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Review

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

by
Lars Schlotawa
1,*,†,
Laura A. Adang
2,†,
Karthikeyan Radhakrishnan
3,‡ and
Rebecca C. Ahrens-Nicklas
4,*,‡
1
Department of Paediatrics and Adolescent Medicine, University Medical Centre Goettingen, 37075 Goettingen, Germany
2
Division of Child Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
3
Department of Chemistry, Bielefeld University, Biochemistry I, 33615 Bielefeld, Germany
4
Division of Human Genetics and Metabolism, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work, respectively.
These authors contributed equally to this work, respectively.
Int. J. Mol. Sci. 2020, 21(10), 3448; https://doi.org/10.3390/ijms21103448
Submission received: 13 March 2020 / Revised: 6 May 2020 / Accepted: 6 May 2020 / Published: 13 May 2020
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management)

Abstract

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.
Keywords: multiple sulfatase deficiency; formylglycine-generating enzyme; lysosomal storage disorder; posttranslational modification; sulfatases; glycosaminoglycans; sulfatides multiple sulfatase deficiency; formylglycine-generating enzyme; lysosomal storage disorder; posttranslational modification; sulfatases; glycosaminoglycans; sulfatides

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MDPI and ACS Style

Schlotawa, L.; Adang, L.A.; Radhakrishnan, K.; Ahrens-Nicklas, R.C. Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. Int. J. Mol. Sci. 2020, 21, 3448. https://doi.org/10.3390/ijms21103448

AMA Style

Schlotawa L, Adang LA, Radhakrishnan K, Ahrens-Nicklas RC. Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. International Journal of Molecular Sciences. 2020; 21(10):3448. https://doi.org/10.3390/ijms21103448

Chicago/Turabian Style

Schlotawa, Lars, Laura A. Adang, Karthikeyan Radhakrishnan, and Rebecca C. Ahrens-Nicklas. 2020. "Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification" International Journal of Molecular Sciences 21, no. 10: 3448. https://doi.org/10.3390/ijms21103448

APA Style

Schlotawa, L., Adang, L. A., Radhakrishnan, K., & Ahrens-Nicklas, R. C. (2020). Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification. International Journal of Molecular Sciences, 21(10), 3448. https://doi.org/10.3390/ijms21103448

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