{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:41:18Z","timestamp":1776447678741,"version":"3.51.2"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"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. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Autosomal recessive inherited ataxia with oculomotor apraxia type 2 (AOA2), caused by <jats:italic>SETX<\/jats:italic> gene mutations, is characterized by early-onset, progressive cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and elevated serum \u03b1-fetoprotein (AFP). This study aimed to expand and summarize the clinical and genetic characteristics of <jats:italic>SETX<\/jats:italic> variants related to AOA2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The biochemical parameters, electromyogram and radiological findings of the patient were evaluated. Whole-exome sequencing (WES) was performed on the patient using next-generation sequencing (NGS), the variants were confirmed by Sanger sequencing and the pathogenicity of the variants was classified according to the American College of Medical Genetics and Genomics\/Association for Molecular Pathology (ACMG\/AMP) guidelines. We reviewed 57 studies of AOA2 patients with <jats:italic>SETX<\/jats:italic> mutations and collected clinical and genetic information.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The patient was a 40-year-old Chinese woman who primarily presented with numbness and weakness of the lower limbs in her teenage years. She had elevated AFP, increased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and decreased anti-M\u00fcllerian hormone (AMH) levels. We identified a novel homozygous missense mutation of the <jats:italic>SETX<\/jats:italic> gene, c.7118 C&amp;gt;T (p. Thr2373Ile), in the patient via Whole-exome and Sanger sequencing. The variant was located in the DNA\/RNA helicase domain and is highly conserved. The protein prediction analysis verified the <jats:italic>SETX<\/jats:italic> variant as a damaging alteration and ACMG\/AMP guidelines classified it as likely pathogenic. Through a literature review, we identified 229 AOA2 cases with <jats:italic>SETX<\/jats:italic> variants, and among the variants, 156 <jats:italic>SETX<\/jats:italic> variants were exonic. We found that 107 (46.7%) patients were European, 50 (21.8%) were African and 48 (21.0%) were Asian. Among the Asian patients, five from two families were Mainland Chinese. The main clinical features were cerebellar ataxia (100%), peripheral neuropathy (94.6%), cerebellar atrophy (95.3%) and elevated AFP concentration (92.0%). Most reported <jats:italic>SETX<\/jats:italic> mutations in AOA2 patients were missense, frameshift and nonsense mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We discovered a novel homozygous variant of the <jats:italic>SETX<\/jats:italic> gene as a cause of AOA2 in the current patient and expanded the genotypic spectrum of AOA2. Moreover, the clinical features of AOA2 and genetic findings in <jats:italic>SETX<\/jats:italic> were assessed in reported cohorts and are summarized in the present study.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2022.1019974","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T06:32:09Z","timestamp":1668061929000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Ataxia with oculomotor apraxia type 2 caused by a novel homozygous mutation in SETX gene, and literature review"],"prefix":"10.3389","volume":"15","author":[{"given":"Shuaishuai","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juping","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huihua","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weibo","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Ying","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanlin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1093\/brain\/awp211","article-title":"Ataxia with oculomotor apraxia type 2: clinical, biological and genotype\/phenotype correlation study of a cohort of 90 patients","volume":"132","author":"Anheim","year":"2009","journal-title":"Brain"},{"key":"B2","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1007\/s12311-019-01012-w","article-title":"Disruption of spermatogenesis and infertility in ataxia with oculomotor apraxia type 2 (AOA2)","volume":"18","author":"Becherel","year":"2019","journal-title":"Cerebellum"},{"key":"B3","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1055\/s-0029-1214424","article-title":"Ataxia with oculomotor apraxia type 2: novel mutations in six patients with juvenile age of onset and elevated serum alpha-fetoprotein","volume":"39","author":"Bernard","year":"2008","journal-title":"Neuropediatrics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1016\/j.rbmo.2018.12.042","article-title":"Germ cell arrest associated with aSETX mutation in ataxia oculomotor apraxia type 2","volume":"38","author":"Catford","year":"2019","journal-title":"Reprod. 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