Dataset Information

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.

ABSTRACT: Aims:The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments. Methods:A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period. Results:A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1,DDHD1, C19orf12,GBA2,TECPR2,DDHD2, C12orf65,REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the "HSPome." Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds. Conclusion:The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.

SUBMITTER: Kumar KR

PROVIDER: S-EPMC6353461 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.

Kumar Kishore R KR Blair Nicholas F NF Sue Carolyn M CM

Movement disorders clinical practice 20150602 3

<h4>Aims</h4>The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments.<h4>Methods</h4>A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period.<h4>Results</h4>A total of 34 ...[more]

PMID: 30838228

Similar Datasets

Project description: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.

Dataset Information

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.

Publications

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets