulla and cervical cord. Diagnosis is confirmed by demonstrating mutations in the GFAP gene. The management of Alexander disease is symptomatic.

10.2.8 L-2–Hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria is a recessively inherited disorder caused by deficiency of L-2-hydroxyglutarate dehydrogenase. This produces a slowly progressive disorder comprising cerebellar ataxia, pyramidal tract signs, dementia, epilepsy, and often a movement disorder and macrocephaly. Early motor and cognitive developmental milestones are often delayed. The children usually present in the first 5 years of life with seizures, mental retardation, or unsteady gait. Thereafter the disease is slowly progressive, but at different rates in different individuals even from the same family (Barth et al. 1992; Moroni et al. 2000). Survival into late adulthood is not unusual, but a severe neonatal form with death in infancy has also been described (Chen et al. 1996; Fujitake et al. 1999).

MRI of the brain is quite characteristic. There is subcortical white matter swelling and signal change, signal change in the internal and external capsule, signal change in the putamen and dentate nuclei, and cerebellar atrophy. Peripheral nerve conduction studies are normal.

L-2-hydroxyglutaric aciduria is characterized by persistently high concentrations of L-2-hydroxyglutaric acid in all body fluids, relatively more in CSF than blood and urine. The diagnosis is made by demonstrating deficiency of L-2-hydroxyglutaric dehydrogenase in cultured skin fibroblasts. The disorder is caused by mutations in the L2HGDH gene on chromosome 14q22.1.

10.2.9 Canavan disease

Canavan disease is named after an early author of the clinical and neuropathological description; however it was only later that it was recognized as a distinct entity by van Bogaert and Bertrand. It is recessively inherited and caused by deficiency of aspartoacylase.

Symptoms of Canavan disease usually present before 6 months of age. Irritability, hypotonia, and abnormal visual behaviour usually develop after the first month but may be present from birth. Affected infants lose previously acquired developmental skills and may have seizures. As the disease progresses, macrocephaly and pyramidal tract signs appear and the limbs become increasingly rigid, opisthotonus and a pseudobulbar palsy develop. Eventually, the infant becomes decorticate and most die in the first 3 years, although prolonged survival into the third decade is well recognized (Ungar and Goodman 1983; Traeger and Rapin 1998).

MRI of the brain shows diffuse signal abnormality throughout the hemispheric white matter, sometimes sparing the internal and external capsules (Brismar et al. 1990). In Canavan disease, the concentration of N-acetylaspartate is raised in all body fluids. Increased concentrations of N-acetylaspartate are also present in the brain when measured using magnetic resonance spectroscopy. The diagnosis is confirmed by demonstrating deficient activity of aspartoacylase in cultured skin fibroblasts. N-acetylaspartate can be detected on standard urine organic acid analysis but it is important to ask the laboratory to search for this particular metabolite if this diagnosis is under consideration (Al-Dirbashi et al. 2007).

10.2.10 Pelizaeus–Merzbacher disease

This X-linked syndrome of central nervous system dysmyelination, occurring mainly in boys, characteristically presents in early infancy with involuntary eye movements or nystagmus. The classical form was described by Pelizaeus in 1885 and Merzbacher in 1910 (Koeppen 2005). Pelizaeus–Merzbacher disease is due to mutations affecting the myelin proteolipid protein gene PLP1 on Xq22 which encodes two proteins expressed in oligodendrocytes, the proteolipid protein which constitutes approximately half of central nervous system myelin protein, and the differently spliced isoform DN20. Duplications of the PLP1 gene are the commonest cause of Pelizaeus–Merzbacher disease (Inoue 2005). PLP1 gene deletions or null mutations are associated with more benign disease than that in patients with PLP1 gene duplications (Garbern 2007). Pelizaeus–Merzbacher disease probably results from accumulation of mutant protein aggregates intracellularly, resulting in oligodendrocyte dysfunction and death. The range of clinical disease associated with PLP1 mutations is wide, ranging from a relatively pure form of spastic paraplegia type 2 (Section 23.4.2), through classical forms of Pelizaeus–Merzbacher disease to severe connatal or congenital forms involving near complete absence of myelin sheaths and oligodendrocytes from the central nervous system. The early onset and slow progression can lead to an incorrect diagnosis of cerebral palsy. In a personal case we diagnosed a neonate presenting with hypotonia, nystagmus, and stridor by re-examining the neuropathology of a maternal uncle dying in early childhood some 30 years earlier with ‘cerebral palsy’.

The classical form

Involuntary eye movements or nystagmus develop in early infancy, associated with poor control of head posture and other motor functions, and tremor or titubation of the head and neck when seated (Garbern 2007). The disorder is slowly progressive, optic atrophy may develop, with paraparesis and cognitive impairment leading to death in the third to seventh decades. Laryngeal stridor, ataxia, athetosis, and spasticity can be prominent. Brain stem auditory evoked potentials are abnormal. This classical form is due to duplications of the PLP1 gene, which are found in up to 70 per cent of all cases of Pelizaeus–Merzbacher disease.

Connatal forms

A much more severe early onset or congenital form of Pelizaeus–Merzbacher disease occurs with some of the PLP1 point mutations, or in patients with three or more copies of the PLP1 gene (Wolf et al. 2005). Brain MRI reveals almost complete absence of myelin signal and extreme thinning of the corpus callosum. However brain MRI may be clinically unhelpful in the first few months of life because the normal infant has very little myelin; failure of normal myelination becomes apparent subsequently. Such patients may never achieve stable head control or other motor milestones, have severe mental retardation, suffer paroxysmal episodes which are probably epileptic in nature, and die between infancy and the second decade of life.

Intermediate forms

These occur between the classical and connatal extremes of the disease, and reflect some of more than 100 missense mutations of the PLP1 gene which account altogether for 15–20 per cent of Pelizaeus–Merzbacher disease pedigrees.

Female carriers

The female carriers of Pelizaeus–Merzbacher disease are either free of clinical disease, or have mild clinical disease compared to boys within the same family (Hurst et al. 2006). Clinical signs are rarely present in carrier females from families where the males are affected by mutations causing severe disease. The lowest risk for female disease occurs with PLP1 gene duplications. Females are most likely to develop significant disease if they have nonsense or null mutations.


Initially the diagnosis of Pelizaeus–Merzbacher disease is suspected when an infant boy develops slowly progressive eye movement and head control difficulties associated with MRI evidence of abnormal brain myelination. Naturally, the reliability of clinical diagnosis is enhanced if other family members are known to be affected. Molecular genetic testing for PLP1 gene reduplications or other mutations is diagnostic. Characteristically at autopsy the cerebral white matter shows a ’tigroid’ appearance with alternating areas of relatively preserved myelin staining, and others with loss of white matter staining. Peripheral nerve myelination is normal and axons are relatively preserved. A small proportion of patients have Pelizaeus–Merzbacher-like disease, unassociated with PLP1 mutations; recessive mutations in the GJA 12/Cx47 gap junction protein gene have been detected in some such patients (Orthmann-Murphy et al. 2007).

10.2.11 Aicardi–Goutières syndrome

This rare familial leukodystrophy was first described in 1984 and produces a progressive encephalopathy of early onset with characteristic basal ganglia calcification, best seen on CT, and features of leukodystrophy, best seen on MRI. There is an associated chronic CSF lymphocytosis with high CSF levels of interferon-alpha but without any other signs of infection (Goutières 2005). The condition can be mistaken for congenital infection. Mutations of genes encoding the exonuclease, TREX1, and the endonuclease complex, RNASEH2, have been identified as causes of the disease (Rice et al. 2007).

10.3 Primary grey matter degenerations of infancy and childhood

10.3.1 Overview of grey matter degenerations

These poliodystrophies mainly affect grey matter and include the Neuronal Ceroid Lipofuscinoses, or Batten’s disease (Section 10.3.2), the neuroaxonal dystrophies (Section 10.3.5), the neuronal storage diseases such as mucopolysaccarhidoses (Section 10.3.3), Lesch–Nyhan syndrome (Sections 10.3.4 and 40.4.11), and other grey matter disorders. They cause a variety of progressive deficits including cognitive decline, epilepsy, visual loss and motor abnormalities. The reader is also referred to other primary grey matter degenerations of infancy and childhood:

  1. Menke’s syndrome (Section 11.6.6);

  2. Alper’s disease (Section 30.5.7);

  3. Niemann–Pick disease type C (Sections 10.4.4 and 40.4.11);

  4. Myoclonic epilepsy with ragged red fibres, MERRF (Section 30.5.7);

  5. Other primary myoclonic epilepsies (Section 30.5.7);

  6. Neuroferritinopathy (Section 40.5.4);

  7. Juvenile Huntington’s disease (Section 40.5.2); and

  8. GM2 gangliosidosis or Tay-Sachs disease (Sections 10.4.2 and 40.4.11).

10.3.2 The neuronal ceroid lipofuscinoses

Frederick Batten (1903) first described two siblings with visual loss and dementia starting in the first decade realizing that these children were clinically distinct from children with Tay Sachs disease. Spelmeyer described a further series in 1905 with further refining of the entity, as being clinically distinct, by Jansky in 1908 and Bielscowsky in 1913. The numerous eponyms used to describe these diseases were confusing (Brett 1997). Batten’s disease is the term most often used in the United Kingdom. The nature of the material accumulating in the nerve cells was unknown until it was shown that the staining characteristics of the stored material was similar to ceroid or lipofuscin. This led to the term ‘neuronal ceroid-lipofuscinoses’ which has become the accepted name for this group of conditions (Zeman and Albert 1963). In terms of approach to diagnosis there are 3 main clinical types of neuronal ceroid lipofuscinoses (Table 10.1, V. 16). Recent genetic and biochemical research suggests there are at least 8 distinct disorders within this diagnostic group including the rare adult form also known as Kuf’s disease (Table 10.8). The morphological hallmark of this group of diseases is loss of nerve cells and accumulation of neuronal ceroid lipofuscinoses-specific lipopigments. There are different phenotypes and genotypes (Mole et al. 2005).

