Disorder
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Other symptoms
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Tests
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Muscle weakness or exercise intolerance
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Fatty acid oxidation defects | ±Cardiomyopathy±hypoglycaemia±liver disease±myoglobinuria | Urine organic acids (fasting) |
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Glycolytic pathway disorders | ±Anaemia ±liver disease, muscle weakness ±cardiomyopathy±endocrinological disorders±ptosis | Red cells or muscle biopsy for enzyme assays |
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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 |
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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
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Adult polyglucosan storage disease | Dementia, neurogenic bladder, sensory loss | Leucocyte glycogen brancher assay (some forms may show normal muscle activity). |
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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
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Glutamic aciduria type 1 | ±Reye's syndrome | Urine organic acids |
±Hypoglycaemia, slow progressive disorder, gait disturbance, dysarthria | blood spot for acyl carnitines |
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GM2 Gangliosidosis (Tay-Sach's and Sandhoff's disease) | Slow progressive disorder | Leucocyte total hexosaminidase and hexosaminidase A |
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Lesch-Nyhan syndrome | Renal stones | Plasma urate and urine, urate/creatinine ratio |
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Methylmalonic aciduria with homocystinuria | ±Anaemia | Urine organic acids and amino acids. urine , and plasma homocystine. |
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Niemann-Pick disease type C | Supranuclear ophthalmoplegia, ataxia, psychomotor retardation, dementia, splenomegaly | Bone marrow aspirate fibroblast cholesterol incorporation and staining |
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Segawa disease | Diurnal variation of symptoms | Levodopa trial (some forms have a defect in biopterin metabolism) |
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Wilson's disease | Kayser-Fleischer rings,±liver disease ±dementia ±choreoathetosis ±renal failure | Plasma copper and caeruloplasmin, urine copper (pre and postpenicillamine), liver copper |
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Ataxia
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Abetalipoproteinaemia | Muscle weakness, fat malabsorption, retinitis pigmentosa | Plasma cholesterol and triglycerides, blood film (acanthocytes), lipoproteins |
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Acaeruloplasminaemia | ±Presenile dementia ±diabetes mellitus, retinal dystrophy | Plasma and urine copper |
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Cerebrotendinous xanthomatosis | Spasticity, cataracts, tendon xanthomas | Urine cholestanol |
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GM2 Gangliosidosis (Tay-Sachs' and Sandhoff's disease) | Slow progressive disorder | Leucocyte total hexosaminidase and hexosaminidase A |
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Hartnup disease | ±Skin lesions | Plasma and urine amino acids |
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Niemann-Pick disease type C | ±Supranuclear ophthalmoplegia, dementia, dystonia, splenomegaly | Bone marrow aspirate |
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Pyruvate dehydrogenase deficiency (X linked) | Episodes in males triggered by carbohydrate feeding | Pre and postprandial blood lactate, CSF lactate, fibroblast pyruvate dehydrogenase |
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Refsum's disease | Retinitis pigmentosa, polyneuropathy | Plasma phytanic acid |
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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. |
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Leukodystrophy (diagnosed radiologically)
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Krabbe's leukodystrophy | Pes cavus, hemiparesis, spastic tetraparesis | Leucocyte β-galactocerebrosidase |
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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 |
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Strokes and stroke-like episodes:
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Fabry's disease | Angiokeratoma, renal disease, developmental delay | Leucocyte α-galactosidase A |
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Homocystinuria | Lens dislocation,occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation | Urine homocystine |
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Mitochondrial myopathy, encephalopathy with lactic acidaemia and stroke-like episodes (MELAS) | Seizures, developmental delay, sensorineural hearing loss ±diabetes mellitus | Blood for mtDNA analysis |
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Urea cycle defects | Postprandial vomiting, coma, confusion | Blood ammonia, plasma, and urine amino acids |
Behavioural and/or psychiatric disorders and/or dementia
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Acaeruloplasminaemia | Ataxia, diabetes mellitus, retinal dystrophy | Plasma copper and caeruloplasmin, plasma iron and ferritin |
