Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome.

Four nicotinamide-adenine dinucleotide phosphate-requiring enzymes were measured in disrupted cultured skin fibroblasts from a 19-year-old patient with juvenile onset of a spinocerebellar and extrapyramidal syndrome. There was marked reduction in the activity of glutamate dehydrogenase (GDH) (22% of mean control activity); GDH activity was also decreased in homogenates of leukocytes from this patient (38% of mean control activity). GDH activity was measured in the leukocytes of two siblings afflicted with adult-onset spinocerebellar syndrome and found to be decreased in both (29% and 31% of mean control activity); an unaffected sibling had normal GDH activity. Mixing experiments with control fibroblast and leukocyte homogenates did not show the presence of a GDH inhibitor in cells from these patients. This allosterically regulated enzyme was stimulated by adenosine 5'-diphosphate (10(-3) M) and inhibited by guanosine 5'-triphosphate (10(-3) M) in both fibroblast and leukocyte homogenates; these changes occurred in equal proportions in the patients and controls. The decreased fibroblast and leukocyte GDH activity persisted at different concentrations of the enzyme's substrates and with successive passages of cultured fibroblasts. GDH may have an important role in the metabolism of glutamate, a putative neurotransmitter in cerebellum, brainstem, and spinal cord. A genetic deficiency of GDH may underlie some forms of spinocerebellar ataxias.