Neurological disorders associated with deficiency of glutamate dehydrogenase

Abstract

Glutamate dehydrogenase (GDH) activity was measured in leukocytes from 88 patients with various types of degenerative neurological disorders affecting primarily the cerebellum and/or the basal ganglia, and 26 healthy control subjects. Twelve patients with slowly progressive multiple-system atrophic disorders were found to have a partial deficiency of this enzyme (52% of control level). The majority of these patients evidenced a constellation of neurological findings consistent with the diagnosis of olivopontocerebellar atrophy, although others were atypical in their neurological manifestations. Thus, GDH-deficient patients were encountered with predominantly extrapyramidal manifestations (atypical Parkinson's disease), cerebellar dysfunction with peripheral neuropathy, or anterior horn cell signs, suggesting that a pleomorphic phenotypic expression of the enzymatic deficiency may occur. Seven cases of GDH deficiency were familial and 5 were sporadic. The former patient group consisted of siblings of either sex, but no parents or offspring were affected. The genetic pattern of the disorder is compatible with autosomal recessive inheritance. Patients with dominantly inherited olivopontocerebellar atrophy or other types of cerebellar or basal ganglia degenerative neurological disorders showed normal GDH activity. Leukocyte GDH was fractionated into "particulate-heat labile" and "soluble-heat stable" components. In the patients the decrease in activity was limited to the "particulate-heat labile" component. A genetic mutation of a GDH "isoenzyme" may occur in some patients with multiple-system degeneration.

Different Antigenic Reactivities of Bovine Brain Glutamate Dehydrogenase Isoproteins

“…It has been reported that the activities of the GDH isotypes differ in their relative resistance to thermal inactivation, detergent extractability, and allosteric regulation characteristics (Colon et al, 1986;Shashidharan et al, 1997). Similar results were reported by other investigators showing that reduction in GDH activity in patients with neurodegenerative disorders was largely limited to the heat-labile form (Plaitakis et al, 1984). Very recently, Stanley et al (1998) have reported that the hyperinsulinism-hyperammonemia syndrome is caused by mutations in the GDH gene that affects enzyme sensitivity to GTP-induced inhibition.…”

Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family.

“…However, different transcript lengths may also correspond to differences elsewhere in the molecule. Even if variation among the transcripts is exclusively at the 3' end, it would be of interest to understand the differential use of the Previous studies with human tissues (12) and rat brain (13) suggested the presence of at least two distinct GLUD activities differing in solubility, kinetic constants, relative resistance to heat denaturation, and allosteric regulation. Further studies using two-dimensional gel electrophoresis revealed the presence of four major isoproteins of GLUD in human brain differing in molecular mass and isoelectric point (M. Hussain, V.Z., and A.P., unpublished data).…”

“…Because of its neuroexcitotoxic potentials (8), glutamate may be involved in the pathogenesis of certain human heredodegenerations (9) or may mediate neuronal damage in response to various metabolic insults (10,11). Evidence implicating a direct role of GLUD in the pathogenesis of human degenerative disorders has been suggested by recent studies showing decreased activity of the enzyme and abnormal glutamate metabolism in patients with neurological disorders characterized by multisystem atrophy (3,12). Further studies have indicated that two distinct forms of GLUD may exist in human tissues and rat brain (12,13).…”

“…Evidence implicating a direct role of GLUD in the pathogenesis of human degenerative disorders has been suggested by recent studies showing decreased activity of the enzyme and abnormal glutamate metabolism in patients with neurological disorders characterized by multisystem atrophy (3,12). Further studies have indicated that two distinct forms of GLUD may exist in human tissues and rat brain (12,13). In some patients with multisystem atrophy associated with decreased GLUD activity, the defect is limited to one of these two enzyme forms (12), thus suggesting that the two activities are under different genetic control.…”

“…Further studies have indicated that two distinct forms of GLUD may exist in human tissues and rat brain (12,13). In some patients with multisystem atrophy associated with decreased GLUD activity, the defect is limited to one of these two enzyme forms (12), thus suggesting that the two activities are under different genetic control.…”