Abstract
ObjectiveHereditary 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.MethodsUsing 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical feature of earlyonset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated Hereditary spastic paraplegia (HSP)
Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and expand the clinical and mutation spectrum of HSP caused by mutations in SPG4, SPG11, and B4GALNT1
These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP
Summary
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetically determined neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs. The disease can occur at any age, but it most commonly affects children between 3 and 15 years. It affects individuals of diverse ethnic groups with significantly variable prevalence estimates ranging from 2 to 10 per 100,000(1). More than 60 genes or sites have been identified, of which SPAST (previously known as SPG4) and SPG11 appear to be the most common genetic cause of the AD-HSP and autosomal recessive disease, respectively [2, 3]
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