Table 10.8 The neuronal ceroid lipofuscinoses. Electrophysiological and diagnostic tests



Late infantile









EEG shows progressive slowing and reduction in amplitude and absent ERG.

Large VEP at slow rates of flash (may be seen on EEG) and absent ERG

Absent ERG and abnormal EEG (Slow with ill defined spike wave complexes)

Photosensitivity prominent in those with progressive myoclonic epilepsy

Vacuolated lymphocytes

[No info]



+ve in 25%(Fig. 10.2)

[No info]

Buffy coat

EM +ve

EM +ve

EM +ve

Rectal biopsy

PAS +ve sudanophilic and auto-fluorescent neuronal inclusions (Finnish snowballs)

PAS+ve sudanophilic and auto-fluorescent material in neurons. Curvilinear structure on EM

PAS+ve sudanophilic and auto-fluorescent granular material in neurons. Granular appearance on EM (fingerprint bodies)

PAS+ve neuronal inclusions required for diagnosis

Enzyme affected

Cathepsin D

White cell or fibroblast palmitoyl-protein thioesterase

White cell tripeptidyl peptidase1

Gene identified (chromosome location)

CTSD (11p15.5)

CLN1 (1p32)

CLN2 (11p15)CLN8 (8p23)CLN5 CLN6

CLN3 (16p12)


EM = electron microscopy

ERG = electroretinogram

LM = light microscopy

VEP = visual evoked potential

Late infantile neuronal ceroid lipofuscinosis

This common paediatric neurodegenerative diseases is familiar to most paediatric neurologists (Augestad and Flanders 2006). It is thought to be one of the commonest inherited neurodegenerative diseases with six new cases per year reported in the United Kingdom Progressive Intellectual and Neurological Deterioration study (Fig. 10.1) and a reported incidence in Germany of 0.46 in 100 000 live births (Mole et al. 2005). Development in the first and most of the second year is usually normal before subsequent slowing and then regression of cognition associated with the onset of a severe seizure disorder. Developmental of cognitive slowing usually predates the onset of seizures, perhaps by up to 1 year but its significance may not have been appreciated until the onset of the seizures. Diagnostic confusion may also occur because other relatively more common epilepsies with an impact on cognition can begin at this time including astatic myoclonic epilepsy (Section 30.5.5) and Lennox Gastaut syndrome (Section 30.5.5). Thus tardy diagnosis is relatively common. Multiple seizure types occur including myoclonic seizures with poor response to antiepileptic drug treatment. Unsteadiness and then pyramidal signs follow. Visual loss occurs with pigmentary retinal changes and the development of optic atrophy. A macular cherry red spot is not a feature. The ophthalmological findings will require examination by an experienced ophthalmologist. Steady progression to death is inevitable with a median age of death at 12 years (Augestad and Flanders 2006).

Brain imaging will show progressive cerebral atrophy but is not diagnostically helpful in the early stages. Electrophysiology is most useful in terms of suggesting the diagnosis. All EEGs in children with epilepsy under 5 years should include photic stimulation at slow rates of flash because of the pathognomonic change of grossly enlarged visual evoked potentials in neuronal ceroid lipofuscinosis (Veneselli et al. 2001). The electroretinogram response will be absent.

Most cases of the late infantile form are associated with mutations of the CLN2 gene. A number of rarer variants are described in association with mutations of the CLN5, CLN6, and CLN8 genes. The CLN8 gene is associated with the Turkish variant and the northern epilepsy variant (Ramirez-Montealegre et al. 2006).

Traditionally the diagnosis required biopsy of nervous tissue; typically examination of the myenteric plexuses in a full thickness rectal biopsy (Table 10.8). Brain biopsy would be diagnostic also but is rarely considered. The neuropathologist needs considerable expertise interpreting the sample and electron microscopy is required to see the characteristic curvilinear bodies. Similar pathological changes can be seen in sweat gland endothelium, smooth muscle, and blood vessel endothelium. Lymphocytes prepared from the blood buffy coat layer will show diagnostic abnormality but electron microscopic examination is required to identify the curvilinear bodies. This blood examination should be undertaken before invasive tissue biopsy. Nowadays the diagnosis should be made on measuring the tripeptidyl peptidase 1 enzyme level in leukocytes and can be confirmed with CLN2 mutation analysis. Biopsy is no longer required unless this enzyme level is normal. Management is symptomatic with no treatment affecting the course of the disease. Treatment with bone marrow transplantation has not proved successful despite initial promise (Lake et al. 1997; Yuza et al. 2005).

Juvenile neuronal ceroid lipofuscinosis

A Norwegian study suggested that this was the commonest form of neuronal ceroid lipofuscinosis with 63 affected cases born in Norway between 1957 and 1998 (Augestad and Flanders 2006). This study identified only seven cases of the late infantile form over the same time period. The child with juvenile neuronal lipofuscinosis will present with progressive visual failure in the first decade, usually during the primary school years. A pigmentary retinopathy develops followed by optic atrophy. Initially the diagnosis of a neurodegenerative disease may be missed because the cognitive decline and sometimes associated behavioural problems have been attributed to the visual difficulties. Epilepsy follows usually some years after the onset of visual symptoms, and then dementia occurs with increasing physical impairment. Many children will remain mobile during their early teens but eventual progression will lead to total dependence and then death usually in the third decade.

Diagnosis of this juvenile form is suggested by the clinical presentation with visual loss and finding an absent or reduced electroretinogram with abnormal EEG. The diagnosis can be confirmed by full thickness rectal biopsy where periodic acid Schiff +ve sudanophilic autoflourescence will be seen (Fig. 10.8) and characteristic ‘fingerprint like’ structures are seen on electron microscopy. In this juvenile form of neuronal ceroid lipofuscinoses 25 per cent of blood lymphocytes may show vacuolation providing a useful and relatively easy screening test. The juvenile form is associated with CLN3 mutations (Table 10.8).

Fig. 10.8 Juvenile neuronal ceroid lipofuscinosis. Electron microscopy of neurone from rectal myenteric plexus showing fingerprint bodies (courtesy of Dr W. Squier).

Fig. 10.8
Juvenile neuronal ceroid lipofuscinosis. Electron microscopy of neurone from rectal myenteric plexus showing fingerprint bodies (courtesy of Dr W. Squier).

Infantile neuronal ceroid lipofuscinoses

The earlier onset of this rapidly progressive form of neuronal ceroid lipfuscinoses distinguishes it from the late infantile form. It is often referred to by the eponym of Santavuori’s disease following a description of a large series in Finland where the condition seems to be more common than elsewhere (Vanhanen et al. 1997). Onset is usually in the first year with progressive mental deterioration, ataxia, and visual failure. Then the child regresses in the second year with loss of social interaction and motor skills and develops hypotonia. The rate of head growth decelerates and microcephaly becomes prominent. Visual loss occurs early and optic atrophy develops. Epilepsy appears relatively late in the course, usually with myoclonic seizures which can be difficult to manage. With progression the child becomes vegetative with increased tone, hyper-reflexia, and extensor plantar responses. The EEG is particularly helpful and will show slowing of rhythmic activity, bursts of sharp and slow waves and spike-wave discharges, and then progressive decrease in amplitude until the record becomes essentially isoelectric when the condition is fully established. The electroretinogram is reduced and then becomes extinguished but the curious abnormality of the visual evoked potentials seen in late infantile neuronal ceroid lipofuscinoses is not seen. The diagnosis is confirmed by finding periodic acid Schiff +ve sudanophilic autofluorescent substance deposited in neurones, smooth muscle cells, and vascular endothelium. These deposits are called ‘granular osmophilic deposits’ or sometimes ‘Finnish snowballs’. Palmitoyl protein thioesterase levels are low in leukocytes and fibroblasts allowing possible diagnosis from assay of blood leukocyte enzymes and thus avoiding tissue biopsy. The infantile form is associated with CLN1 mutations (Table 10.8). Most cases will present in this classical way but later onset variants of this infantile form associated with CLN1 mutation has been recognized including some rare cases presenting in adults (Mole et al. 2005).

Kuf’s disease

Kuf’s disease is a rare adult form of neuronal ceroid lipofuscinoses. Two phenotypes have been described, one characterized by epilepsy and the other with dementia (Berkovic et al. 1988). Autosomal recessive and dominant forms have been described (Josephson et al. 2001). The clinical picture in Kuf’s disease is characterized by dementia, seizures, and extrapyramidal features. By contrast with the earlier onset forms, visual loss is not prominent. Deficiency of palmitoyl protein thioesterase suggests the rare adult onset presentation of CLN1 mutations (Ramadan et al. 2007).

