Mancini Cecilia, Nassani Stefano, Guo Yiran, Chen Yulan, Giorgio Elisa, Brussino Alessandro, Di Gregorio Eleonora, Cavalieri Simona, Lo Buono Nicola, Funaro Ada, Pizio Nicola Renato, Nmezi Bruce, Kyttala Aija, Santorelli Filippo Maria, Padiath Quasar Salem, Hakonarson Hakon, Zhang Hao, Brusco Alfredo
Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy.
J Neurol. 2015 Jan;262(1):173-8. doi: 10.1007/s00415-014-7553-y. Epub 2014 Oct 31.
Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.
常染色体隐性遗传性共济失调是一类日益增多的遗传性疾病。我们报告了两名意大利同胞，他们50多岁，出现行走困难、构音障碍和进行性认知衰退。归因于青光眼的视力丧失在其他症状出现前几年就已出现。脑部磁共振成像显示严重的小脑萎缩，以蚓部为主，双侧大脑半球皮质明显萎缩。外显子组测序在5型类蜡样神经元脂褐质沉积症基因（CLN5）中鉴定出一个新的纯合突变（c.935G > A；p.Ser312Asn）。生物信息学预测和体外研究表明，该突变有害，可能影响内质网-溶酶体蛋白运输。我们的研究结果支持CLN5低表达突变导致常染色体隐性遗传性小脑共济失调，证实了其他显示CLN突变与成人发病的神经退行性疾病相关的报告。我们建议，对于出现成人发病的常染色体隐性遗传性小脑共济失调的患者，在分子分析中应考虑CLN基因。
