Inborn Errors of Amino Acid and Organic Acid Metabolism

We studied 26 children with inborn errors of urea synthesis who survived neonatal hyperammonemic coma. There was a 92 per cent one-year survival rate associated with nitrogen-restriction therapy and stimulation of alternative pathways of waste nitrogen excretion. Seventy-nine per cent of the children had one or more developmental disabilities at 12 to 74 months of age; the mean IQ was 43 +/- 6. There was a significant negative linear correlation between duration of Stage III or IV neonatal hyperammonemic coma and IQ at 12 months (r = -0.72, P less than 0.001) but not between the peak ammonium level (351 to 1800 microM) and IQ. There was also a significant correlation between CT abnormalities and duration of hyperammonemic coma (r = 0.85, P less than 0.01) and between CT abnormalities and concurrent IQ (r = -0.75, P less than 0.02). These results suggest that prolonged neonatal hyperammonemic coma is associated with brain damage and impairment of intellectual function. This outcome may be prevented by early diagnosis and therapy.

An increased amount of N-acetylaspartic acid was found in urine and plasma of three patients, from two families, with the diagnosis of cerebral spongy degeneration (Canavan disease). Aspartoacylase was assayed in cultured skin fibroblasts from one patient of each family and a profound deficiency of this enzyme was found. Although the function of N-acetylaspartic acid is not understood, it is known to occur in high concentration in human brain. The finding of a defect in the metabolism of N-acetylaspartic acid causing progressive spongy degeneration of the brain may lead to a better understanding of the function of this amino acid derivative. The aspartoacylase assay affords a new tool for determining the diagnosis of Canavan disease. Since aspartoacylase activity was present in cultured amniotic cells and chorionic villi, it is likely that the assay for this enzyme can be used for the prenatal diagnosis of Canavan disease.