Dataset Information

Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.

ABSTRACT: BACKGROUND:Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. METHODS:We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. RESULTS:Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C?>?T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (??m), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. CONCLUSIONS:Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP.

SUBMITTER: Dong EL

PROVIDER: S-EPMC6035405 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.

Dong En-Lin EL Wang Chong C Wu Shuang S Lu Ying-Qian YQ Lin Xiao-Hong XH Su Hui-Zhen HZ Zhao Miao M He Jin J Ma Li-Xiang LX Wang Ning N Chen Wan-Jin WJ Lin Xiang X

Molecular neurodegeneration 20180706 1

<h4>Background</h4>Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogen ...[more]

PMID: 29980238

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Project description:BackgroundGenetic investigations of inherited neuromuscular disorders in Africans, have been neglected. We aimed to summarise the published data and comment on the genetic evidence related to inherited neuropathies (Charcot-Marie-Tooth disease (CMT)), hereditary spastic paraplegias (HSP) and spinal muscular atrophy (SMA) in Africans.MethodsPubMed was searched for relevant articles and manual checking of references and review publications were performed for African-ancestry participants with relevant phenotypes and identified genetic variants. For each case report we extracted phenotype information, inheritance pattern, variant segregation and variant frequency in population controls (including up to date frequencies from the gnomAD database).ResultsFor HSP, 23 reports were found spanning the years 2000-2019 of which 19 related to North Africans, with high consanguinity, and six included sub-Saharan Africans. For CMT, 19 reports spanning years 2002-2021, of which 16 related to North Africans and 3 to sub-Saharan Africans. Most genetic variants had not been previously reported. There were 12 reports spanning years 1999-2020 related to SMN1-SMA caused by homozygous exon 7 ± 8 deletion. Interestingly, the population frequency of heterozygous SMN1-exon 7 deletion mutations appeared 2 × lower in Africans compared to Europeans, in addition to differences in the architecture of the SMN2 locus which may impact SMN1-SMA prognosis.ConclusionsOverall, genetic data on inherited neuromuscular diseases in sub-Saharan Africa, are sparse. If African patients with rare neuromuscular diseases are to benefit from the expansion in genomics capabilities and therapeutic advancements, then it is critical to document the mutational spectrum of inherited neuromuscular disease in Africa.HighlightsReview of genetic variants reported in hereditary spastic paraplegia in Africans Review of genetic variants reported in genetic neuropathies in Africans Review of genetic underpinnings of spinal muscular atrophies in Africans Assessment of pathogenic evidence for candidate variants.

Dataset Information

Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.

Publications

Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.

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