Klockgether T
Department of Neurology, University of Bonn, Germany.
Curr Opin Neurol. 2000 Aug;13(4):451-5. doi: 10.1097/00019052-200008000-00014.
Since the discovery of the first mutations that cause hereditary ataxias in the early 1990s, there has been continuous progress in deciphering the molecular pathogenesis of degenerative ataxias. Recent research in Friedreich's ataxia, the most frequent recessive ataxia, has provided further evidence that the clinical phenotype of this disorder is caused by abnormal oxidative phosphorylation due to mitochondrial dysfunction. The dominantly inherited spinocerebellar ataxias (SCAs) are genetically heterogeneous. Up to now, 11 distinct loci have been identified. The mutations that cause SCA1, SCA2, SCA3, SCA6 and SCA7 share the common feature of an expanded CAG sequence, encoding an abnormally long polyglutamine tract within the respective gene products. Recent pathogenetic research points to the importance of abnormal protein-protein interaction and altered gene transcription. The aetiology of many sporadic ataxias remains obscure. In some patients, association of ataxia with specific serum antibodies (antigliadin, antiglutamic acid decarboxylase) suggests an immune pathogenesis.
自20世纪90年代初发现首例导致遗传性共济失调的突变以来，在解读退行性共济失调的分子发病机制方面不断取得进展。对最常见的隐性共济失调——弗里德赖希共济失调的最新研究进一步证明，这种疾病的临床表型是由线粒体功能障碍导致的异常氧化磷酸化引起的。显性遗传性脊髓小脑共济失调（SCA）在遗传上具有异质性。到目前为止，已确定了11个不同的基因座。导致SCA1、SCA2、SCA3、SCA6和SCA7的突变具有共同特征，即CAG序列扩增，在各自的基因产物中编码异常长的聚谷氨酰胺序列。最近的发病机制研究指出了异常蛋白质-蛋白质相互作用和基因转录改变的重要性。许多散发性共济失调的病因仍不清楚。在一些患者中，共济失调与特定血清抗体（抗麦醇溶蛋白、抗谷氨酸脱羧酶）的关联提示存在免疫发病机制。
