First finding of familial spinal cerebellar Ataxia11 in China: clinical, imaging and genetic features
First finding of familial spinal cerebellar Ataxia11 in China: clinical, imaging and genetic features
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DOI：
10.1007/s10072-019-04052-6
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发表时间：
2020-01-01
影响因子：
3.3
通讯作者：
Qi, Xueliang
中科院分区：
文献类型：
--
作者：
Deng, Yan;Fu, Jie;Qi, Xueliang
研究背景脊髓性小脑共济失调11（SCA 11）是一种少见的疾病，以进行性小脑共济失调、眼征异常为特征。据报道，过去有四个家庭。我们报道了中国首例脊髓小脑性共济失调11家系。方法对一个3代家系（包括5名患者）进行临床表现、脑影像学检查、外显子组和桑格测序，以确定致病性遗传变异。结果先证者和受累者在40岁左右开始出现小脑性共济失调、构音障碍、眼球震颤和斜视。家庭中病人的寿命缩短。脑MRI显示小脑萎缩和延髓轻度萎缩。肌电图显示广泛的神经源性损伤。下肢感觉诱发电位显示脊髓-脑干-皮质传导通路受损。遗传分析揭示了编码tau-微管激酶2的TTBK 2基因中的一个新的点突变（c.3290T>C），其导致氨基酸交换（p.Val1097Ala）。错义突变与表型分离。该突变在种群中突变率极低，变异氨基酸在物种间高度保守，突变位点的蛋白质功能损伤预测是不利的，极有可能造成蛋白质损伤。对突变位点的致病性预测表明，它很可能引起疾病。这种变化与SCA 11的诊断一致。结论该家系以步态不稳、运动障碍、构音障碍为主要表现，并伴有明显的小脑萎缩。致病等位基因是TTBK 2基因中的c.3290T>C突变。
Background Spinal cerebellar ataxia 11 (SCA11) is a rare disease, characterized by progressive cerebellar ataxia, abnormal eye sign. Four families have been reported in the past. We report on China's first family with spinocerebellar ataxia 11. Methods A careful investigation of the clinical manifestations, brain imaging, and exome and Sanger sequencing were utilized to identify pathogenic genetic variants in a three-generation pedigree that includes 5 affected individuals. Results The proband and affected members began to develop cerebellar ataxia, dysarthria, nystagmus, and strabismus at approximately age 40 for no apparent reason. The lifespan of patients in the family is shortened. Brain MRIs showed cerebellar atrophy and slight atrophy of the bulbar medulla. Electromyography showed extensive neurogenic damage. Sensory evoked potentials of lower limbs showed damage to the spinal-brainstem-cortical conduction pathway. Genetic analysis revealed a novel point mutation (c.3290T>C) in the TTBK2 gene encoding tau-microtubule kinase 2, which led to an amino acid exchange (p.Val1097Ala). The missense mutation segregated with the phenotype. The mutation has a very low mutation rate in the population, the variant amino acids are highly conserved among species, and protein function damage prediction at the mutation site is detrimental and is highly likely to cause protein damage. The pathogenicity prediction of the mutation site shows that it is likely to cause disease. This variation is consistent with the diagnosis of SCA11. Conclusion The first SCA11-affected family in China was characterized by gait instability, movement disorders and dysarthria with obvious cerebellar atrophy. The pathogenic allele was a c.3290T>C mutation in the TTBK2 gene.