Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia
Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia
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DOI：
10.1007/s12311-017-0883-4
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发表时间：
2018-04-01
期刊：
影响因子：
3.5
通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
--
作者：
Kurihara, Masanori;Ishiura, Hiroyuki;Tsuji, Shoji
脊髓小脑性共济失调19/22 （SCA19/22）是一种罕见的常染色体显性SCA，以前在11个家族中被描述过。我们报告一例30岁的日本男性，无家族史，表现为智力障碍、早发性小脑共济失调、肌阵挛和肌张力障碍。MRI表现为小脑萎缩，脑电图表现为过度通气和光刺激时的阵发性尖波。来自患者及其父母的DNA样本的三联全外显子组测序分析显示，sc19 /22的致病基因KCND3中出现了一个全新的错义突变（c.1150G > a, p.G384S），取代了进化上保守的甘氨酸。生物信息学分析预测该突变是功能有害的。虽然单纯的小脑性共济失调是sc19 /22家族中最常见的临床特征，但在有限数量的家族中也报道了小脑外症状，包括智力残疾和肌萎缩，这表明特定突变的基因型-表型相关。虽然常染色体隐性遗传病在早发散发性小脑性共济失调患者中更为常见，但本研究强调应考虑这种新生突变的可能性。
Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c.1150G > A, p.G384S) in KCND3, the causative gene of SCA19/22, substituting for evolutionally conserved glycine. The mutation was predicted to be functionally deleterious by bioinformatic analysis. Although pure cerebellar ataxia is the most common clinical feature in SCA19/22 families, extracerebellar symptoms including intellectual disability and myoclonus are reported in a limited number of families, suggesting a genotype-phenotype correlation for particular mutations. Although autosomal recessive diseases are more common in patients with early onset sporadic cerebellar ataxia, the present study emphasizes that such a possibility of de novo mutation should be considered.