Glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism, is significantly reduced in patients with heterogenous neurological disorders characterized by multiple system atrophy (MSA) and predominant involvement of the cerebellum and its connections. In human brain, GDH exists in multiple isoforms differing in their isoelectric point and molecular mass. These are differentially reduced in quantity and altered in catalytic activity in patients with clinically distinct forms of MSA, thus suggesting that these GDH isoproteins are under different genetic control. Dysregulation of glutamate metabolism occurs in patients with GDH deficiency and is thought to mediate the disease's neurodegeneration via neuroexcitotoxic mechanisms. This possibility is supported by additional data showing that glutamate binding sites are significantly decreased in cerebellar tissue obtained at autopsy from MSA patients. At the molecular biological level, several cDNAs specific for human GDH have been isolated recently and cloned. Northern blot analysis of various human tissues, including brain, has revealed the presence of multiple GDH-specific mRNAs. In addition, multiple GDH-specific genes are present in humans and these data are consistent with the possibility that the various GDH isoproteins are encoded by different genes. These advances have laid the groundwork for characterizing the human GDH genes and their products in health and disease. RESUME: Deficit en glutamate dehydrogenase dans les degenerescences cerebelleuses: aspects cliniques, biochimiques et de genetique moleculaire. La glutamate dehydrogenase (GDH), un enzyme important du metabolisme du glutamate, est diminuee de facon significative chez les patients souffrant de maladies neurologiques heterogenes caracterisees par une atrophie multi-systemique (AMS) et une atteinte principalement localisee au cervelet et a ses voies de communication. Dans le cerveau humain, la GDH existe sous de multiples isoformes, qui different par leur point isoelectrique et leur masse moleculaire, dont la quantite est diminuee differentiellement et dont l'activite catalytique est alteree, chez les patients qui ont des formes d'AMS cliniquement distinctes, suggerant que ces isoproteines sont sous un controle genetique different. Un dereglement du metabolisme du glutamate survient chez les patients qui ont un deficit en GDH et Ton pense qu'il est a l'origine de la neurodegenerescence presente dans cette maladie via des mecanismes neuro-excitotoxiques. Des donnees additionnelles supportent cette possibilite: les sites de liaison du glutamate sont diminues de facon significative dans le tissu cerebelleux provenant d'autopsies de patients atteints d'AMS. Au niveau de la biologie moleculaire, plusieurs ADN complementaires specifiques pour la GDH humaine ont ete isoles et clones recemment. L'analyse par Northern blot de differents tissus humains incluant le cerveau, a revele la presence de multiples ARN messagers specifiques de la GDH. De plus, plusieurs genes specifiques a la ...