Studies on a Case of HHH-Syndrome (Hyperammonemia, Hyperornithinemia, Homocitrullinuria)

Abstract

A patient with the hyperornithinemia, hyperammonemia, homocitrullinuria syndrome is described. This patient represents the 12th documented case of this rare, presumably autosomal recessive condition. Increased levels of ammonia, ornithine and homocitrulline were demonstrated in blood and cerebrospinal fluid. The blood ammonia concentration could be lowered by supplementation of the diet with low doses of arginine. High doses of arginine precipitated seizures, although plasma levels of arginine and ornithine were not altered. The uptake of ornithine by the particulate fraction of the patient's fibroblasts was lower than that of controls, but still measurable. It is suggested that HHH patients have a partial impairment of the uptake of ornithine by mitochondria.

The pH of mitochondria of fibroblasts from a hyperornithinaemia, hyperammonaemia, homocitrullinuria‐syndrome patient

“…Up till now 12 patients have been described (Fell et al, 1974;Gatfield et al, 1975;Hommes et aI., 1982Hommes et aI., , 1983Shih et al, 1969). Several groups of investigators have provided evidence that this condition is due to an impairment of the transport ofornithine across the inner mitochondrial membrane (Fell et al, 1974;Gray et al, 1982;Haust et al, 19'81 ;Hommes et al, 1982Hommes et al, , 1983Shih et al, 1980Shih et al, , 1982 but direct proof is lacking.…”

“…A second mechanism for the uptake of ornithine has been proposed (Bradford and McGivan, 1980) whereby ornithine and citrulline are exchanged via an antiporter, but these findings could not be confirmed (Hommes et al, 1983). The rate of uptake of ornithine is dependent on the pH of the matrix of the mitochondria (McGivan et al, 1977;Hommes et al, 1983).…”

Ultrastructural changes in fibroblast mitochondria of a patient with HHH‐syndrome

“…Elimination of the proton gradient with concomitant loss of respiratory control can therefore equally lead to abnormal mitochondria. In this context, it should be noted that the matrix pH of H H Hpatient fibroblast mitochondria is not different from that of controls (Metoki and Hommes, 1984).…”

“…The cells were harvested at confluence by trypsinization. The HHH-syndrome patient whose cells were used in the present study has been described elsewhere (Hommes et al, 1984). Control cells were obtained from seven healthy males.…”

Further Evidence for a Separate Enzymic Entity for the Synthesis of Homocitrulline, Distinct from the Regular Ornithine Transcarbamylase

“…Evidence has been presented that the HHH syndrome is dence, [cf. 13,16], or the localization of the activity converting lysine and carbamylphosphate to homocitrulline [ 14] is different from that for the conversion of ornithine and carbamylphosphate to citrulline. The present communication describes experiments ad dressing this problem.…”