Ali Zafar, Zulfiqar Shumaila, Klar Joakim, Wikström Johan, Ullah Farid, Khan Ayaz, Abdullah Uzma, Baig Shahid, Dahl Niklas
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box815, 751 08, Uppsala, Sweden.
Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, 38000, Pakistan.
BMC Med Genet. 2017 Dec 6;18(1):144. doi: 10.1186/s12881-017-0504-6.
Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.
We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.
The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.
脊髓小脑共济失调包括一大类异质性疾病，可表现为孤立性共济失调，或共济失调合并其他神经或非神经症状。最近报道了罕见的小脑综合征病例，这些病例存在单等位基因或双等位基因GRID2突变，伴有不同程度的共济失调、眼部症状、肌张力减退和发育迟缓。
我们报告了一个近亲家庭，三个兄弟姐妹患有常染色体隐性遗传性儿童期起病的缓慢进展性小脑共济失调和精神运动发育迟缓。对一名成年患病家庭成员进行的磁共振成像显示，大脑和小脑沟略有增宽，提示广泛性脑萎缩和轻度小脑萎缩。通过全外显子组测序，我们在GRID2基因中鉴定出一个新的纯合错义变异[c.2128C>T，p.(Arg710Trp)]，该变异与疾病共分离。该错义变异位于编码GluD2蛋白细胞外丝氨酸结合域的保守区域，预测蛋白质构象会发生变化。
广泛的幕上脑异常、无动眼神经症状、外周肌张力增加以及新的错义突变增加了GRID2相关小脑综合征的临床和遗传变异性。我们家族中的神经放射学发现表明，在其他具有复杂临床特征和GRID2突变的家族中，应考虑存在广泛性神经退行性变过程。
