Table 2

Symptom groups associated with adult onset inborn errors of metabolism

Disorder Other symptoms Tests
Muscle weakness or exercise intolerance
 Fatty acid oxidation defects±Cardiomyopathy±hypoglycaemia±liver disease±myoglobinuriaUrine organic acids (fasting)
 Glycolytic pathway disorders±Anaemia ±liver disease, muscle weakness ±cardiomyopathy±endocrinological disorders±ptosisRed cells or muscle biopsy for enzyme assays
 Glycogen storage diseases
  (a) Type II (acid maltase deficiency)±Respiratory difficulties due to diaphragmatic weaknessLymphocyte acid α-glucosidase
  (b) Type III (Cori's disease)History of early hypoglycaemia and hepatomegalyLeucocyte glycogen debrancher enzyme assay
  (c) Type V (McArdle's disease)Myoglobinuria, exercise intolerance, crampsIschaemic exercise test
  (d) Phosphorylase b kinase deficiency±Cardiomyopathy ±liver diseaseErythrocyte or liver phosphorylase b kinase assay
 Myoadenylate deaminase deficiencyNote: most persons are asymptomaticIschaemic exercise test (increased ammonia), muscle biopsy for myoadenylate deaminase assay, blood for DNA analysis for the common mutation.
Motor neuron disease
 Adult polyglucosan storage diseaseDementia, neurogenic bladder, sensory lossLeucocyte glycogen brancher assay (some forms may show normal muscle activity).
 GM2 Gangliosidosis (Tay-Sach's and Sandhoff's disease)Slow progressive disorder, pyramidal signs, cerebellar degenerationLeucocyte total hexosaminidase and hexosaminidase A
Chorea and/or dystonia
 Glutamic aciduria type 1±Reye's syndromeUrine organic acids
±Hypoglycaemia, slow progressive disorder, gait disturbance, dysarthriablood spot for acyl carnitines
 GM2 Gangliosidosis (Tay-Sach's and Sandhoff's disease)Slow progressive disorderLeucocyte total hexosaminidase and hexosaminidase A
 Lesch-Nyhan syndromeRenal stonesPlasma urate and urine, urate/creatinine ratio
 Methylmalonic aciduria with homocystinuria±AnaemiaUrine organic acids and amino acids. urine , and plasma homocystine.
 Niemann-Pick disease type CSupranuclear ophthalmoplegia, ataxia, psychomotor retardation, dementia, splenomegalyBone marrow aspirate fibroblast cholesterol incorporation and staining
 Segawa diseaseDiurnal variation of symptomsLevodopa trial (some forms have a defect in biopterin metabolism)
 Wilson's diseaseKayser-Fleischer rings,±liver disease ±dementia ±choreoathetosis ±renal failurePlasma copper and caeruloplasmin, urine copper (pre and postpenicillamine), liver copper
Ataxia
 AbetalipoproteinaemiaMuscle weakness, fat malabsorption, retinitis pigmentosaPlasma cholesterol and triglycerides, blood film (acanthocytes), lipoproteins
 Acaeruloplasminaemia±Presenile dementia ±diabetes mellitus, retinal dystrophyPlasma and urine copper
 Cerebrotendinous xanthomatosisSpasticity, cataracts, tendon xanthomasUrine cholestanol
 GM2 Gangliosidosis (Tay-Sachs' and Sandhoff's disease)Slow progressive disorderLeucocyte total hexosaminidase and hexosaminidase A
 Hartnup disease±Skin lesionsPlasma and urine amino acids
 Niemann-Pick disease type C±Supranuclear ophthalmoplegia, dementia, dystonia, splenomegalyBone marrow aspirate
 Pyruvate dehydrogenase deficiency (X linked)Episodes in males triggered by carbohydrate feedingPre and postprandial blood lactate, CSF lactate, fibroblast pyruvate dehydrogenase
 Refsum's diseaseRetinitis pigmentosa, polyneuropathyPlasma phytanic acid
 Sialidosis (mucolipidosis type I)Type IUrine oligosaccharides
Visual defect with lens or corneal opacity, ataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia ± cherry red spotfibroblast α-neuraminidase
Type II
Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma.
Leukodystrophy (diagnosed radiologically)
 Krabbe's leukodystrophyPes cavus, hemiparesis, spastic tetraparesisLeucocyte β-galactocerebrosidase
 Metachromatic leukodystrophySlow progressive disorder, impaired nerve conduction ±behavioural problemsLeucocyte arylsulphatase A (common pseudodeficiency state must be excluded)
 X linked adrenoleukodystrophyMalesPlasma very long chain fatty acids
Gait disturbance, spastic paraparesis, rarely dementia ±Addison's disease
Females
Onset >30 y, spastic paraparesis, vibration sense loss, long tract signs, peripheral neuropathy
Strokes and stroke-like episodes:
 Fabry's diseaseAngiokeratoma, renal disease, developmental delayLeucocyte α-galactosidase A
 HomocystinuriaLens dislocation,occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardationUrine homocystine
 Mitochondrial myopathy, encephalopathy with lactic acidaemia and stroke-like episodes (MELAS)Seizures, developmental delay, sensorineural hearing loss ±diabetes mellitusBlood for mtDNA analysis
 Urea cycle defectsPostprandial vomiting, coma, confusionBlood ammonia, plasma, and urine amino acids
Behavioural and/or psychiatric disorders and/or dementia
 AcaeruloplasminaemiaAtaxia, diabetes mellitus, retinal dystrophyPlasma copper and caeruloplasmin, plasma iron and ferritin
 Gaucher's disease type IIIHorizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities psychosisLeucocyte β-glucosidase, bone marrow aspirate
 Hartnup diseaseAtaxia and skin lesionsPlasma and urine amino acids
 Homocystinuria (classic)Occlusive cerebrovascular disease, dislocated lenses, osteoporosis, skeletal deformities.Urine and plasma homocystine and methionine.
