F. Ebinger
Currently, over 300 diseases caused by congenital metabolic anomalies are known, and their numbers are increasing (Fernandes et al., 2000; Blau et al., 2003; Zschocke and Hoffmann, 2004). In most cases they are diagnosed in childhood. However, many metabolic disorders may in some cases not become manifest until adolescence or adulthood, and these later manifestations can differ significantly from the often rapidly progressive clinical course of the same metabolic defects when they appear in early childhood. Symptoms such as neuropathy, ataxia, dystonia, epilepsy, psychosis, and dementia suggest an inflammatory, toxic, vascular, or psychiatric disease. Frequently, a “neurodegenerative disease of unknown etiology” is diagnosed. The first symptoms are often mild or intermittent and can be interpreted correctly only in retrospect. The most important step in diagnosing such diseases is to think of a metabolic etiology in the first place. Table 17.1 lists the cardinal symptoms of selected neurometabolic diseases when they manifest in adulthood (Gray et al., 2000; Saudubray and Charpentier, 2001).
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Table 17.1 Neurological symptoms of congenital metabolic disorders in adulthood |
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Symptoms |
Metabolic defect |
Clinical manifestations |
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Myopathy, stress intolerance |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
Glycogen storage disease type II, Danon's disease |
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Defect in purine metabolism |
Myoadenylate deaminase deficiency |
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Neuropathy |
Lysosomal disorder |
Fabry's disease, Krabbe's disease, metachromatic leukodystrophy |
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Peroxisomal disorder |
Refsum's disease, adrenoleukodystrophy/adrenomyeloneuropathy |
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Mitochondrial disorder |
Electron transport chain defects |
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Defect in cholesterol metabolism |
Cerebrotendinous xanthomatosis |
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Defect in heme biosynthesis |
Porphyria |
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Spinal muscular atrophy |
Lysosomal disorder |
GM2 gangliosidosis |
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Spasticity |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
GM1 gangliosidosis, GM2 gangliosidosis, Gaucher's disease type 3, Krabbe's disease, metachromatic leukodystrophy, Salla disease |
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Peroxisomal disorder |
Refsum's disease, adrenoleukodystrophy/adrenomyeloneuropathy |
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Defect in cholesterol metabolism |
Cerebrotendinous xanthomatosis |
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Defect in urea cycle |
Arginase deficiency |
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Progressive ataxia |
Mitochondrial disorder |
Pyruvate dehydrogenase deficiency, electron transport chain defects |
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Lysosomal disorder |
GM2 gangliosidosis, metachromatic leukodystrophy, Niemann-Pick disease type C, sialidosis, Salla disease |
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Peroxisomal disorder |
Refsum's disease, adrenoleukodystrophy/adrenomyeloneuropathy |
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Defect in cholesterol metabolism |
Cerebrotendinous xanthomatosis |
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Defect in copper metabolism |
Wilson's disease |
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Defect in lipid metabolism |
Abetalipoproteinemia |
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Extrapyramidal symptoms |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs disease, Sandhoff’s disease), metachromatic leukodystrophy, Niemann–Pick disease type C, neuronal ceroid lipofuscinosis (Spielmeyer–Vogt disease, Kufs’ disease) |
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Peroxisomal disorder |
Adrenoleukodystrophy |
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Defect in cholesterol metabolism |
Cerebrotendinous xanthomatosis |
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Defect in copper metabolism |
Wilson's disease |
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Defect in purine metabolism |
Lesch-Nyhan syndrome |
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Organic acid disorder |
Glutaric aciduria type I |
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Leukodystrophy/leukoencephalopathy (specific patterns of distribution) |
Mitochondrial disorder Lysosomal disorder Peroxisomal disorder Defect in cholesterol metabolism Organic acid disorder |
Electron transport chain defects Krabbe's disease, metachromatic leukodystrophy Adrenoleukodystrophy Cerebrotendinous xanthomatosis Canavan's disease |
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(Myoclonic) epilepsy |
Mitochondrial disorder Lysosomal disorder |
Pyruvate dehydrogenase deficiency, electron transport chain defects Sialidosis, neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease, Kufs’ disease) |
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Behavioral abnormalities, psychosis, dementia |
Mitochondrial disorder Lysosomal disorder |
Electron transport chain defects Fabry's disease, GM2 gangliosidosis (Tay–Sachs disease, Sandhoff’s disease), Gaucher's disease type 3, metachromatic leukodystrophy, Niemann-Pick disease type C, neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease, Kufs’ disease) |
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Peroxisomal disorder |
Adrenoleukodystrophy |
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Defect in cholesterol metabolism |
Cerebrotendinous xanthomatosis |
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Defect in copper metabolism |
Wilson's disease |
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Defect in amino acid metabolism |
Homocystinuria |
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Defect in urea cycle |
Ornithine transcarbamylase deficiency |
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Loss of vision |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
Neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease), sialidosis |
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Peroxisomal disorder |
Refsum's disease |
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Defect in urea cycle |
Ornithine aminotransferase deficiency |
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Ophthalmoplegia |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
Gaucher's disease type 3, Niemann-Pick disease type C |
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Stroke, stroke-like episodes |
Mitochondrial disorder |
Electron transport chain defects |
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Lysosomal disorder |
Fabry's disease |
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Defect in amino acid metabolism |
Homocystinuria, methylene tetrahydrofolate reductase deficiency |
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Defect in urea cycle |
Ornithine transcarbamylase deficiency |
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Recurrent attacks of ataxia |
Mitochondrial disorder |
Pyruvate dehydrogenase deficiency, electron transport chain defects |
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Defect in amino acid metabolism |
Branched-chain organic aciduria, methylene tetrahydrofolate reductase deficiency |
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Defect in urea cycle |
Ornithine transcarbamylase deficiency |
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Recurrent psychiatric symptoms |
Defect in amino acid metabolism |
Methylene tetrahydrofolate reductase deficiency |
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Organic acid disorder |
Branched-chain organic acid disorder |
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Defect in urea cycle |
Ornithine transcarbamylase deficiency |
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Defect in heme biosynthesis |
Acute porphyria |
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