{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:47:56Z","timestamp":1786978076555,"version":"build-2736575974"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T00:00:00Z","timestamp":1597881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["KL2TR001879"],"award-info":[{"award-number":["KL2TR001879"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K08NS105865"],"award-info":[{"award-number":["K08NS105865"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K23NS114113"],"award-info":[{"award-number":["K23NS114113"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Multiple sulfatase deficiency (MSD) is an ultra\u2010rare neurodegenerative disorder caused by pathogenic variants in\n                    <jats:italic>SUMF1<\/jats:italic>\n                    . This gene encodes formylglycine\u2010generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X\u2010linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype\u2010phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel\n                    <jats:italic>SUMF1<\/jats:italic>\n                    variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25\u2009years; median age at diagnosis was 2.7\u2009years; and median age at death was 13\u2009years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12298","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T11:02:44Z","timestamp":1596538964000},"page":"1298-1309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra\u2010rare disease"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-1116","authenticated-orcid":false,"given":"Laura A.","family":"Adang","sequence":"first","affiliation":[{"name":"Division of Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania 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Clinic Soroka Medical Centre Beersheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago Oliveira","family":"Silva","sequence":"additional","affiliation":[{"name":"Nuclimed\u2010Clinical Research Center, Hospital de Clinicas de Porto Alegre\u2010RS Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Vanessa D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Nuclimed\u2010Clinical Research Center, Hospital de Clinicas de Porto Alegre\u2010RS Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine University Medical Centre G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"De Castro","sequence":"additional","affiliation":[{"name":"Air Force Medical Genetics Center, Keesler AFB Biloxi 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