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23 Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

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23 Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism 23 Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism Georg F. Hoffmann 23.1 Introduction – 295 23.2 Hyperlysinemia/Saccharopinuria – 295 23.2.1 Clinical Presentation – 295 23.2.2 Metabolic Derangement – 295 23.2.3 Genetics – 296 23.2.4 Diagnostic Tests – 296 23.2.5 Treatment and Prognosis – 296 23.3 Hydroxylysinuria – 296 23.4 2-Amino-/2-Oxo-Adipic Aciduria – 296 23.4.1 Clinical Presentation – 296 23.4.2 Metabolic Derangement – 296 23.4.3 Genetics – 296 23.4.4 Diagnostic Tests – 296 23.4.5 Treatment and Prognosis – 297 23.5 Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency) – 297 23.5.1 Clinical Presentation – 297 23.5.2 Metabolic Derangement – 297 23.5.3 Genetics – 300 23.5.4 Diagnostic Tests – 300 23.5.5 Treatment and Prognosis – 301 23.6 L-2-Hydroxyglutaric Aciduria – 302 23.6.1 Clinical Presentation – 302 23.6.2 Metabolic Derangement – 303 23.6.3 Genetics – 303 23.6.4 Diagnostic Tests – 303 23.6.5 Treatment and Prognosis – 303 23.7 D-2-Hydroxyglutaric Aciduria – 303 23.7.1 Clinical Presentation – 303 23.7.2 Metabolic Derangement – 303 23.7.3 Genetics – 303 23.7.4 Diagnostic Tests – 304 23.7.5 Treatment and Prognosis – 304 23.8 N-Acetylaspartic Aciduria (Canavan Disease) – 304 23.8.1 Clinical Presentation – 304 23.8.2 Metabolic Derangement – 304 23.8.3 Genetics – 304 23.8.4 Diagnostic Tests – 304 23.8.5 Treatment and Prognosis – 305 References – 305 294 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism Catabolism of Lysine, Hydroxylysine, and Tryptophan Lysine, hydroxylysine and tryptophan are degraded with- otide (FAD) and hence to the respiratory chain (. Fig. in the mitochodrion initially via separate pathways but 13.1) via electron transfer protein (ETF)/ETF-dehy- which then converge in a common pathway starting with drogenase (ETF-DH). From the five distinct enzyme de- 2-aminoadipic and 2-oxoadipic acids (. Fig. 23.1). The ficiencies identified in the degradation of lysine, only en- initial catabolism of lysine proceeds mainly via the bifunc- zymes 4 and 6 have proven relevance as neurometabolic tional enzyme, 2-aminoadipic-6-semialdehyde synthase disorders. Glutaric aciduria type I is caused by the isolated (enzyme 1). A small amount of lysine is cata bolized via deficiency of glutaryl-CoA dehydrogenase/glutaconyl- IV pipecolic acid and the peroxisomal enzyme, pipecolic acid CoA decarboxylase. Glutaric aciduria type II, caused by oxidase (enzyme 2). Hydroxylysine enters this pathway ETF/ETF-DH deficiencies, is discussed in 7 Chap. 13. after phosphorylation by hydroxylysine kinase (enzyme Pipecolic acid oxidase deficiency is discussed in 7 Chap. 3). 2-Aminoadipic-6-semialdehyde is converted into glu- 40 and antiquitin deficiency in 7 Chap. 29. taryl-CoA by antiquitin (enzyme 4, deficient in B6 respon- The metabolic origins and fates of L- and D-2-hydro- sive seizures) and a second bifunctional enzyme, 2-ami- xyglutaric acids have not been completely unravelled in noadipate aminotransferase/2-oxoadipate dehydrogenase mammals. Yet, L- and D-2-hydroxyglutaric aciduria (enzyme 5). Glutaryl-CoA is converted into crotonyl- have recently been shown to be caused by deficiencies CoA by a third bifunctional enzyme, glutaryl-CoA dehy- of specific dehydrogenases. Aspartoacylase irreversibly drogenase/glutaconyl-CoA decarboxylase (enzyme 6). splits N-acetylaspartic acid into acetate and aspartate This enzyme tranfers electrons to flavin adenine dinucle- (not illustrated). Fig. 23.1. Tryptophan, hydroxylysine and lysine catabolic dehydro genase; 6, glutaryl-CoA dehydrogenase/glutaconyl-CoA pathways. CoA, coenzyme A. 1, 2-aminoadipic-6-semialdehyde decarboxylase. Enzyme deficiencies are indicated by solid bars synthase; 2, pipecolic acid oxidase; 3, hydroxylysine kinase; across the arrows 4, antiquitin; 5, 2-aminoadipate aminotransferase/2-oxoadipate 295 23 23.2 · Hyperlysinemia/Saccharopinuria share structural similarities with the excitatory amino acid Seven inborn errors are described in this chapter: glutamate (D-2-, L-2-, 3-hydroxyglutarate, glutarate) or Hyperlysinemia I/hyperlysinemia II or saccharopinuria, have been suggested to be neurotransmitters/neuromodu- hydroxylysinuria and 2-amino-/2-oxo-adipic aciduria lators (J-hydroxybutyrate, N-acetylaspartylglutamate) [2]. may all have no clinical significance, but some patients Evidence from in vitro and in vivo studies is growing that are retarded and show variable neurological abnorma- these acids indeed interfere with glutamatergic or gamma lities. amino butyric acid (GABA)-ergic neurotransmission or Glutaric aciduria type I (GA I, synonym glutaryl-CoA impair energy metabolism. Delayed myelination or pro- dehydrogenase