Abstract
BackgroundHereditary 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.MethodsWe 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.ResultsMost 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.ConclusionsOur 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.
Highlights
Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts
During the course of these studies, we discovered that SPG4 (79%), SPG3A (11%), SPG6 (4%) and SPG33 (2%) were the most frequently found in Chinese Autosomal dominant hereditary spastic paraplegia (ADHSP) patients, and were mainly pure forms with wide range age at onset (AAO)
In ADHSP, we found that SPG4 was the most frequent subtype, account for 79% of all cases with causal dominant genes in China (Fig. 1c)
Summary
Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. More than 78 HSP loci have been mapped to cause HSP. Both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. Hereditary spastic paraplegias (HSP) refer to a heterogeneous group of rare neurodegenerative disorders. Pure form is characterized by pyramidal signs, associated with isolated spasticity and weakness confined to the lower limbs [3]. These patients rarely need wheel chairs but may use crutches during the disease course, even they usually have normal lifespan [4]. The functional handicap and lifespan are associated with the full clinical manifestation in complicated form [6]
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