Cerebral Dysfunction in Asymptomatic Carriers of Ornithine Transcarbamylase Deficiency

We tested the hypothesis that female carriers of ornithine transcarbamylase (OTC) deficiency have cerebral dysfunction as a consequence of episodic hyperammonemia. Seven such carriers were identified by pedigree analysis and protein-tolerance testing. The Wechsler Adult Intelligence Scale was used for evaluation. All IQ scores were above 100, but in the protein-tolerant siblings, the full-scale and performance IQ scores were higher by 5.6 and 9.9 points, respectively (P<0.02). The absolute difference between the verbal and performance IQ scores was greater in the OTC carriers by 7.8 points (P<0.01). This study suggests that clinically asymptomatic carriers of OTC deficiency may have intellectual deficits, perhaps as a result of episodic hyperammonemia. (N Engl J Med. 1980; 302:482–485.) Ornithine transcarbamylase (OTC), one of the five enzymes required for ureagenesis, catalyzes the synthesis of citrulline from carbamyl phosphate and ornithine. The metabolic consequences of a complete deficiency of this enzyme include absent or trace levels of plasma citrulline, accumulation of carbamyl phosphate (which is diverted to pyrimidine synthesis and results in accumulation and excretion of orotic acid), and accumulation of the precursors of carbamyl phosphate: ammonium, glutamate, glutamine, and alanine. This disorder is inherited as an X-linked trait. Thus, the male in an OTC-deficient kindred is either normal or severely affected in the newborn period. The female heterozygote, however,. . .