12 Disorders of Ornithine, Lysine, and Tryptophan Georg F. Hoffmann, Andreas Schulze 12.1 Introduction Hyperornithinemia-associatedgyrateatrophyofthechoroidandretina(HOGA) is caused by deficiency of ornithine-5-aminotransferase. HOGA is an autoso- mal recessive disorder characterized by progressive chorioretinal degeneration with myopia, night blindness, and loss of peripheral vision, starting late in the first decade, proceeding to tunnel vision and eventual blindness by the third and fourth decade. Plasma ornithine values range from 400 to 1400 µM. Permanent reduction of plasma ornithine to values < 200 µM slows or stops the chorioreti- nal degeneration. A small proportion of patients respond to pharmacological doses of vitamin B6 (Weleber et al. 1978). Additional therapeutic approaches to reduce ornithine are substrate deprivation by dietary arginine restriction (Kaiser Kupfer et al. 1991) and augmenting of renal losses by administration of pharmacological doses of l-lysine (Giordano et al. 1978; Peltola et al. 2000; Elpe- leg and Korman 2001) or the nonmetabolizable amino acid α-aminoisobutyric acid (Valle et al. 1981). Combined treatment approaches appear to be necessary, since no form of therapy is unequivocally effective. Creatine administration im- proves the histological abnormalities in muscle (Heinanen et al. 1999), but does not halt the progress of chorioretinal degeneration. Hyperlysinemia/saccharopinuria appears to be a rare “non-disease.” It is caused by deficiency of the bifunctional protein 2-aminoadipic semialdehyde synthase, the first enzyme of the main pathway of lysine degradation. The two functions of the enzyme, lysine:2-oxoglutarate reductase and saccharopine de- hydrogenase, may be differently affected by mutations. In most cases, both activities are severely reduced, resulting predominantly in hyperlysinemia and hyperlysinuria, accompanied by relatively mild sacccharopinuria (hyperlysine- mia I). About half of the patients described were detected incidentally and are healthy (Dancis et al. 1979, 1983). Symptoms described to be associated with the disorder include psychomotor retardation, epilepsy, spasticity, ataxia, and short stature. Single patients were described with joint laxity and spherophakia, re- spectively. These observations suggest that it can be accounted for by sampling bias. 2-Aminoadipic and/or 2-oxoadipic aciduria may also have no clinical sig- nificance, but some patients are retarded and show variable neurological ab- 130 Disorders of Ornithine, Lysine, and Tryptophan normalities. The metabolic profile is heterogeneous, with most patients show- ing elevations of 2-aminoadipic acid, 2-oxoadipic acid, and 2-hydroxyadipic acid, whereas some excrete 2-aminoadipic acid only. It can be assumed that isolated 2-aminoadipic aciduria without significant 2-oxoadipic aciduria is caused by a deficiency of 2-aminoadipate aminotransferase; whereas combined 2-aminoadipic/2-oxoadipic aciduria would be caused by a deficiency of the 2-oxoadipate dehydrogenase complex. However, the biochemical profile of the reported patients overlap, loading studies were inconclusive, and a deficiency of either enzyme has as yet not been shown directly. Glutaric aciduria type I (GAI; synonyms: glutaric acidemia type I, glutaryl- CoA dehydrogenase deficiency) is an autosomal recessive inherited neuro- metabolic disease with an estimated incidence of 1:50,000 Caucasian newborns (Schulze et al. 2003). Early diagnosis and treatment of the asymptomatic child is essential, as current therapy has little effect upon the brain-injured child. In the natural course of the disease, 75% of undiagnosed and untreated chil- dren develop acute encephalopathic crises during infancy or early childhood (modal age 6–12 months) precipitated by febrile illnesses or routine vaccina- tions (Hoffmann et al. 1996; Bjugstad et al. 2000). These crises most often result in irreversible damage of vulnerable brain areas, in particular the striatum, and consequently in the development of a dystonic dyskinetic movement disorder. Restriction of protein and lysine, administration of l-carnitine, timely vig- orous treatment during intercurrent illness and neuropharmaceutical agents during the first 6 years of life may completely prevent or at least halt the un- favorable course of the disease. There are, however, some high-risk patients in whom the disease progresses despite therapy (Kolker¨ et al. 2001; Monavari et al. 2000). As GAI has become a treatable neurometabolic disorder, increased inclusion in neonatal screening programs to allow early detection and onset of therapy is the key to further progress. A deeper understanding of the patho- logical mechanisms will reveal additional therapeutic approaches, which will hopefully also prevent brain damage in those 20–30% of patients that suffer neurodegeneration under current therapeutic strategies (Strauss et al. 2003). Nomenclature 131 12.2 Nomenclature No. Disorder/deficiency Definition/comment Gene symbol OMIM No. 12.1 Hyperornithinemia Gyrate atrophy of the choroid OAT, HOGA 258870 (ornithine-5-aminotransferase) and retina 12.2 2-Aminoadipic semialdehyde Bifunctional protein of AASS 238700, 268700 synthetase deficiency 2-oxoglutarate reductase and (hyperlysinemia) saccharopine dehydrogenase 12.2a Hyperlysinemia I Combined decreases in both AASS 238700 enzyme activities 12.2b Hyperlysinemia II Pronounced decrease in AASS 268700 or saccharopinuria saccharopine dehydrogenase activity 12.3 2-Aminoadipic/2-oxoadipic Presumed 2-aminoadipate 204750 aciduria aminotransferase/2-oxoadipate dehydrogenase deficiency 12.4 Tryptophanuria Presumed tryptophan-2,3- 276100 dioxygenase deficiency 12.5 Hydroxykynureninuria Presumed kynureninase KYNU 236800 deficiency 12.6 Hydroxylysinuria Presumed hydroxylysinekinase 236900 deficiency 12.7 Glutaric aciduria I (glutaryl-CoA Pronounced decrease in GCDH, GAI 231670 dehydrogenase deficiency) glutaryl-CoA dehydrogenase 12.3 Treatment I Disorders 12.2, 12.3, 12.6 No treatment. I 12.7 Glutaric aciduria I – Emergency treatment Neurosurgical interventions of subdural hygromas and hematomas in infants andtoddlerswithGAIshouldbeavoidedifatallpossible. 132 Disorders of Ornithine, Lysine, and Tryptophan G At Home (for max. 2 h) Age (years) Maltodextrin Volume/day % kcal/100 ml 0–1 10 40 min. 150 ml/kg BW 1–2 15 60 120 ml/kg BW 2–6 20 80 1200–1500 ml > 6 No-disease specific precautions and interventions Within 2 h, patients must be stabilized under this treatment. If the patients do not respond, they should be taken to the local metabolic center as soon as possible. If treatment is beneficial, formula diet should by reintroduced stepwise during the next 24 h. In any case, the local metabolic center must be informed in good time by the parents. Emergency treatment must be considered during intercurrent illness and after vaccinations. G In Hospital • Stop oral intake of natural protein for a maximum of 24 h. • Intravenous infusion of: 1. Glucose: 10–15%; 1800 ml/m2 2. Electrolyte solution 3. l-Carnitine: 100 mg/kg BW • Early implementation of broad-spectrum antibiotics and antipyretics. • Start stepwise increase in oral intake after 24 h. If oral intake cannot be reestablished after 24 h, start parenteral nutrition including lipids. Monitor: • Blood: glucose, pO2,pCO2, base excess, electrolytes, transaminases, l-carnitine, ammonia, clotting, blood culture, lactate, amylase • Urine: ketone bodies, organic acids 12.4 Pharmacological/Dietary Treatment I 12.1 Gyrate atrophy (Fig. 12.1, Flowchart) I 12.2 Hyperlysinemia/saccharopinuria Long-term dietary restriction of lysine has no proven benefit. As patients with hyperlysinemia/saccharopinuria do not suffer from metabolic decompensa- tions, specific interventions during intercurrent illnesses do not appear neces- sary. Pharmacological/Dietary Treatment 133 I 12.3 2-Aminoadipic aciduria/2-oxadipic aciduria Dietary restriction of lysine also failed to correct the biochemical abnormalities in some patients (Casey et al. 1978) and has no proven long-term benefit. Administration of pharmaceutical doses of vitamins B1 and B6 had no effect on the levels of pathological metabolites (Casey et al. 1978). Specific interventions during intercurrent illnesses do not appear necessary. I 12.4 Tryptophanuria I 12.5 Hydroxykynureninuria I 12.7 Glutaric aciduria I No. Symbol Form Age Medication/Diet Dosage Doses/day (n) 12.1 Vitamin HOGA < 14 yr Pyridoxine hydrochloride 40–200 mg/dayb 2 a B6-responsive form Diet (see below) > 14 yr Pyridoxine hydrochloride 40–500 mg/dayb 2 Diet (see below) 12.1 Vitamin HOGA All ages Diet (see below) B6-nonresponsive forma 12.4 All ages Nicotinamide 50–300 mg/day 2 12.5 Vitamin < 14 yr Pyridoxine hydrochloride 40–200 mg/day 2 B6-responsive form > 14 yr Pyridoxine hydrochloride 40–500 mg/day 2 12.5 Vitamin All ages Nicotinamide 50–300 mg/day 2 B6-responsive and nonresponsive forms 12.7 GAI < 6 yr Carnitine 100 mg/kg 3 per day > 6 yr Carnitine 50 mg/kg 3 per day Riboflavinc 100 mg 2 Diet (see below) Neuropharmaceutical agentsd a Target plasma ornithine concentration < 200 µmol/l b 15–20 mg/day might be as effective in some patients as a higher dosage (Weleber and Kennaway 1981) c Thereisasyetnotasinglecaseofprovenriboflavin responsiveness. Riboflavin may be implemented during the first 6 months of age, then stopped for 4 weeks, and reintroduced in the case of evidence of metabolic effect (acylcarnitines, organic acids) d Several neuropharmaceutical agents havebeentriedtoameliorateneurologicalsymptomsinpatientswithglutaric aciduria type I. In our experience,