Congenital form

These present with severe neurological abnormalities at birth including intractable seizures, spasticity, apnoea, and microcephaly. They are associated with mutations of the CTSD gene on chromosome 11 with abnormal cathepsin D enzyme activity (Table 10.8).

10.3.3 Lesch–Nyhan syndrome

This disorder of purine metabolism is due to deficiency of hypoxanthine-guanine phosphoribosyl transferase, HGPRT, activity (Table 10.1, VII 1a). It is an X-linked disorder, first described biochemically in 1964 by Lesch and Nyhan, which produces a characteristic clinical pattern, with progressive slowing of mental and motor development starting at 6 months. Choreoathetoid movements and dystonic spasms usually emerge in the second year (Section 40.4.11). Self injurious behaviour then emerges subsequently and is almost pathognomonic for the disease. The self mutilation seems to be compulsive yet is clearly distressing for both child and carers.

Biochemically there is overproduction of uric acid leading to hyperuricaemia, nephrolithiasis, and gout. Untreated, gouty tophi appear and death from renal failure results. Orange grit in the urine seen on the nappy suggests the diagnosis. Allopurinol reduces the production of uric acid and helps prevent gouty renal failure but does not affect the neurological manifestations of the disease. The condition can be confused with evolving dyskinetic cerebral palsy and survival to adulthood is now usual.

The pathogenesis of the neurological manifestations is not understood. There is evidence that depletion of dopamine in the basal ganglia during foetal brain development may be important (Smith and Jinnah 2007). However postnatal dopaminergic treatment of affected children is not helpful. The clinical phenotype depends on the level of residual HGPRT activity and milder forms are recognized now. The involuntary movements are difficult to treat. The self injurious behaviour poses most challenging and distressing aspect of management. Curiously not all children develop this self injurious problem, although it can emerge late on. The capacity for harm can be reduced by distraction, providing restraints and by dental clearance. There is some evidence that deep brain stimulation may suppress this distressing phenomenon (Cif et al. 2007).

10.3.4 Infantile neuroaxonal dystrophy

Also known as Seitelberger’s disease, infantile neuroaxonal dystrophy is a neurodegenerative disorder usually of onset between 6 months and 2 years of age. Typically patients develop bilateral upper motor neurone signs with spasticity, sometimes after a hypotonic phase; and the combination of extensor plantar responses with loss of ankle tendon reflexes is typical. Eye movement disturbances, particularly nystagmus, and optic atrophy may be present early on. Impaired hearing can occur. Cognitive deterioration is common, but extrapyramidal disorders and seizures occur less frequently. Electromyography may show signs of denervation with normal motor conduction velocity pointing to anterior horn cell disease and can be helpful diagnostically in distinguishing neuroaxonal dystrophy from other central nervous system degenerations.

MRI typically shows pronounced atrophy of the cerebellum, with diffuse hyperintensity of the cerebellar cortex. Hypointensity of the globus pallidus, subthalamic nuclei, and substantia nigra are variably present, and sometimes the ‘eye of the tiger sign’ normally associated with the PANK2 mutation of pantothenate kinase-associated neurodegeneration, or neuroferritinopathy (Section 40.5.4) can be present (Kumar et al. 2006). MR spectroscopy of the white matter may show significantly reduced N-acetyl aspartate (Khateeb et al. 2006).

The disorder is named after the characteristic histological finding of axonal spheroids on biopsy of peripheral or central nervous tissue, and biopsy of nerve and muscle was initially the diagnostic test. However, similar axonal spheroids can be found in a variety of other neurodegenerative disorders, so this finding is not pathognomic.

Mutations of the PLA2G6 gene on chromosome 22q13.1, encoding phospholipase A2 group VI is associated with infantile neuroaxonal dystrophy (Khateeb et al. 2006; Morgan et al. 2006). Detection of PLA2G6 mutations offers the prospect of non-invasive and more specific diagnosis of infantile neuroaxonal dystrophy. The phospholipase A2 enzymes catalyse the release of fatty acids from phospholipids, and seem to promote brain iron deposition by some mechanism as yet not understood.

Infantile neuroaxonal dystrophy carries a wide differential diagnosis, including metachromatic leukodystrophy (Section 10.2.2), neuronal ceroid lipofuscinoses (Section 10.3.2), Leigh’s syndrome (Section 10.5.3) and the autosomal recessive disorder, Schindler disease due to deficiency of alpha-N-acetylgalactosaminidase (Gordon 2002). In addition neuroferritinopathy due to mutations of the pantothenate kinase-associated neurodegeneration PANK2 gene, previously known as Hallervorden–Spatz disease, may show similar MRI findings, but generally presents as an extrapyramidal syndrome (Section 40.5.4). Neuroferritinopathy does not show axonal steroids in the peripheral nervous system, and tends to present later in infancy, or during childhood, with patients often surviving into their third decade. By contrast, infantile neuroaxonal dystrophy usually causes death before the age of 10 years.

10.4 Lysosomal disorders affecting the brain

10.4.1 Introduction to the neuronal storage diseases

In these conditions deficiency of a lysosomal enzyme leads to accumulation of various metabolites in neurons with subsequent neurodegeneration (Table 10.1, V 1–16). This accumulation or ’storage’ can occur also in other organs and may lead to enlarged liver and spleen or allow diagnosis from examination of blood or bone marrow. Enzyme replacement and gene therapy are being explored as treatments (Beck 2007). These conditions often produce a dysmorphic appearance (Table 10.3) and skeletal deformity, which may lead to secondary spinal cord compression. The gangliosidoses are a group of related disorders in which neuronal storage of gangliosides, which are complex lipids, occurs. The peripheral neuropathy and vascular disorders of Fabry disease, due to α-galactosidase deficiency are considered elsewhere (Table 10.1, V13 and Section 21.8.5). The progressive proximal myopathy of Pompé disease, or α-glucosidase deficiency (Table 10.1, V 2) is considered under muscle disorders (Section 24.6.1).

10.4.2 GM2 gangliosidosis or Tay Sachs disease

First described in London by Warren Tay in 1881 and then in New York by Bernard Sachs in 1887 this condition is caused by deficiency of the enzyme Hexosaminidase allowing massive accumulation of ganglioside in the brain (Table 10.1, V15). This autosomal recessive condition is particularly common among Ashkenazi Jews occurring with a gene frequency in this population in New York of 1:30. The common infantile form of the disease presents in the first year usually before the child has acquired the ability to sit. The rapid development of blindness may initially cause diagnostic confusion. Loss of visual interest and social interaction may lead to initial thought that the child has developed an early and severe autistic-like regression. However, the rapid developmental decline soon suggests the metabolic nature of the underlying problem. Ophthalmological examination will reveal optic atrophy and a cherry red spot in 90 per cent of cases. Once seen this finding is very characteristic and in this clinical setting is diagnostic (Fig. 10.9). Affected infants develop a characteristic exaggerated startle response which usually appears early on in the course of the disease and is suggestive of the diagnosis. Muscle tone is initially reduced but then increases steadily as the disease progresses. The tendon reflexes are brisk and plantar responses extensor. This neuronal storage disorder causes a striking increase in head size (Fig. 10.10). Epilepsy is common although the early EEG may show very little abnormality but then deteriorates as the disease progresses.

Fig. 10.9Cherry red spot at the macula on fundoscopy. Gaucher’s disease showing a cherry red macular spot with surrounding retinal pallor. ( A.)

Fig. 10.9
Cherry red spot at the macula on fundoscopy. Gaucher’s disease showing a cherry red macular spot with surrounding retinal pallor. ( A.)

Fig. 10.10 Tay Sachs disease, GM2 gangliosidosis. Family photographs showing (A) normal head size and attentiveness at 3 months age and (B) macrocephaly and diffuse impairment at 4 years of age (C) Head circumference chart showing progressive disproportionate increase in head size. (With kind permission of the family.)

Fig. 10.10
Tay Sachs disease, GM2 gangliosidosis. Family photographs showing (A) normal head size and attentiveness at 3 months age and (B) macrocephaly and diffuse impairment at 4 years of age (C) Head circumference chart showing progressive disproportionate increase in head size. (With kind permission of the family.)

The electroretinogram is not affected by this disease as compared with the neuronal ceroid lipofuscinoses. The diagnosis is made by measurement of hexosaminadase activity in blood. The enzyme exists as hexosaminidase A and B and 3 patterns of deficiency are recognized:

  1. Type 1 GM2 gangliosidosis is commonest and involves marked deficiency of hexosaminidase type A and high levels of type B;

  2. In Type 2, Sandhoff’s disease, components A and B are both reduced; and

  3. In Type 3, the rarest form, the levels of A and B are normal on assay but there is deficiency of an activator protein.

The clinical picture is the same with all 3 types. GM2 ganglioside accumulates in brain and other tissues and the condition can be diagnosed by biopsy although this is not necessary for diagnosis unless the rare activator protein deficiency is suspected. Survival beyond the age of 4 years is rare.

Late onset forms of GM2 gangliosidosis are described but are rare. Recently a series of patients with juvenile or subacute GM2 gangliosidosis has been described (Maegawa et al. 2006). A range of neurological symptoms and rates of progression are described. In general, the earlier the onset of the disease the more rapid the progression.

10.4.3 GM1 gangliosidosis

This disorder is also known as generalized gangliosidosis, Landings disease, or pseudo-Hurler’s disease. The disorder is less common than GM2 gangliosidosis (Section 10.4.2) and usually presents in two forms (Table 10.1, V14 a, b) with an additional rare adult onset variety

Type 1 with early onset

In this, infants present with failure to thrive, abdominal visceromegaly, coarse features, and kyphosis. Affected infants do not feed well, have low tone, and do not make any developmental progress. Extensive Mongolian spots in the newborn have been described in this condition and can suggest the diagnosis before more obvious clinical features have developed (Table 10.3) (Ashrafi et al. 2006). The facial dysmorphism increases as the infant grows older and development is significantly impaired; these infants usually fail to acquire the ability to sit unsupported and show early loss of any acquired skills. Epilepsy occurs and a macular cherry red spot can appear. In the past the term ‘Tay-Sachs disease with visceral involvement’ was used to describe these children.

The condition is due to deficiency of the enzyme β-galactosidase causing accumulation of the ganglioside GM1 within neurons and other terminal β-galactose residue compounds in the viscera causing significant hepatosplenomegaly. Foamy cells will be seen in the bone marrow and vacuolated lymphocytes are seen in the peripheral blood film. Firm diagnosis depends on enzyme assay in leukocytes or skin fibroblasts. The condition is autosomal recessive and rapidly progressive with most type 1 cases dying before their 3rd birthday, usually with respiratory infection.

Type 2, the late infantile or juvenile form

This presents between 1 and 5 years of age with loss of acquired skills, evolution of pyramidal tract signs, and decerebrate rigidity. The early dysmorphism, hepatosplenomegaly, and severe skeletal deformity are absent in this form of GM1 gangliosidosis but minor skeletal changes are evident on X-ray such as beaking of the lumbar vertebrae as seen in Hurler’s syndrome. Death in the first decade is usual (Chen et al. 1998).

Type 3, with adult onset

This very rare form shows slower progression with the evolution of both pyramidal and prominent extrapyramidal signs and with dementia. The absence of visceromegaly in the juvenile and adult forms and the non-specific bone marrow findings makes the diagnosis difficult. Diagnosis requires assay of the leukocyte enzymes driven by consideration of this diagnostic possibility (Muthane et al. 2004).

10.4.4 Niemann-Pick disease

Niemann–Pick disease refers to a group of lipid storage disorders which are usually classified into two main groups with two subtypes in each (Table 10.1, V8 and 9):

  1. Group 1 includes Niemann–Pick disease types A and B and are due to sphingomyelinase deficiencies

  2. Group 2 includes Niemann–Pick disease types C and D and are due to a defect in cholesterol transport.

Niemann–Pick type A

The infantile form is the classical subtype of the disease and accounts for half of all cases. Onset may be prenatal leading to many infants being born with low birth weight. There is early hepatosplenomegaly and jaundice develops in some. There is failure to thrive and early neurological involvement. Most infants fail to acquire the ability to sit independently. Pyramidal tract signs develop along with ‘head retraction’, squint, and seizures. Few survive beyond 2 years. There is deficiency of the enzyme sphingomyelinase with toxic accumulation of the fatty substance sphingomyelin in brain and visceral cells. The effects of pulmonary and bony infiltration of the toxin may be seen on X-rays of the chest and long bones. Treatment is symptomatic.

Niemann–Pick type B

This differs from type A in that there is no neuronal storage but massive visceral storage of sphingomyelin. This form of the disease is called visceral, non-neuronopathic Niemann–Pick but is also due to deficiency of spingomyelinase activity. These children present after 2 years with recurrent respiratory symptoms. Pulmonary infiltrates may be seen on chest X-ray. Bone involvement is also seen and haematological problems are common. Survival into adulthood occurs although individuals are prone to infection and may die from liver failure due to cirrhosis.

Intermediate types between A and B are described and the disease is best considered a single entity with a spectrum of phenotypes (Schuchman 2007).

Niemann–Pick type C

This is not due to sphingomyelinase deficiency but due to a defect in cholesterol transport. This disorder is grouped with types A and B because the bone marrow shows similar storage cells. Early jaundice occurs in 60 per cent of cases, often labelled as neonatal hepatitis. This settles and then the child presents with neurological symptoms and splenomegaly. The neurological symptoms can appear at any time during childhood and may be delayed until the teenage years. Epilepsy is common although it is not myoclonic. The most striking clinical finding is a vertical ophthalmoplegia with particular difficulty looking downwards which may lead to problems going downstairs and avoiding objects at ground level. The ocular motor problem is restricted to voluntary eye movements and the vestibulo-ocular reflex is full. Although defects of ocular movement are seen in other conditions, including ataxia telangiectasia (Section 11.5), this vertical supranuclear ophthalmoplegia coupled with a progressive neurodegenerative disorder, is pathognomonic for Niemann–Pick type C. Other neurological features include ataxia, dementia, and in some an akinetic rigid syndrome has been described. Many patients do not have abdominal visceromegaly. The disorder is due to mutations of the NPC1 gene in 95 per cent of cases and the NPC2 gene in the remainder. The clinical heterogeneity and wide age range for presentation often causes delay in diagnosis including late into adult life. The biochemical diagnosis of Niemann–Pick disease type C can be determined by assay of skin fibroblasts (Sevin et al. 2007b). The diagnosis is suggested by bone marrow examination or rectal biopsy showing cells with characteristic inclusions. The classic Niemann–Pick cell in Types A and B is large with ‘foamy’ cytoplasm but in type C the vacuoles are not uniform and their contents do not stain with Sudan dyes. Sea blue histiocytes may be seen in the older patient but are rare. Experienced pathological examination is required to confirm this diagnosis histopathologically. The diagnosis can be confirmed on skin fibroblast culture and with mutation analysis (Millat et al. 2001).

Niemann–Pick type D

This refers to a specific population of patients with a condition similar to Type C who originated in Nova Scotia. Treatment is symptomatic and survival is dependant on the age of onset and rate of progression. Some do survive into adulthood.

10.4.5 Mucopolysaccharidoses

The mucopolysaccharidoses are a large group of lysosomal storage diseases caused by deficiency of enzymes catalysing the degradation of glycosaminoglycans, or mucopolysaccharides. Children within this group of disorders develop characteristic clinical findings. In all there is developmental slowing with early mental retardation. Corneal clouding may become apparent and there is usually enlargement of the liver and spleen and the development of coarse dysmorphic features. Bony involvement causes skeletal deformity and the hands tend to be broad with short fingers; this can be diagnostically helpful. The tongue often protrudes and growth is restricted. There are a large number of variants within this group (Table 10.1, V1a–o). All the mucopolysaccharidoses are autosomal recessive, apart from Hunter’s syndrome which is X-linked recessive, and have varying biochemical bases (Brett 1997; Clarke 2008). Screening for mucopolysaccharidosis is performed by analysis of urinary glycosaminoglycans, GAG. A raised urinary glycosaminoglycan: creatinine ratio is suggestive of mucopolysaccharidosis but this must be followed up by glycosaminoglycans electrophoresis which shows characteristic patterns for the different mucopolysaccharidosis disorders.

Hurler’s syndrome or MPS IH

This is the common classical and most severe type. The diagnosis may not be obvious in the first year because development may seem normal or only slightly delayed. Then, there is developmental standstill, before regression with loss of skills and evolution of the dysmorphic features and corneal clouding. Increasing hepatosplenomegaly occurs. Previously their appearance led to these children being described by the derisory term ‘gargoyles’. With time, poor growth and skeletal deformity increase, obstructive hydrocephalus can develop and visual impairment and deafness can occur. Excessive respiratory secretions with nasal obstruction and respiratory infection complicate the toddler years. Cardiac and respiratory tract involvement combined with the neurological decline leading to death before the end of the first decade. The deficient enzyme is α-L-iduronidase and there is increased urinary excretion of both heparan and dermatan sulphate.

Scheie’s syndrome or MPS IS

This involves deficiency of the same α-L-iduronidase enzyme, but intelligence and growth are not affected with survival well into adult life. Carpal tunnel syndrome may occur.

Hunter’s syndrome or MPS II

In this X-linked recessive variant, boys do not develop corneal clouding and progression is slower than that seen in Hurler’s syndrome. The range of disease severity is wide. Severe forms involve facial dysmorphism, short stature, hepatosplenomegaly, bone abnormalities, heart valve disease, mental retardation and early death. Mild forms can show no central nervous system involvement and prolonged survival. The severity of the disease is linked to the particular mutation affecting the gene encoding iduronate sulfatase, IDS, located at Xq28 with over 300 mutations described (Vafiadaki et al. 1998; Muñoz et al. 2008).

Sanfilippo disease or MPS III

In this the dysmorphic features are relatively mild and there is no corneal clouding. This diagnosis may be overlooked. However the cognitive decline and often severe behavioural problems should alert the clinician to the possibility (Moog et al. 2007).

Morquio’s disease or MPS IV

This is a mucopolysaccharidosis without direct neurological involvement unless these are secondary to skeletal complications, a circumstance posing complex management decisions (Giugliani et al. 2007). The skeletal involvement is severe but there is no facial dysmorphism. Compression of the spinal cord and medulla from atlanto-axial subluxation pose a challenging neurosurgical decision. Carpal tunnel syndrome can also occur.

Maroteaux–Lamy disease MPS VI

This resembles Hurler’s syndrome but there is normal intelligence and urinary excretion of dermatan sulphate is absent. Corneal clouding can occur and skeletal deformity cause spinal cord compression. Several subtypes are described. Management guidelines for this disorder have recently been published (Giugliani et al. 2007).

Sly disease MPS VII

This has a variable phenotype ranging from the manifestations of Hunter’s to those of Morquio’s disease.

Several lysosomas storage disorders are now treatable through a range of therapies. Bone marrow transplantation is effective in MPS I Hurler (Boelens 2006, Orchard et al. 2007). If performed early enough in life, < 18 months, sufficient enzyme is produced in the central nervous system to prevent neurological deterioration allowing normal intellectual development. Some aspects of disease such as spinal scoliosis progress despite bone marrow transplantation. The recognition that enzymes are targeted to the lysosome by mannose-6 phosphate has allowed the development of successful enzyme replacement therapy for several lysosomal storage diseases (MPS I Hurler/Scheie and Scheie phenotypes, II, VI, Pompe, Gaucher and Fabry) (Rohrbach et al., 2007). Enzyme replacement therapy, however, does not cross the blood–brain barrier and is not suitable for disorders associated wiith neuroregression. Other new therapies using small molecules have the advantage of blood-brain barrier penetration. These treatments may function a ‘chaperones’, by ’stabilising a misfolded enzyme’ or substrate reduction therapies (Winchester et al. 2000, Butters et al. 2003). With such approaches to treatment, the long-term outcome of these disorders is likely to be radically altered over the next few years.

10.4.6 Gaucher’s disease

First described in 1882 by Gaucher this disease is now recognized to be a group of a disorders which have in common the presence of ‘Gaucher cells’ in the bone marrow and reticulo-endothelial system. There are both visceral and neuronopathic forms and in all there is a defect in the cleavage of glucose from glucocerebroside due to deficient activity of the enzyme β-glucocerebrosidase (Table 10.1, V10a–c). Four common gene mutations are recognized although other rarer mutations may explain the considerable heterogeneity particularly in Type 1 and Type 3 forms of the disease (Beutler 2006).

Adult Gaucher’s disease or Type 1

This is the commonest form and is a slowly progressive disorder with marked hepatosplenomegaly. There is accumulation of glucocerebroside in reticuloendothelial cells. The condition is non-neuronopathic and is rare in children. The disease causes problems because of its effects on the haematological and the skeletal systems. Clinical problems include pain, pathological fractures and hypersplenism.

Acute infantile Gaucher’s disease or Type 2

This presents in infancy with poor feeding and failure to thrive. Mental development is slow from the start and then stalls with the development of spasticity, head retraction, and increasing bulbar dysfunction. Occasionally there may be a retinal cherry red spot. Seizures can occur and examination shows enlarged liver and spleen, characteristically with the spleen bigger than the liver. The haematological effects are severe with anaemia and thrombocytopenia. The serum acid phosphatase is raised. Measurement of the enzyme in leukocytes or fibroblasts and finding Gaucher cells in marrow will distinguish this disease from Niemann Pick and other neurovisceral storage diseases. Infants with the severe infantile form will rarely survive beyond 1 year.

Subacute/juvenile Gaucher’s disease or Type 3

This is a curious intermediate form of the disease first described in Sweden with a wide range of clinical severity noted even within the same family. Onset can be between birth and adulthood with an average age at diagnosis of 2.5 years. Presentation is often with abdominal distension due to splenomegaly (Brett 1997). Although the splenomegaly can be massive, splenectomy should be avoided for as long as possible because this seems to be associated with a more rapid progression of the disease. The skeletal and haematological effects of the disease are prominent but neurological involvement develops with cognitive slowing. Seizures and oculomotor apraxia are sometimes seen. The prognosis for all the neurological variants is an inevitable decline and eventual death. Survival into adulthood is uncommon.

In recent years enzyme replacement therapy has proved highly effective for patients with Gaucher’s disease type 1 (Weinreb et al. 2002) and some patients with type 3 disease (Davies et al. 2007a). In type 1 disease treatment reduces the size of the liver and spleen and improves the skeletal abnormalities. Enzyme replacement has no effect on neurological progression of type 2 Gaucher disease. Bone marrow transplantation will reverse the non-neurological effects but carries a high mortality and also does not affect the neurological outcome. Enzyme replacement therapy has an uncertain effect on the neurological progression in type 3 disease. Severity scoring tools can be used to monitor the neurological features in type 3 disease and to assess the efficacy of treatment (Davies et al. 2007b).

10.5 Brain mitochondrial diseases

10.5.1 Overview of the respiratory chain deficiencies

Genetic disorders impairing oxidative phosphorylation are responsible for a wide range of neurological, muscular, and systemic disorders presenting in childhood or later. They all impair ATP synthesis by the respiratory chain in mitochondria, and result from mutations of either nuclear or mitochondrial genes encoding mitochondrial respiratory chain proteins (Fig. 10.11). Since mitochondria are passed on through the female germ line, being contained in the ovum, those mitochondrial disorders resulting from mutations of mitochondrial DNA show a maternal pattern of inheritance or are sporadic.

Fig. 10.11 The mitochondrial respiratory chain located in the inner mitochondrial membrane which oxidizes body fuel molecules to create ATP. Of the five complexes, only the peptides of complex 2 are entirely encoded by nuclear DNA.(Adapted from Munnich et al. 2000.) Key:——♦ electron flux——♦ proton fluxETF electron transfer favoproteinUQ quinineC cytochrome C

Fig. 10.11
The mitochondrial respiratory chain located in the inner mitochondrial membrane which oxidizes body fuel molecules to create ATP. Of the five complexes, only the peptides of complex 2 are entirely encoded by nuclear DNA.(Adapted from Munnich et al. 2000.) Key:

——♦ electron flux

——♦ proton flux

ETF electron transfer favoprotein

UQ quinine

C cytochrome C

Two important principles underlie clinical suspicion of a mitochondrial disorder:

  1. Usually they are progressive disorders commencing in the first third of life. A notable exception is Leber’s hereditary optic neuropathy (Section 12.5.2); and

  2. Because mitochondria are the ubiquitous energy source of the cells in actively metabolizing organs, the diagnosis is particularly suggested on encountering a patient with a constellation of seemingly unconnected clinical abnormalities. Furthermore, patients who present with one discrete symptom, often progress to develop other seemingly unrelated symptoms, thereby providing a clue to a mitochondrial disorder.

Although this section addresses neurological and muscular presentations of mitochondrial disorders, it should be noted that mitochondrial disorders often include, or can present with systemic features of cardiac, renal, nutritional, hepatic, endocrine, haematological, audiological or dermatologic disease, or dysmorphic features. The main neurological and skeletal muscular mitochondrial disorders are summarized in Table 10.9, which directs the reader to the main section in which these individual disorders are covered. Neuromuscular symptoms are the most common reason for referral of patients with mitochondrial disorders (Von Kleist-Retzow et al. 1998).

Table 10.9 Inherited mitochondrial disorders causing nervous system or skeletal muscle disease. The characteristic presenting symptom is shown in bolditalics for each syndrome


Neurological features

Systemic features



Usual age of onset

Section with main coverage

Alpers progressive sclerosing poliodystrophy

Myoclonic epilepsy


Hepatic enlargement/insufficiency


POLG (most)



Barth syndrome






Chronic progressive external ophthalmoplegia

Progressive external opthalmoplegia


Various nuclear genes including POLG1, Twinkle, ANT1

Also multiple mtDNA mutations




Hereditary spastic paraplegia

Leg spasticity


6q24/SPG7 – paraplegin

Young adults


Kearns Sayre syndrome

Progressive external ophthalmoplegia

Cerebellar ataxia

Retinitis pigmentosa

Heart block

Growth retardation


MtDNA – various mutations

Childhood and adolescence



Leber hereditary optic neuropathy

Subacute visual loss—often sequential

Optic atrophy

Cardiac involvement


Various MtDNA mutations

Young adults


Leigh’s syndrome of subacute necrotising encephalomyopathy

Progressive psychomotor deterioration

Movement disorders (older children) Neurogenic respiratory failure

MRI leukodystrophy and changes in basal ganglia, brain stem




Various nuclear mutations including SURF1

Various mtDNA mutations

Pyruvate dehydrogenase E1 gene

Infancy and early childhood


Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes ‘MELAS’

Recurrent stroke-like episodes

Migraine-like headaches

Proximal weakness




mtDNA point mutations 3243-tRNALeu (UUR) (in 80%)




Mitochondrial, neurogastrointestinal encephalomyopathy ‘MNGIE’

Peripheral neuropathy

MRI leukoencephalopathy

Eye movement disorder


Thin body Gastrointestinal dysmotility


22q13/Thymidine phosphorylase gene


Young adults


Myoclonic epilepsy with ragged red fibres ‘MERRF’

Myoclonic epilepsy




mtDNA 8344-tRNALys


Young adults



Neuropathy, Ataxia, Retinitis Pigmentosa ‘NARP’


Cerebellar ataxia

Retinitis pigmentosa


mtDNA/nt-8993 ATPase 6



Pearson Syndrome

Kearns–Sayre syndrome in survivors of >5 years

Refractory sideroblastic anaemia


Diabetes mellitus



Similar to Kearns Sayre syndrome



Wolfram syndrome

Optic atrophy

Diabetes mellitus

Diabetes insipidus




Key: AD = autosomal dominant

AR = autosomal recessive

POLG = polymerase gamma

Neurological presentations. Patients may present at birth or in infancy with hypotonia, movement disorders, seizures, reduced alertness, poor sucking, respiratory distress, or lactic acidosis. Other children may develop normally, only to present in childhood with encephalopathy. In older children and young adults, abnormal eye movements, altered respiratory control, ataxia, myoclonic seizures, peripheral neuropathy, or spastic paraplegia are likely to be the main neurological features. MRI evidence of leukodystrophy with psychomotor retardation is common in mitochondrial neurological disorders (Table 10.7). Some patients initially present, or worsen during intercurrent infections, or in association with a suspected toxin exposure; this may reflect the precarious pre-existing tissue energy metabolism in patients with mitochondrial disorders.

Muscular presentations. Because of its role in translating aerobic metabolism into mechanical energy, muscle is prominently affected in mitochondrial disorders. In older patients, proximal muscle weakness is often a feature of mitochondrial cytopathies. Muscle biopsies, revealing ragged red fibres reflecting aggregations of mitochondria are present in many, although not all, mitochondrial cytopathies (Section 24.1.7). Thus, muscle biopsy can provide a useful clue to the presence of an underlying mitochondrial disorder, not only in those with symptoms and signs of muscle weakness, but also in other patients in whom mitochondrial disease is suspected. Mitochondrial myopathy is often associated with lactic acidosis, or significant elevation in lactic acid levels triggered by exercise. A severe infantile mitochondrial myopathy may be due to cytochrome C oxidase deficiency, sometimes reversibly, but usually leading to death in the first year of life (DiMauro et al. 1983). Episodic myalgia or myoglobinuria has been attributed to respiratory chain deficiencies (de Lonlay-Debeney et al. 1999).

Investigation of mitochondrial encephalomyopathies. In older children and adults with typical syndromes of mitochondrial disease, specific molecular genetic testing may be ordered (Section 3.8.3). However, with presentations earlier in life, when the full syndrome may not have become evident, targeted molecular genetic testing may not be possible. Mitochondrial genetic testing may be negative on blood, but positive on muscle mitochondria due to the phenomenon of heteroplasmy, in which mutated mitochondrial DNA molecules may be differently distributed in tissues. This reinforces the diagnostic role of muscle biopsy, not only by revealing ragged red fibres, but as a source of genetic material. MRI of the brain commonly shows white matter abnormalities, or diffuse leukodystrophy, in mitochondrial disorders. Alternatively it may show the changes of Leigh’s disease in the basal ganglia, thalamus, and brain stem (Section 10.5.3).

Measurement of serum lactate and pyruvate, and CSF lactate’ can be especially revealing of a respiratory chain deficiency, especially in children with acute clinical presentations. Blood samples should be taken fasting and 1 hour after feeding, with scrupulous sampling and sample processing techniques to avoid artefactually high levels of lactic acid. Respiratory chain deficiencies are particularly suggested by lactate:pyruvate ratios elevated above 20, in the presence of persistent hyperlactataemia (Munnich et al. 1996). Lactate, alanine, and lactate:pyruvate ratios can be measured in the CSF if no elevation of plasma lactate has been observed in a patient suspected of having central nervous system disease due to respiratory chain disorders.

Because mitochondrial disorders often affect other organs as well as the central nervous system, the diagnosis and full assessment of a mitochondrial disorder usually requires careful examination and investigation of muscle, heart, kidney, endocrine system, liver, gut, bone marrow, eyes, and ears. Sometimes the first line biochemical tests, apart from the blood lactate, can suggest a mitochondrial disorder: raised alanine and proline on analysis of plasma amino acids, or raised 3-methylglutaconic acid and 3-methylglutaric acid on urine organic acid analysis.

Treatment. For the vast majority of patients with a mitochondrial disorder, there is no treatment that improves the function of the defective mitochondria and hence leads to clinical improvement in central nervous system disease. Exceptions to this include:

  1. High dose ubiquinone, coenzyme Q10, in some patients in whom reduced activity of complex II + III is secondary to a defect in ubiquinone synthesis.

  2. Riboflavin in some patients with complex I deficiency.

Defective functioning of mitochondria in the central nervous system sometimes leads to secondary problems which can be corrected, such as central nervous system folate deficiency in Kearns Sayre syndrome. In patients with the MELAS syndrome of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, a beneficial effect of L-arginine on the outcome of stroke-like episodes has been reported. Drugs known to inhibit the respiratory chain, such as valproate and barbiturates should be avoided in patients with mitochondrial disease. Antioxidants such as vitamin E, vitamin C, and ubiquinone are frequently used but firm evidence of their ability to slow the progress of respiratory chain disorders is lacking. The same is true of the use of multivitamin cocktails. Some neuromuscular problems may be treatable including surgery for ptosis, kyphoscoliosis, and feeding difficulties or reflux. Hearing difficulties respond well to aids and cochlear implantation. For problems outside the central nervous system, there are many possibilities for treatment including cardiac pacing, anti-heart failure medications and heart transplantation, and treatment of diabetes, hypoparathyroidism, adrenal insufficiency, correction of electrolyte problems caused by tubulopathy, renal transplantation, pancreatic enzyme replacement, and parenteral nutrition. The ethics surrounding the use of treatments such as transplantation need to be considered carefully given the tendency of mitochondrial disorders to involve progressively more tissues and organs.

10.5.2 Pearson syndrome

The Pearson marrow-pancreas syndrome is of neurological interest because 20 per cent of affected infants have hypotonia, developmental delay, or ataxia, and approximately 10 per cent will develop Kearns Sayre syndrome subsequently (Lee et al. 2007). In the first year of life, half of the patients present with a refractory sideroblastic anaemia, often with pancytopaenia, and half present with diarrhoea and failure to thrive, representing exocrine pancreatic dysfunction sometimes associated with subtotal villus atrophy. Bone marrow examination shows vacuolization of erythrocyte prescursors, and on electron microscopy haemosiderin laden mitochondria are present. Insulin dependent diabetes mellitus may develop, lactic acidosis and 3-methyl-glutaconic aciduria are present, and ragged red fibres evident on muscle biopsy. Pearson syndrome is usually due to single large scale deletions or duplications of mitochondrial DNA. Having presented in the first year of life, Pearson syndrome is fatal during infancy or early childhood in more than 60 per cent (Rotig et al. 1990, 1995).

Those who survive beyond the age of 5 undergo spontaneous improvement in their haematological disorder, and go on to develop Kearns Sayre syndrome or Leigh’s disease. The variable phenotype is illustrated by the cases of a mother and her infant son who harboured identical 5355 mtDNA single deletions and respectively manifested a chronic progressive external ophthalmoplegia accompanied by muscle weakness, and the Pearson syndrome (Shanske et al. 2002). In those Pearson patients with neurological manifestations, white matter changes are variably present on brain MRI (Lee et al. 2007). Central nervous system folate deficiency should be excluded.

10.5.3 Leigh’s syndrome

This encephalopathy usually presents in early infancy, is usually fatal, and is also known as Leigh’s encephalopathy, or subacute periventricular necrotizing encephalopathy. The condition is genetically heterogeneous, with a wide variety of mitochondrial and nuclear gene mutations being reported, variously producing enzyme deficiencies in complexes I, II, IV of the mitochondrial respiratory chain. Enzyme defects causing isolated deficiency of complex I seem particularly common (McFarland et al. 2004), usually presenting sporadically or with an autosomal recessive pattern of inheritance representing the predominance of nuclear gene mutations. Mutations affecting the mitochondrially encoded complex I subunit genes ND3, ND4, ND5 and ND6 are also recognized. Other autosomal recessive cases with complex IV deficiency are associated with mutations of SURF 1, a mitochondrial assembly protein gene (Lee et al. 1998). Autosomally recessively inherited pyruvate carboxylase deficiency can also cause Leigh’s syndrome. Pyruvate dehydrogenase deficiency can be responsible for X-linked or autosomal recessive Leigh’s syndrome, and coenzyme Q deficiency can also cause Leigh’s syndrome (Section 10.5.5).

Leigh’s syndrome commonly presents perinatally or in early infancy, and constitutes the commonest mitochondrial disorder of these age groups. It is characterized by diffuse encephalopathy with poor feeding and aspiration; seizures are relatively uncommon. Neurogenic respiratory failure may result from the brain stem lesions. Infants usually show lost or reduced responsiveness to visual, auditory, and tactile stimuli. They are generally hypotonic, although spastic diplegia can develop. More than 80 per cent of older infants and children develop dystonias, tremors, or cerebellar disorders (Macaya et al. 1993). Movement disorders may be the primary presenting feature. Rarely Leigh’s syndrome first presents in adulthood, resembling ataxic paraparetic forms of multiple sclerosis (Section 37.5.3) or acute disseminated encephalomyelitis (Section 37.4.1) (Malojcic et al. 2004).

The serum lactate is usually elevated in Leigh’s syndrome, and if not the CSF lactate. MRI shows perventricular white matter abnormalities, with T2-weighted hyperintensity in the basal ganglia and thalamus. Although muscle biopsy does not show ragged red fibres, abnormal mitochondria are evident on electron microscopy, and quantitative studies will show abnormalities of mitochondrial respiratory chain enzymes. Neuropathologically there is destruction of the white matter periventricularly with symmetric necrotic lesions in the thalamus, brain stem, and dorsal columns of the spinal cord.

Leigh’s syndrome carries a poor prognosis with most infants dying within days or weeks of presentation. Death occurs within months to years in patients of later infantile or childhood onset. A ketogenic diet may be helpful in those with underlying pyruvate dehydrogenase deficiency (Wexler et al. 1997).

10.5.4 Neuropathy, ataxia, retinitis pigmentosa syndrome

This syndrome is genetically directly related to Leigh’s syndrome through sharing a common point mutation of the ATPase 6 gene due to a point mutation at the 8993 locus of mtDNA (Holt et al. 1990). The resultant inhibition of oxidative phosphorylation leads to increased production of free radical species (Mattiazzi et al. 2004).

The onset of sensorimotor polyneuropathy, cerebellar ataxia, and retinitis pigmentosa, NARP, is usually in childhood, with limb weakness and sensory disturbance being followed by loss of night vision. When the heteroplasmy involves mutation of the great majority of mitochondrial DNA, Leigh’s syndrome results, whereas when only moderate amounts of mtDNA are affected, NARP results. Correspondingly, mixed syndromes can occur in those with intermediate degrees of mtDNA heteroplasmy.

10.5.5 Deficiencies of pyruvate dehydrogenase and co-enzyme Q10

Although these deficiencies can produce encephalomyopathies resembling Leigh’s syndrome, they are considered separately because of the wider range of disorders they can cause, and because both are potentially treatable. Deficiencies of both pyruvate dehydrogenase and co-enzyme Q10 can present with infantile lactic acidosis, and progressive psychomotor retardation and death in infancy. Neurological syndromes of later onset, including cerebellar ataxia and epilepsy, are also described.

Pyruvate dehydrogenase deficiency

Pyruvate dehydrogenase catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. Most cases of deficiency are X-linked, with a range of mutations affecting the PDHA1 gene (Lissens et al. 2000). Autosomal recessive inheritance of pyruvate dehydrogenase deficiency can occur as the result of mutations in the PDHX, DLAT, PDHB, PDHP, and DLD genes. DLD mutations, affecting dihydrolipoamide dehydrogenase, produce a combined defect of pyruvate dehydrogenase and branch chain keto acid dehydrogenase, the latter giving rise to an amino acid profile similar to maple syrup urine disease. Autosomal recessive disorders affecting the PDHAX gene produce other variants of the pyruvate dehydrogenase complex deficiency (Schiff et al. 2006). These various mutations produce a range of clinical disorders involving lactic acidosis, which range from infantile Leigh’s syndrome to intermittent ataxias. Roughly equal numbers of affected males and females have been identified associated with the X-linked form, and this is attributed to developmental lethality in some males with severe mutations, and the pattern of X-inactivation in females (Lissens et al. 2000). Treatment with a ketogenic diet reportedly improves the lactic acidosis and neurological disorder in Leigh’s syndrome resulting from pyruvate dehydrogenase deficiency (Wexler et al. 1997).

Co-enzyme Q10 deficiency

A number of neurological syndromes have been associated with reduced levels of co-enzyme Q10 in muscle and may reflect blocks at different stages of the Co-enzyme Q10 synthetic pathway (diMauro et al. 2007; Gempel et al. 2007):

  1. Myopathy involving proximal limb and trunk muscles, with slow progression (Horvath et al. 2006). Muscle biopsies may show ragged red fibres. This may be associated with mutations of the electron-transferring-flavoprotein dehydrogenase gene, ETFDH (Gempel et al. 2007).

  2. Myopathy with ragged red fibres, recurrent myoglobinuria, and signs of a central nervous system disorder (di Giovanni et al. 2001).

  3. Leigh’s syndrome presenting from infancy to early adulthood (Rotig et al. 2000; Van Maldergem et al. 2002). This form is often associated with nephrotic syndrome and subsequent renal failure. Retinitis pigmentosa, optic atrophy, and sensorineural deafness have been noted (Rötig et al. 2000).

  4. Cerebellar ataxia occurring on an autosomal recessive basis, and variably associated with other neurological disorders such as seizures or psychomotor delay (Lamperti et al. 2003). This ataxic variant is not associated with ragged red fibres on muscle biopsy, and is associated with mutations of the aprataxin gene, APTX, which is known to be responsible for ataxia with oculomotor apraxia type 1. This may represent a form of secondary coenzyme Q10 deficiency.

Thus, co-enzyme Q10 deficiencies seem to occur as both primary and secondary disorders. The primary disorders have been attributed to mutations within three of the nine nuclear genes required for synthesis of co-enzyme Q10, PDSS1, PDSS2, and COQ2 (DiMauro et al. 2007). A primary deficiency of co-enzyme Q10 is particularly suggested by the muscle biopsy findings of ragged red fibres, and severe reduction in co-enzyme Q10 content, to as little as 5 per cent of normal. The importance of diagnosing co-enzyme Q10 deficiency is the often dramatic clinical response to oral ubiquinone supplementation (Rötig et al. 2000; Van Maldergem et al. 2002).

10.5.6 Polymerase gamma mutations

Mutations of the nuclear gene encoding polymerase gamma, POLG, are responsible for up to 25 per cent of all mitochondrial diseases (Chinnery and Zeviani 2007). Polymerase gamma is a DNA polymerase which replicates mitochondrial DNA. Mutations can cause both autosomal dominant and recessive disorders. Furthermore the same mutation can cause a wide spectrum of severity of mitochondrial disease, an example being the severe depletion of mitochondrial DNA seen in Alper’s syndrome, yet the same genetic abnormality causing mild progressive external ophthalmoplegia of late onset. Autosomal dominant disease associated with POLG mutations particularly involve chronic progressive external ophthalmoplegia, and some families show psychiatric disorders, parkinsonism, or primary gonadal failure. By contrast, autosomal recessive disorders associated with POLG mutations tend to show cerebellar ataxia and axonal peripheral neuropathy. Alper’s syndrome causes seizures, visual failure, and severe hepatic failure and is autosomal recessively inherited also due to POLG mutations (Table 10.9 and Section 30.3.4) (Chinnery and Zeviani 2007).

10.6 Brain peroxisomal biosynthesis disorders

10.6.1 The range of peroxisomal disorders

Peroxisomes are single membrane-lined organelles present in virtually all cells. They contain multiple enzymes involved in a variety of metabolic processes including α- and β-oxidation of certain fatty acids, biosynthesis of bile acids which also involves β-oxidation, and biosynthesis of ether phospholipids, plasmologens. Thus, tests for peroxisomal disorders include the detection of:

  1. raised concentrations of very long chain fatty acids, pristanic acid and the C27 bile acids, THCA and DHCA which are all substrates for peroxisomal β-oxidation;

  2. a raised concentration of phytanic acid, a substrate of peroxisomal α-oxidation, typical of Refsum disease (Section 21.8.1);

  3. low levels of plasmalogens in the red blood cells.

In the past peroxisomal disorders have been classified into those disorders that affect the assembly of peroxisomes, those that affect the import of peroxisomal proteins, and those that affect single peroxisomal enzymes (Table 10.1 IV). The first two groups have been amalgamated in recent years into the disorders of peroxisome biogenesis (Table 10.1 IV, 1–2) (Steinberg et al. 2006; Wanders and Waterham 2006). It has become clear that mutations in the same gene can cause disorders of a very wide spectrum of severity, referred to as the Zellweger spectrum. However, the original classification by syndromes such as Zellweger syndrome or infantile Refsum’s disease remains important to the clinician who is trying to determine the likely prognosis for a particular child.

Once the first line tests have indicated a peroxisomal disorder, a wide variety of tests can be undertaken in cultured skin fibroblasts to define the disorder at the protein and gene level. This nearly always leads to the possibility of prenatal diagnosis. Peroxisomal disorders show autosomal recessive inheritance with the exception of X-linked adrenoleukodystrophy.

The main clinical syndromes that can occur in the peroxisome biogenesis disorders are:

  1. Zellweger syndrome (Section 10.6.2);

  2. Neonatal adrenoleukodystrophy;

  3. Infantile Refsum’s disease (Section 10.6.3);

  4. Childhood onset leukodystrophy due to peroxisome biogenesis defects (Section 10.6.4); and

  5. Rhizomelic chondrodysplasia punctata (Section 10.6.5).

10.6.2 Zellweger syndrome

Zellweger syndrome is the most severe disease in this group and is also known as cerebro-hepato-renal syndrome. It presents in the newborn period with dysmorphism, including prominent high forehead, widely spaced sutures and large fontanelles, with severe hypotonia, poor sucking, and depressed or absent tendon reflexes. The hypotonia in the neonatal period may be confused with Down’s syndrome, Prader–Willi Syndrome, and spinal muscular atrophy. Early seizures occur with poor development, failure to thrive, deafness, and visual impairment. A pigmentary retinopathy may develop with loss of the electroretinogram, and with optic atrophy, sometimes cataracts. Hepatomegaly and deranged liver function are often present. Adrenocortical function is often abnormal. Electromyography and nerve conduction velocities are usually normal. EEG is always abnormal. MR brain scan often shows a neuronal migration abnormality and may also show a leukodystrophy. The kidneys often show small cortical cysts. There is no treatment and most die in the first year. The diagnostic tests are listed in Table 10.1 IV, 1a. Structural brain abnormality combined with involvement of other organs can suggest the diagnosis before birth (Mochel et al. 2006) An attempt to treat a child with Zellwegers syndrome with Lorenzo’s oil and docosahexaenoic acid has recently been described but despite biochemical improvement the infant died after 144 days (Tanaka et al. 2007).

10.6.3 Infantile Refsum disease

Infantile Refsum disease is a milder peroxisome biogenesis disorder. These infants are normal in the neonatal period and then, from 6 months of age, develop nonspecific symptoms including failure to thrive and apparent malabsorption. Hepatomegaly with abnormal liver function, low cholesterol, and facial dysmorphism are apparent on careful evaluation. As toddlers these children show delayed development with hypotonia, ataxia, visual impairment with choroido-retinopathy, and deafness. Severe cognitive impairment and survival to the teenage years can occur. Phytanic acid is elevated but accumulation of this metabolite is not as pathogenetically important as in adult Refsum disease (Section 21.8.1).

10.6.4 Leukodystrophy

In the mildest form of peroxisome biogenesis defect no abnormality, apart from sensorineural deafness, is detected in the first two years of life. However, in the preschool years, ataxia and upper motor neurone signs, particularly in the legs, become apparent and MRI shows white matter changes and often evidence of cerebellar atrophy. Very long chain fatty acids may show minor elevation or be normal; measurements of phytanate, pristanate, and C27 bile acids are important additional pointers to this diagnosis.

10.6.5 Rhizomelic chondrodysplasia punctata

In the classical form of this disorder affected infants have microcephaly and severe developmental delay. Additional features include shortening of the proximal limb bones restricted joint movements and the radiological features of punctuate epiphyseal calcification and metaphysical splaying and cupping. Plasma phytanate is usually elevated if it has been given in feeds (cow’s milk-based formula), and red cell plasmalogens are reduced.

10.6.6 Single peroxisomal enzyme or transporter disorders

  1. Acyl-CoA oxidase and D-bifunctional protein deficiencies show phenotypes similar to the Zellweger spectrum (Section 10.6.2);

  2. X-linked adrenoleukodystrophy is discussed in Section 10.2.4;

  3. Refsum’s disease is discussed in Section 21.8.1;

  4. Alpha-methyl-acyl-CoA racemase deficiency can present with cholestatic liver disease in infancy, with developmental delay, with episodes of encephalopathy and with an adult onset sensorimotor neuropathy and/or pigmentary retinopathy; and

  5. Dihydroxyacetone phosphate acyl transferase deficiency and alkyl-dihydroxyacetone phosphate synthase deficiency usually present in the neonatal period with features similar to rhizomelic chondrodysplasia punctata. Milder forms may present in early childhood with developmental delay.

10.7 Other inborn errors of metabolism

A wide range of inborn errors of metabolism can cause neurological abnormalities (Table 10.1 I, II), and some are particularly associated with episodes of acute encephalopathy (Table 10.2).

10.7.1 Metabolic causes of epileptic encephalopathy

A number of metabolic diseases can present with epilepsy particularly early in life (Section 30.5.2). These include conditions themselves causing encephalopathy of which some are potentially treatable:

  1. Pyridoxine dependency should always be considered as the cause of early onset drug resistant seizures (Table 10.2, V 1 and 2). Neonatal units consider a trial of pyridoxine in an infant with refractory epilepsy and this recommendation is often included in protocols for the management of status epilepticus in infants and young children. Although rare, its treatability makes it an important condition to identify. The biochemical basis for pyridoxine responsive epilepsy is now better understood thereby allowing diagnostic testing by checking pipecolic acid in body fluids, CSF and blood, or urine alpha-aminoadipic semialdehyde levels (Willemsen et al. 2005; Bok et al. 2007). While awaiting these results a therapeutic trial of pyridoxine can be undertaken, provided that full resuscitation facilities are available. Pyridoxal phosphate is required in infants with a deficiency of pyridoxine phosphate oxidase although the preparation can be difficult to obtain (Mills et al. 2005). Hopefully the availability of diagnostic testing will resolve some of the previous uncertainty surrounding the offering of this treatment to infants and children.

  2. Biotinidase deficiency is another important treatable cause of refractory seizures. Usually it is associated with skin rash and abnormal hair (Table 10.1, IX 3a). This disorder is now detected by newborn screening in some countries although not in the United Kingdom. Late diagnosis can be associated with visual impairment due to optic atrophy, hearing loss and psychomotor retardation, with pyramidal motor impairment and spasticity (Weber et al. 2004). The condition can be detected by checking the biotinidase level in blood, and usually shows a characteristic abnormality on the urine organic acid profile. A trial of biotin should be considered while awaiting the results of diagnostic tests.

  3. Other potentially treatable conditions presenting with early seizures include folinic acid responsive seizures and Glut 1 deficiency (Frye et al. 2003; Klepper and Leiendecker 2007).

Other important metabolic causes of early onset epilepsy are glycine encephalopathy, or non-ketotic hyperglycinaemia, serine deficiency syndromes and sulphite oxidase deficiency:

  1. Glycine encephalopathy. The infant with non-ketotic hyperglycinaemia presents with early intractable seizures and severe encephalopathy. These infants often require ventilatory support and many do not survive. Those that do survive will usually have persisting neurodevelopmental problems. Rare later onset variants are recognized that are less severe but are associated with epilepsy. There may be a curious gender difference in terms of survival with boys having a better outcome than girls (Hoover-Fong et al. 2004). The diagnosis is suggested by finding a high glycine level in the CSF with a plasma:CSF glycine ratio > 0.08. A transient benign form of neonatal hyperglycinemia is recognized (Lang et al. 2008).

  2. Serine deficiency (Table 10.2, V 10). Patients with serine deficiency syndromes are diagnosed by finding low levels of serine in blood and CSF. These disorders involve microcephaly, developmental retardation and epilepsy. They are potentially treatable although the limited therapeutic response in reports to date may be due to delay in diagnosis (De Koning and Klomp 2004).

  3. Sulfite oxidase deficiency (Table 10.2, V 3) usually presents in early infancy with seizures, irritability, and reduced muscle tone. The condition can resemble birth asphyxia both clinically and radiologically. The diagnosis is suggested by finding elevated urinary levels of sulphite, thiosulphite and S-sulfocysteine. The human sulfite oxidase gene, SUOX, is located at 12q13.13 and at least 16 pathogeneic mutations are recognized. The condition is usually fatal with no effective long term treatment. Onset is usually at birth but can be delayed for many months with survival for many years (Tan et al. 2005).

10.7.2 Congenital disorders of glycosylation

Congenital disorders of glycosylation are a relatively newly described group of metabolic disorders characterized by defective synthesis of N- and/or O-linked oligosaccharides (Table 10.1, VI). The term ‘congenital disorders of glycosylation’ is now preferred to the former ‘carbohydrate deficient glycoprotein syndrome’. There is considerable phenotypic variation, with more than 20 types being described. The usual screening test for the diagnosis is isoelectric focusing of a glycoprotein, usually serum transferrin (Marklova et al. 2007). The clinical presentation can range from early onset severe developmental delay, hypotonia, and multi-organ involvement through to hypoglycaemia and protein losing enteropathy with normal development. The commonest type is 1a and survival to adulthood is recognized. These adults have moderate mental retardation, ataxia, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, and endocrinopathies (Krasnewich et al. 2007).

Rett syndrome

Rett syndrome is a common neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2, MECP2 (Section 9.6.2). The condition was first described in the German literature in 1966 after Andreas Rett saw two girls sitting together in his waiting room. The genetic basis for the disorder was not recognized until 1999. The condition is often listed with neurodegenerative diseases yet there is no biochemical marker and destructive changes in the central nervous system are not seen. The condition is described as a postnatal progressive neurodevelopmental disorder (Chahrour and Zoghbi 2007). Typically the child is initially normal; then development stagnates before regressing with loss of speech, hand skills, and the development of characteristic hand-wringing stereotypies. Affected girls often develop epilepsy, respiratory irregularities, and autonomic dysfunction. Many survive to adulthood and some to old age. Many lose mobility during adolescence and early adult life. Rett syndrome affects 1:10 000 births and is most often sporadic; 95 per cent of cases have a mutation in MECP2. Most cases arise in the paternal germ line which is why it is very rare in males. The cyclin-dependent kinase like 5, CDKL5 gene is another X-linked gene which produces a severe Rett-like phenotype presenting in the first 6 months, often with infantile spasms or severe early onset epilepsy.


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