{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T20:35:59Z","timestamp":1770669359292,"version":"3.49.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Hereditary spastic paraplegia (HSP) caused by mutations in <jats:italic>ALDH18A1<\/jats:italic> have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B). SPG9 is rare and has shown phenotypic and genotypic heterogeneity in previous reports.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> This study screened <jats:italic>ALDH18A1<\/jats:italic> mutations in autosomal recessive HSP patients using combined whole exome sequencing and RNA splicing analysis. We conducted <jats:italic>in silico<\/jats:italic> investigations, co-segregation analysis, and ELISA-based analysis of P5CS (\u03941-pyrroline-5-carboxylate synthetase; encoded by <jats:italic>ALDH18A1<\/jats:italic>) concentration to validate the pathogenicity of the detected <jats:italic>ALDH18A1<\/jats:italic> variants. All previously reported bi-allelic <jats:italic>ALDH18A1<\/jats:italic> mutations and cases were reviewed to summarize the genetic and clinical features of <jats:italic>ALDH18A1<\/jats:italic>-related HSP.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A novel missense mutation c.880T&amp;gt;C, p.S294P and an intronic splicing mutation c.-28-13A&amp;gt;G were both detected in <jats:italic>ALDH18A1<\/jats:italic> in an autosomal recessive family presenting with a complicated form HSP. ELISA assays revealed significantly decreased P5CS concentration in the proband's plasma compared with that in the healthy controls. Moreover, review of previously reported recessive cases showed that SPG9B patients in our cohort presented with milder symptoms, i.e., later age at onset and without cognitive impairment.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The present study expands the genetic and clinical spectrum of SPG9B caused by <jats:italic>ALDH18A1<\/jats:italic> mutation. Our work defines new genetic variants to facilitate future diagnoses, in addition to demonstrating the highly informative value of splicing mutation prediction in the characterization of disease-related intronic variants.<\/jats:p>","DOI":"10.3389\/fneur.2021.627531","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T06:12:18Z","timestamp":1621404738000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia"],"prefix":"10.3389","volume":"12","author":[{"given":"Yi-Jun","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zai-Qiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Wen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Sen","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ru-Ying","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"En-Lin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Tao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Jin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"B1","article-title":"Hereditary spastic paraplegia overview","volume-title":"GeneReviews","author":"Hedera","year":"2020"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1093\/brain\/awv143","article-title":"Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia","volume":"138","author":"Coutelier","year":"2015","journal-title":"Brain."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/s10038-018-0477-0","article-title":"Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment","volume":"63","author":"Koh","year":"2018","journal-title":"J Hum Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1002\/pro.340","article-title":"Pyrroline-5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease","volume":"19","author":"P\u00e9rez-Arellano","year":"2010","journal-title":"Protein Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"eaau7500","DOI":"10.1126\/scisignal.aau7500","article-title":"Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion","volume":"13","author":"Lee","year":"2020","journal-title":"Sci Signal."},{"key":"B6","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s00401-013-1115-8","article-title":"Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms","volume":"126","author":"Fink","year":"2013","journal-title":"Acta Neuropathol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/S1474-4422(19)30235-2","article-title":"Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches","volume":"18","author":"Shribman","year":"2019","journal-title":"Lancet Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13024-018-0269-1","article-title":"Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China","volume":"13","author":"Dong","year":"2018","journal-title":"Mol Neurodegener."},{"key":"B9","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1002\/acn3.50967","article-title":"A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases","volume":"7","author":"Verdura","year":"2020","journal-title":"Ann Clin Transl Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/ana.24611","article-title":"Hereditary Spastic paraplegia: clinicogenetic lessons from 608 patients","volume":"79","author":"Sch\u00fcle","year":"2016","journal-title":"Ann Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2238","DOI":"10.1093\/brain\/awz158","article-title":"Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia","volume":"142","author":"Lin","year":"2019","journal-title":"Brain"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1093\/brain\/aww111","article-title":"Genetic and phenotypic characterization of complex hereditary spastic paraplegia","volume":"139","author":"Kara","year":"2016","journal-title":"Brain."},{"key":"B13","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature13835","article-title":"Genetic and epigenetic fine mapping of causal autoimmune disease variants","volume":"518","author":"Farh","year":"2015","journal-title":"Nature."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"Maurano","year":"2012","journal-title":"Science."},{"key":"B15","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell."},{"key":"B16","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.cell.2009.02.011","article-title":"RNA and disease","volume":"136","author":"Cooper","year":"2009","journal-title":"Cell."},{"key":"B17","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.parkreldis.2019.06.008","article-title":"Chinese patients with adrenoleukodystrophy and Zellweger spectrum disorder presenting with hereditary spastic paraplegia","volume":"65","author":"Chen","year":"2019","journal-title":"Parkinsonism Relat Disord."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/s41422-020-0304-y","article-title":"Base editing-mediated splicing correction therapy for spinal muscular atrophy","volume":"30","author":"Lin","year":"2020","journal-title":"Cell Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics."},{"key":"B22","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s10048-018-0547-7","article-title":"Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia","volume":"19","author":"Steenhof","year":"2018","journal-title":"Neurogenetics."},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s40035-019-0157-9","article-title":"Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia","volume":"8","author":"Wei","year":"2019","journal-title":"Transl Neurodegener."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1002\/acn3.50821","article-title":"P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9","volume":"6","author":"Magini","year":"2019","journal-title":"Ann Clin Transl Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.braindev.2020.07.015","article-title":"Tremor as an early sign of hereditary spastic paraplegia dueto mutations in ALDH18A1","volume":"43","author":"Kalm\u00e1r","year":"2020","journal-title":"Brain Dev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1093\/brain\/awv247","article-title":"ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism","volume":"139","author":"Panza","year":"2016","journal-title":"Brain."},{"key":"B28","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","article-title":"Splicing mutations in human genetic disorders: examples, detection, and confirmation","volume":"59","author":"Anna","year":"2018","journal-title":"J Appl Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1038\/s10038-020-0786-y","article-title":"Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy","volume":"65","author":"Hiraide","year":"2020","journal-title":"J Hum Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1086\/302418","article-title":"Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences","volume":"64","author":"Teraoka","year":"1999","journal-title":"Am J Hum Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1093\/hmg\/9.2.237","article-title":"Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1","volume":"9","author":"Ars","year":"2000","journal-title":"Hum Mol Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1007\/s40291-019-00426-w","article-title":"Genetic and clinical profile of Chinese patients with autosomal dominant spastic paraplegia","volume":"23","author":"Zhao","year":"2019","journal-title":"Mol Diagn Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.ajhg.2015.08.001","article-title":"Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa","volume":"97","author":"Fischer-Zirnsak","year":"2015","journal-title":"Am J Hum Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1093\/hmg\/9.19.2853","article-title":"Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase","volume":"9","author":"Baumgartner","year":"2000","journal-title":"Hum Mol Genet."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.627531\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T06:12:20Z","timestamp":1621404740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.627531\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,19]]},"references-count":34,"alternative-id":["10.3389\/fneur.2021.627531"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.627531","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,19]]},"article-number":"627531"}}