A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-10-28 DOI:10.1002/mds.30048

Yan Shi PhD, Junhao Xie MD, Junyi Jiang MD, Xinyu Yan MD, Xuejiao Chen MD, PhD, Shunyan Hong MD, Jiyuan Liu MD, Guorong Xu MD, PhD, Huizhen Su MD, PhD, Wanjin Chen MD, PhD, Ning Wang MD, PhD, Xiang Lin MD, PhD

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Abstract

Background

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases.

Objectives

To identify novel genetic causes of HSP.

Methods

Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family.

Results

We found a homoplasmic MT-TV (mitochondrial tRNA^Val) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria.

Conclusions

The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.

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与遗传性痉挛性截瘫的线粒体遗传有关的同质 MT-TV 突变。

背景：遗传性痉挛性截瘫（HSP遗传性痉挛性截瘫（HSP）以进行性下肢无力和痉挛为特征，许多病例的遗传原因不明：方法：表型特征描述、基因筛选、转录因子分析：方法：对一个中国 HSP 家系进行表型鉴定、基因筛查、转录组测序和腓肠神经活检：结果：我们在一个复杂 HSP 家族的四代人中发现了一个同质 MT-TV（线粒体 tRNAVal）突变，即 m.1661A > G。第四代受影响的个体发病较早，可能是由于推测性预测，而且症状更严重，可能是线粒体 DNA（mtDNA）拷贝数减少所致。这些患者线粒体自噬基因的上调表明，MT-TV突变可能导致mtDNA拷贝数减少。神经活检显示髓鞘和线粒体的超微结构异常：结论：罕见的MT-TV m.1661A > G突变与HSP有关。结论：罕见的 MT-TV m.1661A > G 突变与 HSP 有关，mtDNA 拷贝数的变化可能是导致临床表型差异的原因之一。© 2024 国际帕金森和运动障碍协会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.