deficiency) causes severe neurometa- gressive demyelination, basal ganglia and cerebellum patho- bolic disease. The first months may be uneventful with logy, the main pathologies in cerebral organic acid dis orders, only subtle neurological abnormalities and/or macro- are also characteristic of mitochondrial disorders suggest- cephaly, but progressive cerebral atrophy or subdural ing at least partial common pathological mechanisms. hemorrhages on neuroimaging. Between age 6 to Patients with cerebral organic acid disorders often 18 months most untreated patients suffer an acute en- suffer a diagnostic odyssey and may even remain undiag- cephalo pathy resulting in irreversible destruction of nosed. Metabolic hallmarks such as hypoglycemia, meta- suscep tible brain regions, in particular the striatum, bolic acidosis or lactic acidemia, the usual concomitants of a dystonic-dyskinetic syndrome and, ultimately, often disorders of organic acid metabolism, are generally absent. early death. Restriction of lysine, administration of Furthermore, elevations of diagnostic metabolites may be L-carnitine and timely vigorous treatment during inter- small and therefore missed on »routine« organic acid ana- current illness is able to completely prevent or at least lysis, e.g. in glutaric aciduria type I. The correct diagnosis halt the disease. requires an increased awareness of these disorders by the L-2-Hydroxyglutaric aciduria shows an insidious referring physician as well as the biochemist in the meta- onset with delay of unsupported walking and speech, bolic laboratory. Diagnostic clues can be derived from neuro- febrile convulsions, and macrocephaly. Over the years, imaging findings . Fig. 23.2). Progressive disturbances of severe mental retardation and cerebellar ataxia devel- myelination, cerebellar atrophy, frontotemporal atrophy, op with or without dystonia, pyramidal signs, and hypodensities and/or infarcts of the basal ganglia and any seizures. symmetrical (fluctuating) pathology, apparently indepen- D-2-Hydroxyglutaric aciduria causes severe early- dent of defined regions of vascular supply, are suggestive of onset epileptic encephalopathy with neonatal seizures, cerebral organic acid disorders. lack of psychomotor development and early death. In contrast to the cerebral organic acid disorders, the Some patients exhibit milder neurological symptoms other know defects of lysine and hydroxylysine degradation such as mild developmental delay, delayed speech and all appear to be rare biochemical variants of human meta- febrile convulsions. bolism without clinical significance. N-Acetylaspartic aciduria (synonyms: aspartoacylase deficiency, spongy degeneration of the brain, Van Bogaert- Bertrand disease or Canavan disease) is an infantile 23.2 Hyperlysinemia/Saccharopinuria degenerative disease primarily affecting the cerebral white matter. It commonly manifests with poor head 23.2.1 Clinical Presentation control and hypotonia at 2-4 months, macrocephaly, marked developmental delay, optic nerve atrophy, Hyperlysinemia/saccharopinuria appears to be a rare »non- progressive spasticity, opisthotonic posturing, seizures disease«. About half of the patients described were detected and death in childhood. incidentally and are healthy [3]. Symptoms have included psychomotor retardation, epilepsy, spasticity, ataxia and short stature. Individual patients have been described with joint laxity and spherophakia, respectively. 23.1 Introduction A group of organic acid disorders presents exclusively with 23.2.2 Metabolic Derangement progressive neurological symptoms of ataxia, epilepsy, myo- clonus, extrapyramidal symptoms, metabolic stroke, and Hyperlysinemia/saccharopinuria is caused by deficiency macro cephaly [1]. The core »cerebral« organic acid dis- of the bifunctional protein 2-aminoadipic semialdehyde orders are glutaric aciduria type I, D-2-hydroxyglutaric acid- synthase, the first enzyme of the main route of lysine de- uria, L-2-hydroxyglutaric aciduria, 4-hydroxybutyric acid- gradation [4]. The two functions, lysine-2-oxoglutarate uria and N-acetylaspartic aciduria. Strikingly, in all these reductase and saccharopine dehydrogenase, may be differ- disorders the pathological compounds that accumulate ently affected by mutations. Most often, both activities are 296 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism severely reduced, resulting predominantly in hyperlysine- 23.3 Hydroxylysinuria mia and hyperlysinuria, accompanied by relatively mild sacccharopinuria (hyperlysinemia I). In hyperlysinemia II Hydroxylysinuria and concomitant hydroxylysinemia has or saccharopinuria [5], there is a relatively more pronounced been identified in only six patients, all of whom showed decrease in saccharopine dehydrogenase activity with re- some degree of mental retardation
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