NeurometPlus

Incidence

Citrullinemia type I is inherited in an autosomal recessive manner.

Clinical Characteristics

Citrullinemia is an autosomal recessive inherited condition due to arginosuccinate synthetase deficiency, an enzyme involved in the urea cycle. The deficiency causes hyperammonemic coma, accumulation of citrulline and orotic acid, and arginine deficiency (Citrullinemia type I). Onset occurs soon after birth with severe hyperammonemic coma which may be associated with lactic acidosis. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, the infant develops hyperammonemia and becomes progressively lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure. Without prompt intervention, hyperammonemia and the accummulation of other toxic metabolites (e.g., glutamine) result in increased intracranial pressure, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurological deficit. Diagnosis is based on the presence of hyperammonemia and on the chromatography of plasmatic and urinary aminoacids showing major elevation of citrulline, glutamine and alanine, and low levels of arginine. Another finding is orotic aciduria. Patients with citrullinemia type I are treated with a strict, lifelong diet of very limited protein intake, associated with arginine and both sodium benzoate and phenylbutyrate supplementation. Untreated individuals with the severe form of citrullinemia type 1 have hyperammonemia with plasma ammonia concentration of 1000-3000 µmol/L. Results of plasma quantitative amino acid analysis shows a concentration of citrulline usually >1000 µmol/L (normal is <50 µmol/L), accompanied by absent argininosuccinic acid in plasma. Argininosuccinate synthase enzyme activity, measured in fibroblasts, liver, and in all tissues and cells in which ASS is expressed, is decreased. ASS is the only gene known to be associated with citrullinemia type I. Sequence analysis and linkage analysis are clinically available.

Precipitants

Protein intake.

Provocation Tests

Not recommended, but if child is fed with protein, ammonia goes up fast.

Diagnostic Procedures

EB-L, EB-F. Hepatic and fibroblasts argininosuccinate synthetase deficiency. Classic neonatal-onset citrullinemia type I is suspected in infants who have been on a full protein diet and who present in the first week of life with: Hyperammonemia resulting in increasing lethargy, somnolence, refusal to feed, vomiting, and tachypnea. Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus. Plasma ammonia concentration: In the severe form of the initial plasma ammonia concentration may be 1000-3000 µmol/L. In the milder neonatal and in the adult form, a lower plasma concentration may be seen. (Adult upper limit of normal is <35µmol/L). Plasma quantitative amino acid analysis: Citrulline: Usually >1000 µmol/L. Normal is <50 µmol/L. Argininosuccinic acid: Absent. Arginine and ornithine: Low to normal range. Lysine, glutamine, and alanine: Increased. Urinary organic acids: Normal, except orotic acid may be detected as part of urinary organic acid analysis by GC/MS; however, the sensitivity depends upon the extraction method.