{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T11:47:51Z","timestamp":1784720871989,"version":"3.55.0"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl J of Devlp Neuroscience"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metachromatic leukodystrophy (MLD) is a severe metabolic disorder caused by the deficient activity of arylsulfatase A due to <jats:italic>ARSA<\/jats:italic> gene mutations. According to the age of onset, MLD is classified into three forms: infantile, juvenile, and adult. In our study, we aimed to perform a genetic analysis for two siblings with juvenile MLD for a better characterization of the molecular mechanisms behind the disease. A consanguineous family including two MLD patients (PII.1 and PII.2) was enrolled in our study. The diagnosis was made based on the clinical and neuroimaging investigations. The sequencing of <jats:italic>ARSA<\/jats:italic> gene was performed followed by in silico analysis. Besides, the <jats:italic>cis\/tran<\/jats:italic>s distribution of the variants was verified through a PCR\u2010RFLP. The <jats:italic>ARSA<\/jats:italic> gene sequencing revealed three known variants, two exonic c.1055A\u2009&gt;\u2009G and c.1178C\u2009&gt;\u2009G and an intronic one (c.1524\u2009+\u200995A\u2009&gt;\u2009G) in the 3\u2032UTR region. All variants were present at heterozygous state in the two siblings and their mother. The assessment of the <jats:italic>cis<\/jats:italic>\/<jats:italic>trans<\/jats:italic> distribution showed the presence of these variants in <jats:italic>cis<\/jats:italic> within the mother, while PII.2 and PII.2 present the c.1055A\u2009&gt;\u2009G\/c.1524\u2009+\u200995A\u2009&gt;\u2009G and the c.1178C\u2009&gt;\u2009G in <jats:italic>trans<\/jats:italic>. Additionally, PII.1 harbored a de novo novel missense variant c.1119G\u2009&gt;\u2009T, whose pathogenicity was supported by our predictive results. Our genetic findings, supported by a clinical examination, confirmed the affection of the mother by the adult MLD. Our results proved the implication of the variable distribution of the found variants in the age of MLD onset. Besides, we described a variable severity between the two siblings due to the de novo pathogenic variant. In conclusion, we identified a complex genotype of <jats:italic>ARSA<\/jats:italic> variants within two MLD siblings with a variable severity due to a de novo variant present in one of them. Our results allowed the establishment of an adult MLD diagnosis and highlighted the importance of an assessment of the <jats:italic>trans<\/jats:italic>\/<jats:italic>cis<\/jats:italic> distribution in the cases of complex genotypes.<\/jats:p>","DOI":"10.1002\/jdn.10306","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T02:08:42Z","timestamp":1697594922000},"page":"35-46","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Complex genotypes in family with metachromatic leukodystrophy: Effect of <i>trans<\/i> and <i>cis<\/i> mutations distribution on the phenotype variability"],"prefix":"10.1002","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2271-3522","authenticated-orcid":false,"given":"Abir","family":"Ben Issa","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Functional Genetics, Faculty of Science of Sfax University of Sfax  Sfax Tunisia"},{"name":"Research laboratory \u201cNeurop\u00e9diatrie\u201d (LR19ES15), Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Kamoun","sequence":"additional","affiliation":[{"name":"Research laboratory \u201cNeurop\u00e9diatrie\u201d (LR19ES15), Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"},{"name":"Child Neurology Department CHU Hedi Chaker  Sfax Tunisia"},{"name":"Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa","family":"Bouchaala","sequence":"additional","affiliation":[{"name":"Research laboratory \u201cNeurop\u00e9diatrie\u201d (LR19ES15), Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"},{"name":"Child Neurology Department CHU Hedi Chaker  Sfax Tunisia"},{"name":"Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chahnez","family":"Charfi Triki","sequence":"additional","affiliation":[{"name":"Research laboratory \u201cNeurop\u00e9diatrie\u201d (LR19ES15), Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"},{"name":"Child Neurology Department CHU Hedi Chaker  Sfax Tunisia"},{"name":"Faculty of Medicine of Sfax University of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiza","family":"Fakhfakh","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Functional Genetics, Faculty of Science of Sfax University of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1684\/abc.2010.0448"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","unstructured":"Barboura I. Reguez S. Soyah N. Sahli C.A. Chkioua L. 2022.The missense mutation in ARSA gene causes the juvenile form of MLD (preprint). 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