A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies

IF 1.4 4区 医学 Q4 CLINICAL NEUROLOGY
Sareh Hosseinpour , Ehsan Razmara , Morteza Heidari , Zahra Rezaei , Mahmoud Reza Ashrafi , Ali Zare Dehnavi , Reyhaneh Kameli , Ali Hosseini Bereshneh , Hassan Vahidnezhad , Reza Azizimalamiri , Zahra Zamani , Neda Pak , Maryam Rasulinezhad , Bahram Mohammadi , Homa Ghabeli , Mohammad Ghafouri , Mahmoud Mohammadi , Gholam Reza Zamani , Reza Shervin Badv , Sasan Saket , Ali Reza Tavasoli
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引用次数: 0

Abstract

Objective

Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies.

Methods

This study summarizes the clinical, imaging, and molecular data of these patients for five years.

Results

The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis.

Conclusions

The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

儿童线粒体白质营养不良症的突变和表型异质性综合研究
目的线粒体白质营养不良症(MLs)主要由线粒体呼吸链受损引起。本研究报告了在320名分子诊断为白质营养不良症的患者中,来自39个不同家族的41名小儿MLs患者的突变和表型谱。由于核DNA突变在小儿ML中占很大比例,因此对所有患者进行了全外显子组测序。共检测到 39 个同源变异。此外,在两名患者中还发现了两种之前报道过的mtDNA变异,异质性程度不同。在41个突变等位基因中,33个(80.4%)为错义突变,4个(9.8%)为框移突变(包括3个缺失和1个重复),4个(9.8%)为剪接突变。27例(65.8%)患者的氧化磷酸化和8例(19.5%)患者的mtDNA维持途径是最常受影响的线粒体途径。此外,还在 PDSS1、NDUFB9、FXBL4、SURF1 和 NDUSF1 中发现了 5 个新型变异。这项研究的结果表明,全外显子组测序是一种强有力的基因诊断工具,可用于鉴定小儿ML的致病变异。氧化磷酸化(OXPHOS)组与mtDNA维持组相比,OXPHOS组更常见脑干和uctal灰质周围受累(P值分别为0.002和0.009),而mtDNA维持组更常见胼胝体变薄(P值为0.042)。
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
Brain & Development
Brain & Development 医学-临床神经学
CiteScore
3.60
自引率
0.00%
发文量
153
审稿时长
50 days
期刊介绍: Brain and Development (ISSN 0387-7604) is the Official Journal of the Japanese Society of Child Neurology, and is aimed to promote clinical child neurology and developmental neuroscience. The journal is devoted to publishing Review Articles, Full Length Original Papers, Case Reports and Letters to the Editor in the field of Child Neurology and related sciences. Proceedings of meetings, and professional announcements will be published at the Editor''s discretion. Letters concerning articles published in Brain and Development and other relevant issues are also welcome.
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