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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 usually occurs soon after birth with severe hyperammonemic coma which may be associated with lactic acidosis, but a chronic juvenile form also exists with anorexia, vomiting, hypotonia, growth and psychomotor retardation, and convulsions. 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. Citrullinemia type II has been identified as the consequence of a deficiency of the mitochondrial aspartate glutamate carrier (citrin). The result is an intramitochondrial deficiency of aspartate. The disorder presents at two ages: in the neonatal period with a liver disease (cholestasis) with in general no symptom of hyperammonemia and normal citrulline levels: in adulthood with typical symptoms of hyperammonemia and intermediate citrulline levels (200-500 µmol/l). There is no specific treatment for this disorder. Citrullinemia type III is characterized by partial arginosuccinate synthetase deficiency with a high residual enzyme activity, the pathogenicity of which is questionable.
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