Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome
Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome
复制标题
三例脊髓小脑综合征患者谷氨酸脱氢酶缺乏症
作者：
A. Plaitakis;W. Nicklas;R. Desnick
我们在一名19岁青少年脊髓小脑和锥体外系综合征患者的皮肤成纤维细胞中检测了四种烟酰胺腺嘌呤二核苷酸磷酸必需酶。谷氨酸脱氢酶（GDH）活性显著降低（平均对照活性的22%）；该患者白细胞匀浆中GDH活性也降低（为对照组平均活性的38%）。在两个患有成人发病脊髓小脑综合征的兄弟姐妹的白细胞中测量GDH活性，发现两者均降低（平均对照活性的29%和31%）；未受影响的兄弟姐妹GDH活性正常。与对照成纤维细胞和白细胞匀浆混合实验未显示来自这些患者的细胞中存在GDH抑制剂。在成纤维细胞和白细胞匀浆中，这种变构调节酶被5′‐二磷酸腺苷（10−3 M）刺激，被5′‐三磷酸鸟苷（10−3 M）抑制；这些变化在患者和对照组中发生的比例相同。在不同浓度的酶底物和培养成纤维细胞的连续传代中，成纤维细胞和白细胞GDH活性的下降持续存在。GDH可能在谷氨酸代谢中起重要作用，谷氨酸是小脑、脑干和脊髓中的一种神经递质。遗传缺陷的GDH可能是某些形式的脊髓小脑共济失调的基础。
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.