Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: physiologic and biochemical implications.

N-Acetyl-L-glutamate synthetase (NAG synthetase) is a mitochondrial matrix enzyme which catalyzes the synthesis of N-acetyl-Lglutamate (NAG), a physiologic activator of the urea cycle enzyme carbamylphosphate synthetase I. Deficiency of NAG synthetase in humans has been reported only three times previously. Two cases presented with uncontrolable neonatal hyperammonemia leading to death, while a third child presented with hyperammonemia and a neurodegenerative picture at 15 months of age after previously being healthy. We report here a new case of NAG synthetase deficiency who presented at 4 years, 10 months of age with an episode of hyperammonemia. Diagnosis was made at age 5 years, 6 months when a liver biopsy showed 9.7% of normal activity. Urine orotic acid was low, and total NAG content in liver was normal. Liver pathology revealed micro- and macrovesicular fat and mitochondria of irregular size and shape with intracristae crystallizations. NAG content in liver in patients with NAG synthetase deficiency has not previously been reported. Its normal value in the face of NAG synthetase deficiency suggests an abnormal localization of NAG to the cytoplasm and the likelihood of aberrant cytoplasmic synthesis of this compound. Additional physiologic implications of this speculative abnormal compartmentalization are discussed.