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A clinical and genetic study of SPG31 in Japan


SPG31 is an autosomal dominant hereditary spastic paraplegia caused by pathogenic variants in the receptor expression-enhancing protein 1 (REEP1) gene. We analyzed 488 DNA samples from unrelated HSP patients collected by Japan Spastic Paraplegia Research Consortium and found 15 Japanese SPG31 families. We investigated each family and found a total of 25 individuals with REEP1 variants (comprising 22 patients and three asymptomatic carriers). Fourteen REEP1 variants (five missense, three nonsense, four frameshift, one splice site, and one large deletion) including 11 novel ones were detected. Seventy percent of the patients (14 of 20) showed a pure form and the others (6 of 20) showed a complicated form with peripheral neuropathy. Fifty percent of the patients had neurological symptoms before the age of 10 and 20% of them at age 41–50. The mean age of onset was 19.6 ± 18.7 (from 5 to 67, n = 15) years for males and 32.8 ± 24.7 (from 4 to 60, n = 5) years for females. Although the difference was not statistically significant (p = 0.38, Mann–Whitney U test), males tended to have an earlier age of onset. Moreover, all three asymptomatic carriers were female. We investigated additional factors as to phenotypic appearance in one family with apparent intrafamilial variability in age at onset and clinical severity, but no additional factors including gene variants could be found. This is the first report of clinical and genetic findings of SPG31 in Japan, which may lead to further studies of the genotype–phenotype correlation of SPG31.

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We thank all the participants and cooperating doctors in the Japan Spastic Paraplegia Research Consortium. The following programs provided financial support to the conduct of this research, including the study design, collection, analysis and interpretation of data, and writing of the manuscript: Grants-in-Aid from the Research Committee for Ataxic Disease (YT) the Ministry of Health, Labor and Welfare, Japan, and JSPS KAKENHI Grant Numbers 19K16910 (KK) and JP21K07456 (YT) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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TH and YT designed and organized the study. TH acquired the clinical and laboratory data. TH, HN, KK and HI carried out the molecular genetic studies, and TH, ST and YT analyzed the molecular and clinical data. TH wrote the manuscript, which was edited by HI, ST and YT. All authors have read and approved the final version of the manuscript submitted by YT.

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Correspondence to Yoshihisa Takiyama.

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Hata, T., Nan, H., Koh, K. et al. A clinical and genetic study of SPG31 in Japan. J Hum Genet 67, 421–425 (2022).

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