Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Abstract

Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

“…In addition, R239C ( n  = 31) [6, 9, 11, 13, 15, 17, 21, 22, 27–29, 31, 32, 36, 39, 45, 51, 53, 54, 56] and R495W ( n  = 14) [15–17, 21, 32, 36, 43, 50, 52, 54] mutations were the most commonly reported mutations in all studied families. Zhao et al reported that the three families with R239C mutations were not apparently related and haplotype analysis did not exclude a distant founder effect [6].…”

“…Additionally, there are some asymptomic cases that contain the ATL1 gene mutations. Incomplete penetrance has been previously reported in 10.56% HSPs families [8, 12, 15, 24, 27, 45]. The scarce penetrance of the mutations favours a modulator gene or strong epigenetic factor hypothesis, which may influence the phenotype.…”

“…Although several large cohorts of patients with mutant ATL1 gene were reported [17, 21, 27, 29, 32, 36, 45, 50, 54, 56], a genotype-phenotype correlation still remains unclear. Here, we reanalysed the observations on 142 families and confirmed three previously reported observations.…”

“…The reported frequency of ATL1 gene mutations varied from 2.9 to 38.7% though most studies reported a frequency of less than 15%. For example, we found that there were eight studies which reported a frequency of ATL1 gene mutations less than 15%: 2.9% [27] in ADHSP families, 3.7% in ADSHP probands [45], 4.2% in HSP families [36], 8.3% in unrelated early onset pure ADHSP families [9], 6.6% in a heterogeneous population including both pure and complicated HSP phenotypes [21], 8.6% in ADHSP families [29], 11.3% in the ADHSP families [32], and 11.7% in ADHSP probands [44]. We also found four studies which reported a higher frequency of ATL1 gene mutations: 20.0% in pure HSP [55], 20.0% (3/15) in early onset autosomal dominant HSP [13], 38.5% in SPG4-negative pure ADHSP families [11], and 38.7% in pure ADHSP families [15].…”

Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology

“…Sex-dependent penetrance or severity has been suggested for SPAST mutations on the basis of a significant excess of affected males (Starling et al 2002 ; Proukakis et al 2011 ) and/or an earlier age at onset (Mitne-Neto et al 2007 ) This was also suggested for ATL1 mutations (Varga et al 2013 ; Luo et al 2014 ).…”