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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 |
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Homocystinuria (classic) | Occlusive cerebrovascular disease, dislocated lenses, osteoporosis, skeletal deformities. | Urine and plasma homocystine and methionine. |
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Homocystinuria (remethylation defect) | Paraesthesia, limb weakness, mental retardation | Urine and plasma homocystine and methionine. |
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Juvenile Batten's disease | Visual loss, seizures, retinitis pigmentosa | Skin or rectal biopsy for histological analysis, DNA for the common deletion |
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Kuf's disease | Dementia, psychosis, motor loss | Skin or rectal biopsy for histological analysis |
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Metachromatic leukodystrophy | Slow progressive disorder, impaired nerve conduction, leukodystrophy | Leucocyte arylsulphatase A (pseudodeficiency state must be excluded) |
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Niemann-Pick disease type C | Vertical supranuclear ophthalmoplegia, psychomotor retardation, ataxia, dystonia, splenomegaly | Bone marrow aspirate, fibroblast cholesterol incorporation and staining |
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Ornithine transcarbamylase deficiency | Episodic symptoms (often postprandial), sleep disorders, comatose episodes | Plasma ammonia (1h postprandial), plasma amino acids, urine amino acids and orotic acid |
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Porphyriria | Limb, neck, or chest pain, muscle weakness, abdominal pain, photosensitivity. | Urine and fecal porphyrins, urine delta aminolaevulinic acid and porphobilinogen |
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Wilson's disease | Kayser-Fleischer rings ±liver disease, dysarthria, loss of coordination, pseudobulbar palsy , parkinsonian features | Plasma copper and caeruloplasmin |
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X linked adrenoleukodystrophy | Gait disturbance ±Addison's disease | Plasma very long chain fatty acids |
leukodystrophy, spastic paraparesis, impotence |
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Eye disorders
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Cerebrotendinous xanthomatosis | Spasticity, cataracts, tendon xanthomas | Urine cholestanol |
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Galactokinase deficiency | Cataracts | Postprandial urine sugar, chromatography |
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Gaucher's disease type III | Horizontal supranuclear gaze defect, developmental delay, hydrocephalus, skeletal abnormalities, psychosis | Leucocyte β-glucosidase |
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Homocystinuria (classic form) | Lens dislocation, occlusive cerebrovascular disease, osteoporosis, skeletal deformities, mental retardation | Urine and plasma homocystine and methionine |
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Hyperornithinaemia with gyrate atrophy of the retina | Optic atrophy | Plasma and urine amino acids (ornithine) |
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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 |
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Leber's hereditary optic atrophy | Bilateral optic atrophy (may be alcohol or tobacco triggered) | Blood for mtDNA analysis |
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Neuropathy ataxia and retinitis pigmentosa (NARP) | Retinitis pigmentosa, ataxia, neuropathy | Blood for mtDNA analysis |
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Niemann-Pick disease type C | Psychomotor retardation leading to dementia ataxia with dystonia, vertical supranuclear ophthalmoplegia | Bone marrow aspirate, fibroblast cholesterol uptake and staining. |
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Oculocutaneous albinism | Pale complexion, blue eyes | Hair follicle tyrosinase |
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Refsum's disease | Peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia | Plasma phytanic acid |
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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. |
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Tyrosinaemia type II | Cataracts, skin lesions, slight developmental delay | Plasma and urine amino acids |
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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
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Electron transport chain disorders | Any combination of symptoms | CSF and blood lactate, blood mtDNA analysis, muscle biopsy for enzyme assay. |
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Juvenile Batten's disease | Visual loss | Skin or rectal biopsy for histological analysis, DNA for the common mutation |
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Kuf's disease | Progressive myoclonic epilepsy | Skin or rectal biopsy for histological analysis |
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Myoclonic epilepsy with ragged red fibres | Myoclonus | Blood for mtDNA analysis. |
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Pyridoxine dependent seizures | Persistent seizures responsive to pyridoxine | Pyridoxine response trial (primary defect not known) |
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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 |