 Homocystinuria (remethylation defect)Paraesthesia, limb weakness, mental retardationUrine and plasma homocystine and methionine.
 Juvenile Batten's diseaseVisual loss, seizures, retinitis pigmentosaSkin or rectal biopsy for histological analysis, DNA for the common deletion
 Kuf's diseaseDementia, psychosis, motor lossSkin or rectal biopsy for histological analysis
 Metachromatic leukodystrophySlow progressive disorder, impaired nerve conduction, leukodystrophyLeucocyte arylsulphatase A (pseudodeficiency state must be excluded)
 Niemann-Pick disease type CVertical supranuclear ophthalmoplegia, psychomotor retardation, ataxia, dystonia, splenomegalyBone marrow aspirate, fibroblast cholesterol incorporation and staining
 Ornithine transcarbamylase deficiencyEpisodic symptoms (often postprandial), sleep disorders, comatose episodesPlasma ammonia (1h postprandial), plasma amino acids, urine amino acids and orotic acid
 PorphyririaLimb, neck, or chest pain, muscle weakness, abdominal pain, photosensitivity.Urine and fecal porphyrins, urine delta aminolaevulinic acid and porphobilinogen
 Wilson's diseaseKayser-Fleischer rings ±liver disease, dysarthria, loss of coordination, pseudobulbar palsy , parkinsonian featuresPlasma copper and caeruloplasmin
 X linked adrenoleukodystrophyGait disturbance ±Addison's diseasePlasma very long chain fatty acids
leukodystrophy, spastic paraparesis, impotence
Eye disorders
 Cerebrotendinous xanthomatosisSpasticity, cataracts, tendon xanthomasUrine cholestanol
 Galactokinase deficiencyCataractsPostprandial urine sugar, chromatography
 Gaucher's disease type IIIHorizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosisLeucocyte β-glucosidase
 Homocystinuria (classic form)Lens dislocation, occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardationUrine and plasma homocystine and methionine
 Hyperornithinaemia with gyrate atrophy of the retinaOptic atrophyPlasma and urine amino acids (ornithine)
 Juvenile Batten's diseaseSeizures, visual loss, retinitis pigmentosa, dementiaSkin or rectal biopsy for histological analysis, blood for DNA analysis for the common mutation
 Leber's hereditary optic atrophyBilateral optic atrophy (may be alcohol or tobacco triggered)Blood for mtDNA analysis
 Neuropathy ataxia and retinitis pigmentosa (NARP)Retinitis pigmentosa, ataxia, neuropathyBlood for mtDNA analysis
 Niemann-Pick disease type CPsychomotor retardation leading to dementia ataxia with dystonia, vertical supranuclear ophthalmoplegiaBone marrow aspirate, fibroblast cholesterol uptake and staining.
 Oculocutaneous albinismPale complexion, blue eyesHair follicle tyrosinase
 Refsum's diseasePeripheral neuropathy, retinitis pigmentosa, cerebellar ataxiaPlasma phytanic acid
 Sialidosis (mucolipidosis type I)Type IUrine oligosaccharides
Visual defect with lens or corneal opacityataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia ± cherry red spotFibroblast α-neuraminidase
Type II
Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma.
 Tyrosinaemia type IICataracts, skin lesions, slight developmental delayPlasma and urine amino acids
 Wilson's diseaseCataracts, Kayser-Fleischer rings, liver disease, dementia, renal failure, parkinsonian features, dysarthria, loss of coordination of voluntary movement.Plasma copper and caeruloplasmin
Epilepsy
 Electron transport chain disordersAny combination of symptomsCSF and blood lactate, blood mtDNA analysis, muscle biopsy for enzyme assay.
 Juvenile Batten's diseaseVisual lossSkin or rectal biopsy for histological analysis, DNA for the common mutation
 Kuf's diseaseProgressive myoclonic epilepsySkin or rectal biopsy for histological analysis
 Myoclonic epilepsy with ragged red fibresMyoclonusBlood for mtDNA analysis.
 Pyridoxine dependent seizuresPersistent seizures responsive to pyridoxinePyridoxine response trial (primary defect not known)
 Sialidosis (mucolipidosis type I)Type IUrine oligosaccharides
Visual defect with lens or corneal opacityataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia±cherry red spotFibroblast α-neuraminidase
Type II
Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma