Georg F. Hoffmann, Andreas Schulze
12.1 Introduction
Hyperornithinemia-associated gyrate atrophy of the choroid and retina (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 1400µM. Permanent reduction of plasma ornithine to values < 200µM 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 acidα-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 (K¨olker 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).
12.2 Nomenclature
No. Disorder/deficiency Definition/comment Gene symbol OMIM No.
12.1 Hyperornithinemia
(ornithine-5-aminotransferase)
Gyrate atrophy of the choroid and retina
OAT, HOGA 258870
12.2 2-Aminoadipic semialdehyde synthetase deficiency (hyperlysinemia)
Bifunctional protein of 2-oxoglutarate reductase and saccharopine dehydrogenase
AASS 238700, 268700
12.2a Hyperlysinemia I Combined decreases in both enzyme activities
AASS 238700
12.2b Hyperlysinemia II or saccharopinuria
Pronounced decrease in saccharopine dehydrogenase activity
AASS 268700
12.3 2-Aminoadipic/2-oxoadipic aciduria
Presumed 2-aminoadipate aminotransferase/2-oxoadipate dehydrogenase deficiency
204750
12.4 Tryptophanuria Presumed tryptophan-2,3-
dioxygenase deficiency
276100 12.5 Hydroxykynureninuria Presumed kynureninase
deficiency
KYNU 236800
12.6 Hydroxylysinuria Presumed hydroxylysinekinase deficiency
236900 12.7 Glutaric aciduria I (glutaryl-CoA
dehydrogenase deficiency)
Pronounced decrease in glutaryl-CoA dehydrogenase
GCDH, GAI 231670
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 and toddlers with GAI should be avoided if at all possible.
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.
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 B1and B6had 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
B6-responsive forma Diet (see below)
> 14 yr Pyridoxine hydrochloride 40–500 mg/dayb 2
Diet (see below) 12.1 Vitamin
B6-nonresponsive forma
HOGA All ages Diet (see below)
12.4 All ages Nicotinamide 50–300 mg/day 2
12.5 Vitamin
B6-responsive form
< 14 yr Pyridoxine hydrochloride 40–200 mg/day 2
> 14 yr Pyridoxine hydrochloride 40–500 mg/day 2
12.5 Vitamin B6-responsive and nonresponsive forms
All ages Nicotinamide 50–300 mg/day 2
12.7 GAI < 6 yr Carnitine 100 mg/kg
per day
3
> 6 yr Carnitine 50 mg/kg
per day
3
Riboflavinc 100 mg 2
Diet (see below) Neuropharmaceutical agentsd
aTarget plasma ornithine concentration < 200µmol/l
b15–20 mg/day might be as effective in some patients as a higher dosage (Weleber and Kennaway 1981)
cThere is as yet not a single case of proven riboflavin 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)
dSeveral neuropharmaceutical agents have been tried to ameliorate neurological symptoms in patients with glutaric aciduria type I. In our experience, baclofen (Lioresal, 1–2 mg/kg daily) or benzodiazepines (Diazepam, 0.1–1 mg/kg daily)
reduce involuntary movements and improve motor function. In some patients its use and dosage is limited by worsening of truncal hypotonia. There are single positive reports of treatment with intrathecal baclofen or consecutive botulinum injections. Valproic acid should not be given as it effectively competes with glutaric acid for esterification with l-carnitine and may promote disturbances in the mitochondrial acyl-CoA to CoA ratio (Hoffmann et al. 1991)
134 Disorders of Ornithine, Lysine, and Tryptophan
Dangers/Pitfalls
1. Acute respiratory failure after institution of vitamin B6 reported in a few neonates with severe seizure disorder.
2. Peripheral neuropathy associated with long-term ingestion of high dosage vitamin B6(> 1000 mg/day)
3. Higher doses of carnitine administration may result in gastrointestinal upset and dysfunction.
I 12.1 Gyrate atrophy – Dietary treatment Age Protein requirement
(g/kg per day)
Natural protein (g/kg per day)a
Arginine-free essential AAMb
Type g/kg per dayc
Children 1.0–1.7 0.3–0.5 2 0.3–0.5
Adults 0.9 0.25 2 0.25–0.3
aIntended arginine intake 15 mg/kg per day
b0.6 g essential amino acids corresponds to 1 g protein equivalent
cSpread as evenly as possible through the 24 h
Beware/Pitfalls
Overtreatment by protein restriction
I 12.7 Glutaric aciduria I – Dietary treatment
0–12 months 1–6 years 6–14 years Adults
Lysine (mg/kg per day) 100–80 80–50 n.a. n.a.
