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© 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Objective

Hereditary spastic paraplegias (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central‐southern China.

Methods

Using targeted exome‐sequencing technology, we investigated the genetic and clinical features in five HSP families. We reviewed the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analysis of an intron variant of SPAST in vitro.

Results

We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD‐HSP) and four novel variants in two HSP families and a sporadic case. These identified four novel variants included a variant in SPG11 (p.Val1979Ter), two variants in B4GALNT1 (p.Ser475Phe and c.1002 + 2 T > G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the splicing variant in SPAST (c.1245+5G>A) revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying c.1245+5G>A variant in SPAST exhibited genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical features of early‐onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11‐associated HSP.

Conclusions

Our findings strongly support variable phenotype of B4GALNT1‐related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPAST, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

Details

Title
The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China
Author
Wang, Chen 1 ; Yun‐Jian Zhang 1 ; Ci‐Hao Xu 2 ; Li, De 3 ; Zhi‐Jun Liu 1   VIAFID ORCID Logo  ; Wu, Yan 1 

 Department of Neurology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
 Department of Radiology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
 Biobank, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 
Section
ORIGINAL ARTICLES
Publication year
2021
Publication date
May 2021
Publisher
John Wiley & Sons, Inc.
e-ISSN
23249269
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2535986136
Copyright
© 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.