Objective: To provide a comprehensive systematic review of the genotype-phenotype association in the most common three autosomal dominant genes of hereditary spastic paraplegia (HSP): SPAST, ATL1 and REEP1.

Background: HSP is a group of inherited neurodegenerative disorders that are primarily characterised by progressive lower limb spasticity and weakness. HSP is known to demonstrate genetic heterogeneity, with approximately 80 genes identified, either in an autosomal dominant, autosomal recessive, X-linked or mitochondrial mode of inheritance.

Method: This systematic review followed MDSGene’s standardised data extraction protocol. A systematic literature search was performed using NCBI’s PubMed database. Titles, abstracts and articles published in English were screened for SPAST on 12 Nov 2017, REEP1 on 12 May 2018, and ATL1 on 13 Nov 2018. Articles with clinically affected mutation carriers were included, where demographic, clinical and genetic data were extracted.

Results: In total, 341 citations were screened, and amongst 1643 included patients, 573 potentially pathogenic variants were identified. SPAST was the major contributor, having 1245 patients with 444 identified variants. ATL1 has the earliest median age at onset of 3 (IQR: 8.3) years, with REEP1 at 10.5 (IQR: 27.8) years, SPAST at 32 (IQR: 25.0) years old (p <0.0001). Missense mutations represented the major mutation type for ATL1 (87.5%), but were less frequent for SPAST (34.0%) and REEP1 (24.4%) (p<0.0001). The next two most common mutation types in SPAST and REEP1 are frameshift (SPAST: 18.9%, REEP1 17.1%) and splice site (SPAST: 16.7%, REEP1 14.6%). Exon deletions make up 14.4% of SPAST, 9.8% in REEP1, and none in ATL1. The systematic pathogenicity scoring identified 17.0% of ATL1 and 4.9% of REEP1 having ‘definite’ pathogenic variants, with SPAST pending. Data availability for the major HSP symptoms (lower limb spasticity, hyperreflexia, weakness and Babinski reflex) were 64.9% for ATL1, 79.4% for REEP1, and 39.1% for SPAST (p<0.0001).

Conclusion: Firstly, age at onset varied between ATL1, REEP1 and SPAST-related HSP (youngest to oldest). Secondly, missense variants predominate in ATL1 but are much less frequent in SPAST and REEP1. Thirdly, major phenotypic data is most available for REEP1 patients. Nevertheless, missing data is a problem that still limits the degree of meaningful phenotype-genotype relationship that can be drawn.

References: Harding, A.E., Classification of the hereditary ataxias and paraplegias, Lancet, 1983;1:1151–5, PubMed PMID: 6133167 Hedera P. Hereditary Spastic Paraplegia Overview. 2000 Aug 15 [Updated 2018 Sep 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1509/

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