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±myoglobinuria	Urine organic acids (fasting)

Glycolytic pathway disorders	±Anaemia ±liver disease, muscle weakness ±cardiomyopathy±endocrinological disorders±ptosis	Red cells or muscle biopsy for enzyme assays

Glycogen storage diseases
(a) Type II (acid maltase deficiency)	±Respiratory difficulties due to diaphragmatic weakness	Lymphocyte acid α-glucosidase
(b) Type III (Cori's disease)	History of early hypoglycaemia and hepatomegaly	Leucocyte glycogen debrancher enzyme assay
(c) Type V (McArdle's disease)	Myoglobinuria, exercise intolerance, cramps	Ischaemic exercise test
(d) Phosphorylase b kinase deficiency	±Cardiomyopathy ±liver disease	Erythrocyte or liver phosphorylase b kinase assay

Myoadenylate deaminase deficiency	Note: most persons are asymptomatic	Ischaemic exercise test (increased ammonia), muscle biopsy for myoadenylate deaminase assay, blood for DNA analysis for the common mutation.
Motor neuron disease

Adult polyglucosan storage disease	Dementia, neurogenic bladder, sensory loss	Leucocyte 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 degeneration	Leucocyte total hexosaminidase and hexosaminidase A
Chorea and/or dystonia

Glutamic aciduria type 1		±Reye's syndrome	Urine organic acids
Glutamic aciduria type 1		±Hypoglycaemia, slow progressive disorder, gait disturbance, dysarthria	blood spot for acyl carnitines

GM2 Gangliosidosis (Tay-Sach's and Sandhoff's disease)	Slow progressive disorder	Leucocyte total hexosaminidase and hexosaminidase A

Lesch-Nyhan syndrome	Renal stones	Plasma urate and urine, urate/creatinine ratio

Methylmalonic aciduria with homocystinuria	±Anaemia	Urine organic acids and amino acids. urine , and plasma homocystine.

Niemann-Pick disease type C	Supranuclear ophthalmoplegia, ataxia, psychomotor retardation, dementia, splenomegaly	Bone marrow aspirate fibroblast cholesterol incorporation and staining

Segawa disease	Diurnal variation of symptoms	Levodopa trial (some forms have a defect in biopterin metabolism)

Wilson's disease	Kayser-Fleischer rings,±liver disease ±dementia ±choreoathetosis ±renal failure	Plasma copper and caeruloplasmin, urine copper (pre and postpenicillamine), liver copper

Ataxia

Abetalipoproteinaemia	Muscle weakness, fat malabsorption, retinitis pigmentosa	Plasma cholesterol and triglycerides, blood film (acanthocytes), lipoproteins

Acaeruloplasminaemia	±Presenile dementia ±diabetes mellitus, retinal dystrophy	Plasma and urine copper

Cerebrotendinous xanthomatosis	Spasticity, cataracts, tendon xanthomas	Urine cholestanol

GM2 Gangliosidosis (Tay-Sachs' and Sandhoff's disease)	Slow progressive disorder	Leucocyte total hexosaminidase and hexosaminidase A

Hartnup disease	±Skin lesions	Plasma and urine amino acids

Niemann-Pick disease type C	±Supranuclear ophthalmoplegia, dementia, dystonia, splenomegaly	Bone marrow aspirate

Pyruvate dehydrogenase deficiency (X linked)	Episodes in males triggered by carbohydrate feeding	Pre and postprandial blood lactate, CSF lactate, fibroblast pyruvate dehydrogenase

Refsum's disease	Retinitis pigmentosa, polyneuropathy	Plasma phytanic acid

Sialidosis (mucolipidosis type I)		Type I	Urine oligosaccharides
		Visual defect with lens or corneal opacity, ataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia ± cherry red spot	fibroblast α-neuraminidase
		Type II
		Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma.

Leukodystrophy (diagnosed radiologically)

Krabbe's leukodystrophy	Pes cavus, hemiparesis, spastic tetraparesis	Leucocyte β-galactocerebrosidase

Metachromatic leukodystrophy	Slow progressive disorder, impaired nerve conduction ±behavioural problems	Leucocyte arylsulphatase A (common pseudodeficiency state must be excluded)
X linked adrenoleukodystrophy		Males	Plasma 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 disease	Angiokeratoma, renal disease, developmental delay	Leucocyte α-galactosidase A

Homocystinuria	Lens dislocation,occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation	Urine homocystine

Mitochondrial myopathy, encephalopathy with lactic acidaemia and stroke-like episodes (MELAS)	Seizures, developmental delay, sensorineural hearing loss ±diabetes mellitus	Blood for mtDNA analysis

Urea cycle defects	Postprandial vomiting, coma, confusion	Blood ammonia, plasma, and urine amino acids
Behavioural and/or psychiatric disorders and/or dementia

Acaeruloplasminaemia	Ataxia, diabetes mellitus, retinal dystrophy	Plasma copper and caeruloplasmin, plasma iron and ferritin

Gaucher's disease type III	Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities psychosis	Leucocyte β-glucosidase, bone marrow aspirate
Hartnup disease	Ataxia and skin lesions	Plasma 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 retardation	Urine and plasma homocystine and methionine.

