{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:16:09Z","timestamp":1789179369426,"version":"build-2803163510"},"reference-count":72,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,13]],"date-time":"2020-05-13T00:00:00Z","timestamp":1589328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE\/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.<\/jats:p>","DOI":"10.3390\/ijms21103448","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T02:55:41Z","timestamp":1589424941000},"page":"3448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7415-4905","authenticated-orcid":false,"given":"Lars","family":"Schlotawa","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, University Medical Centre Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-1116","authenticated-orcid":false,"given":"Laura A.","family":"Adang","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1731-7410","authenticated-orcid":false,"given":"Karthikeyan","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Bielefeld University, Biochemistry I, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Ahrens-Nicklas","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and Metabolism, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0092-8674(03)00348-9","article-title":"The Multiple Sulfatase Deficiency Gene Encodes an Essential and Limiting Factor for the Activity of Sulfatases","volume":"113","author":"Cosma","year":"2003","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.bbamcr.2008.11.015","article-title":"Molecular basis of multiple sulfatase deficiency, mucolipidosis II\/III and Niemann\u2013Pick C1 disease\u2014Lysosomal storage disorders caused by defects of non-lysosomal proteins","volume":"1793","author":"Dierks","year":"2009","journal-title":"Biochim. 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