Table 1

Inherited metabolic disorders with adult onset forms

Disease Clinical symptoms Tests
Lysosomal storage diseases
 Acid maltase deficiencyMuscle weakness, respiratory difficultyLymphocyte α-glucosidase
 Fabry's diseasePeripheral nerve pain (±renal failure±angiokeratoma±cardiomyopathy), stroke-like episodesLeucocyte α-galactosidase A
 Gaucher's disease type IIIHorizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosisLeucocyte β-glucosidase, bone marrow aspirate
 GM1 gangliosidosis(i) Extra pyramidal signs, flattening of vertebral bodies, normal cognitive function. sometimes with psychosisLeucocyte β-galactosidase, urine oligosaccharides
 GM2 gangliosidosis (Tay Sach's and Sandhoff's disease)(i) Lower motor neuron disease with onset 20–40 y, pyramidal signs, and cerebellar degenerationLeucocyte total, hexosaminidase, and hexosaminidase A
(ii) Atypical amyotropic lateral sclerosis
 Krabbe's leukodystrophyPes cavus, hemiparesis, spastic tetraparesis, leukodystrophyLeucocyte β-galactocerebrosidase
 Metachromatic leukodystrophyLoss of cognitive function or behavioural abnormalities, neuromuscular weakness with impaired nerve conduction, leukodystrophyLeucocyte arylsulphatase A (the pseudodeficiency state must be excluded)
 Sialidosis (mucolipidosis type I)Type IUrine oligosaccharides, fibroblast α-neuraminidase
Visual defect with lens or corneal opacity, ataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia
Type II
Dementia±cherry red spot
Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma.
 Niemann-Pick's disease type CPsychomotor retardation leading to dementia, ataxia with dystoniaBone marrow aspirate, fibroblast cholesterol uptake and staining.
Amino acid disorders
 Arginase deficiencyDisorientation, comaPlasma and urine amino acids, plasma ammonia (1 h postprandial).
 CitrullinaemiaDisorientation, restlessness, comaPlasma and urine amino acids, plasma ammonia (1 h postprandial).
 Hartnup's diseaseDementia, ataxia ±skin lesions.Plasma and urine amino acids
 Homocystinuria (cystathionine synthasedeficiency: classic form)Occlusive cerebrovascular disease, dislocated lenses, osteoporosis, psychiatric disturbancesUrine homocystine, plasma homocystine and methionine
 Homocystinuria (methylene tetrahydrofolatereductase deficiency remethylation defect).Parasthaesia, hallucinations, tremor, withdrawal, mental retardation, limb weakness, memory lossUrine homocystine, plasma homocystine and methionine
 Hyperornithinaemiawith gyrate atrophy of the retinaGyrate atrophy of choroid and retinaPlasma and urine amino acids (ornithine)
 Ornithine transcarbamylase deficiencyBehavioural disturbances, comatose episodes, sleep disordersPlasma ammonia (1 h postprandial)plasma amino acids, urine amino acids and orotic acid
Organic acid disorders
 Fatty acid oxidation defectsMuscle weakness, easy fatigability ±liver disease ±cardiomyopathy ±hypoglycaemiaUrine organic acids (fasting)
 Glutaric aciduria type 1Dystonia±hypoglycaemia, may present with a Reye-like syndromeUrine organic acids, blood spot acyl carnitines
 Propionic acidaemiaChorea and dementia, recurrent vomitingUrine organic acids, blood spot acyl carnitines
Peroxisomal disorders
 X linked adrenoleukodystrophy(i) Onset 20–30 y in males, gait disturbance, spastic paraparesis, intellectual function usually intact, impotence±Addison's disease, occasionally cerebral symptoms may occur, eg dementia and psychosis.Plasma very long chain fatty acids.
(ii) Onset >30 y in females, spastic paraparesis, vibratory sense loss, long tract signs, peripheral neuropathy
Lactic acidaemias
 Electron transport chain disorders
  (i) mtDNA encodedNARP, MELAS, MERRF, Kearns-Sayre syndrome, LHONBlood or tissue mtDNA analysis
  (ii) Nuclear DNA encodedMuscle weakness, multisystem diseaseCSF/plasma lactate, muscle biopsy for respiratory chain assays
Disorders of the glycogenolytic and glycolytic pathway
 Glycogen storage diseasesMuscle weakness, cardiomyopathy, hepatomegaly, hypoglycaemia, myopathyMuscle enzyme assays, but many of the glycogen storage diseases can be diagnosed by leucocyte or erythrocyte enzyme assays
 Glycolytic pathway disordersMuscle weakness (second wind phenomenon), exercise intolerance, myoglobinuriaMuscle enzyme assays, but many of the glycolytic disorders can be diagnosed by erythrocyte enzyme assay
± haemolytic anaemia
Other disorders
 AbetalipoproteinaemiaAtaxia, retinitis pigmentosaPlasma cholesterol, blood film (acanthocytes), lipoproteins
 AcaeruloplasminaemiaAtaxia, retinal dystrophy±diabetes mellitus±presenile dementiaPlasma and urine copper, plasma iron and ferritin
 Adult polyglucosan body diseaseUpper and lower motor neuron signs, sensory loss, neurogenic bladder, dementiaLeucocyte glycogen brancher enzyme (some forms may show normal muscle activity).
 Cerebrotendinous xanthomatosisSpasticity, ataxia, cataracts, tendon xanthomasUrine bile alcohols
 Hereditary vitamin E deficiencyTremor, ataxia, head titubation, loss of vibration sense.Plasma vitamin E, plasma cholesterol and triglycerides
 Homocystinuria and methylmalonic aciduria (combined defect)Megaloblastic anaemia, dystoniaUrine organic acids and homocystine
 Juvenile Batten's diseaseSeizures, visual loss, dementiaSkin or rectal biopsy for histological analysis, DNA analysis for the common mutation
 Kuf's diseaseType ASkin or rectal biopsy for histological analysis
Progressive myoclonic epilepsy
Type B
Motor problems, psychosis, dementia
 Lesch-Nyhan syndromeSome forms may present late with choreiform movements, dysarthria ± renal problemsPlasma urate and urine,urate/creatinine
 PorphyriasLimb, neck, and chest pain, muscle weakness, sensory loss, seizures,behavioural abnormalities±abdominal symptoms±photosensitivityUrine delta amino laevulinic acid and porphobilinogen, urine and fecal porphyrins
 Pyridoxine responsive seizuresPersistent seizures responsive to pyridoxineIn vivo pyridoxine response test: primary defect not known
 Refsum's diseaseRetinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxiaPlasma phytanic acid
 Segawa diseaseCyclical dystoniaLevodopa trial (some forms have a defect in biopterin metabolism)
 Sjogren-Larrson syndromeSpastic tetraplegia ±ichthyosis, mental retardationFibroblast fatty alcohol, oxidoreductase assay
 Wilson's diseaseDysarthria, loss of coordination of voluntary movements, pseudobulbar palsy, parkinsonian features, renal failure, liver disease, Kayser-Fleischer rings, dementiaUrine copper (pre and postpenicillamine)
Plasma copper and caeruloplasmin