Juvenile Batten's disease	Visual loss, seizures, retinitis pigmentosa	Skin or rectal biopsy for histological analysis, DNA for the common deletion

Kuf's disease	Dementia, psychosis, motor loss	Skin or rectal biopsy for histological analysis

Metachromatic leukodystrophy	Slow progressive disorder, impaired nerve conduction, leukodystrophy	Leucocyte arylsulphatase A (pseudodeficiency state must be excluded)

Niemann-Pick disease type C	Vertical supranuclear ophthalmoplegia, psychomotor retardation, ataxia, dystonia, splenomegaly	Bone marrow aspirate, fibroblast cholesterol incorporation and staining

Ornithine transcarbamylase deficiency	Episodic symptoms (often postprandial), sleep disorders, comatose episodes	Plasma ammonia (1h postprandial), plasma amino acids, urine amino acids and orotic acid

Porphyriria	Limb, neck, or chest pain, muscle weakness, abdominal pain, photosensitivity.	Urine and fecal porphyrins, urine delta aminolaevulinic acid and porphobilinogen

Wilson's disease	Kayser-Fleischer rings ±liver disease, dysarthria, loss of coordination, pseudobulbar palsy , parkinsonian features	Plasma copper and caeruloplasmin

X linked adrenoleukodystrophy		Gait disturbance ±Addison's disease	Plasma very long chain fatty acids
X linked adrenoleukodystrophy		leukodystrophy, spastic paraparesis, impotence	Plasma very long chain fatty acids

Eye disorders

Cerebrotendinous xanthomatosis	Spasticity, cataracts, tendon xanthomas	Urine cholestanol

Galactokinase deficiency	Cataracts	Postprandial urine sugar, chromatography

Gaucher's disease type III	Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis	Leucocyte β-glucosidase

Homocystinuria (classic form)	Lens dislocation, occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation	Urine and plasma homocystine and methionine

Hyperornithinaemia with gyrate atrophy of the retina	Optic atrophy	Plasma and urine amino acids (ornithine)

Juvenile Batten's disease	Seizures, visual loss, retinitis pigmentosa, dementia	Skin or rectal biopsy for histological analysis, blood for DNA analysis for the common mutation

Leber's hereditary optic atrophy	Bilateral optic atrophy (may be alcohol or tobacco triggered)	Blood for mtDNA analysis

Neuropathy ataxia and retinitis pigmentosa (NARP)	Retinitis pigmentosa, ataxia, neuropathy	Blood for mtDNA analysis

Niemann-Pick disease type C	Psychomotor retardation leading to dementia ataxia with dystonia, vertical supranuclear ophthalmoplegia	Bone marrow aspirate, fibroblast cholesterol uptake and staining.

Oculocutaneous albinism	Pale complexion, blue eyes	Hair follicle tyrosinase

Refsum's disease	Peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia	Plasma phytanic acid

Sialidosis (mucolipidosis type I)		Type I	Urine oligosaccharides
		Visual defect with lens or corneal opacityataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia ± cherry red spot	Fibroblast α-neuraminidase
		Type II
		Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma.

Tyrosinaemia type II	Cataracts, skin lesions, slight developmental delay	Plasma and urine amino acids

Wilson's disease	Cataracts, 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 disorders	Any combination of symptoms	CSF and blood lactate, blood mtDNA analysis, muscle biopsy for enzyme assay.

Juvenile Batten's disease	Visual loss	Skin or rectal biopsy for histological analysis, DNA for the common mutation

Kuf's disease	Progressive myoclonic epilepsy	Skin or rectal biopsy for histological analysis

Myoclonic epilepsy with ragged red fibres	Myoclonus	Blood for mtDNA analysis.

Pyridoxine dependent seizures	Persistent seizures responsive to pyridoxine	Pyridoxine response trial (primary defect not known)

Sialidosis (mucolipidosis type I)		Type I	Urine oligosaccharides
		Visual defect with lens or corneal opacityataxia, myoclonus, generalised seizures sometimes with nystagmus, ataxia, dementia±cherry red spot	Fibroblast α-neuraminidase
		Type II
		Myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma