Genotype–phenotype associations in hereditary spastic paraplegia: a systematic review and meta-analysis on 13,570 patients
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The hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurodegenerative disorders. Although, several genotype–phenotype studies have carried out on HSPs, the association between genotypes and clinical phenotypes remain incomplete since most studies are small in size or restricted to a few genes. Accordingly, this study provides the systematic meta-analysis of genotype–phenotype associations in HSP.
Methods and results
We retrieved literature on genotype–phenotype associations in patients with HSP and mutated SPAST, REEP1, ATL1, SPG11, SPG15, SPG7, SPG35, SPG54, SPG5. In total, 147 studies with 13,570 HSP patients were included in our meta-analysis. The frequency of mutations in SPAST (25%) was higher than REEP1 (3%), as well as ATL1 (5%) in AD-HSP patients. As for AR-HSP patients, the rates of mutations in SPG11 (18%), SPG15 (7%) and SPG7 (13%) were higher than SPG5 (5%), as well as SPG35 (8%) and SPG54 (7%). The mean age of AD-HSP onset for ATL1 mutation-positive patients was earlier than patients with SPAST, REEP1 mutations. Also, the tendency toward younger age at AR-HSP onset for SPG35 was higher than other mutated genes. It is noteworthy that the mean age at HSP onset ranged from infancy to adulthood. As for the gender distribution, the male proportion in SPG7-HSP (90%) and REEP1-HSP (78%) was markedly high. The frequency of symptoms was varied among patients with different mutated genes. The rates of LL weakness, superficial sensory abnormalities, neuropathy, and deep sensory impairment were noticeably high in REEP1 mutations carriers. Also, in AR-HSP patients with SPG11 mutations, the presentation of symptoms including pes cavus, Neuropathy, and UL spasticity was higher.
Our comprehensive genotype–phenotype assessment of available data displays that the mean age at disease onset and particular sub-phenotypes are associated with specific mutated genes which might be beneficial for a diagnostic procedure and differentiation of the specific mutated genes phenotype among diverse forms of HSP.
KeywordsHSP Genotype–phenotype associations Meta-analysis
The authors thank the Shahid Beheshti University of Medical Sciences for continuous support.
The presented article is financially supported by “Research Department of the School of Medicine Shahid Beheshti University of Medical Sciences”.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no competing interests.
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