ATP13A2 相关遗传性痉挛性截瘫的临床与遗传学分析扩展了表型谱。
Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype.
机构信息
Department of Human Genetics, McGill University, Montréal, QC, Canada.
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
出版信息
Mol Genet Genomic Med. 2020 Mar;8(3):e1052. doi: 10.1002/mgg3.1052. Epub 2020 Jan 15.
BACKGROUND
Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.
METHODS
Whole-exome sequencing was done in a Canada-wide HSP cohort.
RESULTS
Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.
CONCLUSION
Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.
背景
遗传性痉挛性截瘫（HSP）是一种以下肢痉挛和无力为特征的神经退行性疾病，伴有或不伴有其他症状。已知导致 Kufor-Rakeb 综合征（KRS）的 ATP13A2 突变最近也与 HSP 有关。
方法
在加拿大 HSP 队列中进行了全外显子组测序。
结果
又鉴定出了 3 名纯合 ATP13A2 突变患者，占所有 HSP 家族的 0.7%。痉挛性截瘫是主要特征，所有患者均有精神症状，1 名患者有癫痫发作。鉴定出的突变中，c.2126G>C；（p.[Arg709Thr]）是新的，c.2158G>T；（p.[Gly720Trp]）在 ATP13A2 相关疾病中尚未报道，c.2473_2474insAAdelC;p.[Leu825Asnfs*32]）以前在 KRS 中报道过，但在 HSP 中没有报道。突变的结构分析表明存在破坏性影响，富集分析表明特定途径可能存在潜在参与。
结论
我们的研究表明，在有精神症状的 HSP 患者中，应怀疑存在 ATP13A2 突变，尤其是如果他们还有锥体外系症状。
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