MICU1的双等位基因变异导致锥体外系症状的肌病:61例患者的病例系列、表型谱和基因型-表型相关性

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Pegah Beheshti, Fahimeh Akbarian, Emran Esmaeilzadeh, Hamid Galehdari, Mehdi Khorrami, Sadeq Vallian, Alireza Abdi, Özge Güngör, Rasim Tuncel, Ayca Aykut, Özgul Ekmekci, Haluk Akın, Asude Durmaz, Atefeh Sohanforooshan Moghaddam, Niloofar Chamanrou, Fatemeh Karimi, Arezu Kazemi, Mahvash Habibi, Mohammad Amin Tabatabaiefar, Hamid Reza Khorram Khorshid, Farshid Parvini, Uluç Yiş, Ipek Polat, Leila Youssefian, Hassan Vahidnezhad, Morteza Heidari, Payam Sarraf, Ehsan Ghayoor Karimiani, Reza Maroofian, Sajjad Biglari
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引用次数: 0

摘要

锥体外系体征肌病(MPXPS)是一种罕见的常染色体隐性多系统疾病,由MICU1的双等位基因功能丧失(LOF)变异引起,MICU1是线粒体钙单转运蛋白的钙敏感守门人。我们对来自6个伊朗-土耳其近亲家庭的7名受影响个体进行了临床和遗传特征分析,并将这些数据与先前发表的54例病例(共62例)相结合。靶向神经肌肉评估,以及肌肉活检和外显子组测序,确定了6种致病性MICU1变异,包括c.355C>T;p.Arg119*, c.493 + 1G>A, c.508C >t;p.Gln170 *, c.547C > T;p.Gln183 *, c.1226C > G;p.Ser409*, c.553C>T;p.Arg185 *。值得注意的是,我们报告了一名成人发病患者,其症状始于29岁,进展速度比儿童期发病病例快。一个单独的谱系包含同卵双胞胎,他们表现出难以区分的临床过程,强调基因型驱动表型的一致性。在整个联合队列中,平均发病年龄为5.9±7.3岁(中位数= 3岁);61.5%在5岁前出现,9.5%在15岁后出现。61例不同种族背景患者的深度表型分析显示,常见症状包括学习困难(72%)、肌病(51%)和语言障碍(51%)。针对MCU调节的功能研究可能为未来的治疗提供选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients.

Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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