Large study in China confirms previous findings
A large HSP population study in China has largely reproduced and confirmed findings from previous studies elsewhere regarding the types and patterns of HSP inheritance.
The study also confirmed impairments in mitochondrial dynamics in lab experiments on patient-derived SPG4/SPAST HSP cells as well as other changes in cell organelles also reported previously.
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 (Δψm), 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 presents a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidence for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP.
SOURCE: Mol Neurodegener. 2018 Jul 6;13(1):36. doi: 10.1186/s13024-018-0269-1. PMID: 29980238
Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.
Dong EL1, Wang C1, Wu S1, Lu YQ1, Lin XH1, Su HZ1, Zhao M1, He J1, Ma LX2, Wang N1,3, Chen WJ4,5, Lin X6.
1 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
2 Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
3 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.
4 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. [email protected].
5 Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China. [email protected].
6 Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. [email protected].