Tryptophan (mg/kg per day)
20–17 17–13 n.a. n.a.
Protein (formula) (g/kg per day)
1.0–0.8 0.8 n.a. n.a.
Protein (total) (g/kg per day)
2.3–2.0 2.2–1.9 1.0–1.5 0.8–1.0
Energy (kcal/kg per day) 120–100 100–90 60–70 40–50 n.a. not applicable
Dangers/Pitfalls
1. Overtreatment by protein restriction. Special care must be taken to avoid tryptophan deficiency. Tryptophan-free protein formulas should not be used.
2. Increased muscular tension and sweating, common findings in neu- rologically injured patients with GAI, require a higher intake of calo- ries and water. Percutaneous gastrostomy often leads to a dramatic improvement of nutritional status, and even reduction of the dystonic- dyskinetic symptoms.
12.5 Alternative Therapies/Experimental Trials
I 12.1 Gyrate atrophy
No. Symbol Age Medication/diet Dosage (g/day) Doses/day References
12.1 HOGA Adults Creatine monohydrate 1.5–2 (1–1.5 g/m2
per day)
2–3 Heinanen et al.
1999
Adults l-Lysine 10–15
(5 g/m2per day) 5
a Peltola et al.
2000;
Elpeleg and Korman 2001 Adults α-Aminoisobutyric
acid
0.1 5a Valle et al. 1981
aSpread within the diet as evenly as possible through the 24 h
Dangers/Pitfalls
1. Creatine administration corrects skeletal muscle abnormalities but not progress of ophthalmological abnormalities.
2. No studies of the long-term efficacy of these approaches have been reported.
136 Disorders of Ornithine, Lysine, and Tryptophan 12.6 Follow-up/Monitoring
I 12.2 Gyrate atrophy
Age Biochemical
monitoringa
Clinical monitoringb Opthalmological monitoring and fundus photography
Children 6 monthly 6 monthly Yearly
Adults Yearly Yearly Yearly
aPlasma AA, ammonia, urea, ferritin, folate, vitamin B12, blood cell count
bDiet: nutrient intake including micronutrients, body growth, general health. B6treatment: check for peripheral neuropa- thy and ataxia; if in doubt, perform electrophysiological tests (quantitative sensory thresholds, sural nerve electrophysiology)
I 12.7 Glutaric aciduria I
Age Biochemical monitoringa Clinical and developmen- tal monitoringb
Cranial ultrasound/cranial MRIc
Infants Every 4 weeks Every 8 weeks 3 monthly
Children < 6 years 3 monthly 6 monthly At age 24 months
Children > 6 years 6 monthly 6 monthly
Adolescents/adults Yearly Yearly
aPlasma AA, including tryptophan, blood cell count, transaminases, albumin, total protein, Fe, ferritin, folate, vitamin B12, carnitine status in plasma, organic acids in urine
bBody growth, general health. Detailed psychomotor and neurobehavioral examination and testing every 2 years until the age of 6, starting from the age of 24 months, e. g., with the Bayley Scales of Infant Development
cAs long as the fontanelle allows cranial ultrasound, it should be performed quarterly, mainly to detect hygromas. All children shall have a cranial MRI at age 24 months. Neuroradiological investigations at earlier time points are optional;
however, they should be performed in the following situations: (a) abnormalities (e. g., hygromas) found by cranial ultrasound, (b) after acute encephalopathic crises, (c) if new clinical symptoms highly suggestive of neurological damage develop (e. g., movement disorders)
Vitamin B6
< 6 ys 200 mg/day
> 6 ys 500 mg/day for 1–2 months
Significant reduction of plasma ornithine
Plasma ornithine
< 200 µM
Leave on B treatment6
Dietary arginine restriction
B treatment + dietary arginine restriction6
Plasma ornithine
< 200–400 µM
Plasma ornithine
< 200 µM
Dietary arginine restriction + experimental trial with
-lysine or -aminoiosobutyric acid
α L
Leave on B treatment + dietary arginine restriction6 Leave on
dietary arginine restriction
Keep plasma ornithine < 200–400 µM
Keep plasma ornithine as low as possible
Keep plasma ornithine < 200 µM Leave on B treatment
+ dietary arginine restriction6 yes
yes
no no
yes
no no
yes
Fig. 12.1. Treatment in gyrate atrophy
References
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3. Dancis J, Hutzler J, Cox RP (1979) Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology. Am J Hum Genet 31:290–299
138 References
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