Kazuhiko Oyanagi

Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency

A Leu148Phe substitution of the ornithine transcarbamylase (OTC) gene was identified in a 2-year-old girl with OTC deficiency (14% of control). Her two elder sisters died in childhood of hyperammonemia, and the patient also died of OTC deficiency. Enzyme activity in Cos1 cells transfected by the mutant cDNA was undetectable, thereby indicating a definite pathogenic mutation. Familial gene analysis showed that the mother had wild-type OTC alleles on both X-chromosomes and the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. This clinical case shows that a somatic and germline mosaicism for a single-gene disorder led to an unusual pattern of X-linked inheritance in the family, and all three daughters in the family died of OTC deficiency. The possibility that inherited factors will lead to skewed X-inactivation needs to be considered.

Nonlinear elimination of benzoate in patients with congenital hyperammonemia

Sodium benzoate is effective for treatment of hyperammonemia caused by inborn errors of urea synthesis) -4 Although previous reports ~, 2 have suggested that relatively large doses of benzoate can be tolerated without toxicity, Sorrie adverse effects, 3,4 including death, were reported at higher doses. At present, however, there is little information concerning the blood elimination kinetics of benzoate. We studied the pharmacokinetics of benzoate in two patients with hyperammonemia.

Treatment of congenital hyperammonemia with L-carnitine

Carnitine status was evaluated in patients with congenital hyperammonemia caused by ornithine trans-carbamylase (OTC) deficiency, carbamyl phosphate synthetase (CPS) deficiency, systemic carnitine deficiency and in identical twins who were born from a partially OTC-deficient mother. We found decreased free carnitine and increased acylcarnitine levels in the serum and in the liver tissues. The ratio of acyl/free carnitine was significantly elevated in both serum and liver tissues. After oral administration of L-carnitine (20–150 mg/kg/day) in the patient with congenital hyperammonemia, hyperammonemic episodes and metabolic acidosis disappeared and the ammonia level in the blood decreased significantly, accompanied by an increase in serum free carnitine levels.

Therapeutic basis for congenital hyperammonemia: The role of amino acids and their transport systems in ureogenesis in the primary culture of adult rat hepatocytes

The urea cycle enzyme deficiencies are the most common genetic causes of hyperammonemia in children and the clinical and biochemical features of respective diseases have been reported. However, the mechanism regulating ureogenesis has not been well clarified at the cellular level. We studied the relationship between urea synthesis and the transport of amino acids using the primary culture of hepatocytes from adult rats. The ammonia detoxication and urea synthesis were affected by the amino acids of urea cycle intermediates. The concentration of ammonia in the incubation medium containing ornithine, aspartate and arginine (2 mM) decreased more than it did in the medium with any other amino acids. But when glutamine was added to the medium, elimination of ammonia from the medium was inhibited. The rates of urea synthesis were high when these amino acids were added to the medium. When the hepatocytes were incubated in the medium containing 1 mM ammonium chloride, the transport activity of system-A mediated amino acid (MeAIB) did not change compared with the control level. The uptake of system-L mediated amino acid (BCH) increased slightly.