The primary defect in patients presenting with a history of
protein intolerance,
mental retardation, and
epilepsy of variable degree, with the unique triad of hyperornithinemia,
hyperammonemia, and homocitrullinuria (the
HHH syndrome) has been postulated to be a defect in translocation of
ornithine into the mitochondria. In a 12-year-old boy with the
HHH syndrome, the
hyperammonemia observed following a
protein load was prevented when the same load was given orally with a 1 mmol/kg of
ornithine-HCl. At a dosage level of 0.5 to 1.0 mmol/kg/day of
ornithine HCl, administered in 3 divided doses with meals, the patient's
protein tolerance improved. As pretreatment
hyperammonemia reverted to normal levels, the patient was able to cope with increased
dietary protein and his growth accelerated. During the 2-year interval of the study, the
ornithine HCl supplements were withdrawn on 2 occasions, and within a week the
hyperammonemia recurred. Whereas cultured fibroblasts from the HHH patient were capable of oxidizing U-14C-glutamate to 14CO2 as rapidly as normal cells. 1-14C-ornithine or 5-14C-ornithine were oxidized at only 1/28 or 1/49 of the normal rate. Ultrastructural studies of the HHH cultured fibroblast mitochondria revealed distinctive alterations in size and shape; unusually long, branching, and "curling," HHH mitochondria also showed accelerated regressive changes.