Original Article Multiple Sulfatase Deficiency: A Case Series With a Novel Mutation Leen Hijazi, MD 1 , Amna Kashgari, MD 1,2 , and Majid Alfadhel, MD, MHSc, FCCMG 1,3 Abstract Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder due to a deficiency in formylglycine-generating enzyme, which is encoded by the Sulfatase Modifying Factor 1 (SUMF1) gene. Clinically, the disorder is variable. The most common characteristics are developmental regression, intellectual disability, ichthyosis, and periventricular white matter disease. Herein, we report 6 Saudi patients with multiple sulfatase deficiency caused by a novel homozygous missense mutation in the SUMF1 gene (NM_182760.3; c.785A>G [p.Gln262Arg]). The patients are 2 females and 4 males between 5 and 13 years of age, with an age of onset of 1 to 3 years. All patients are consanguineous and suffer from developmental regression, intellectual disability, ichthyosis, and periventricular white matter disease. This cohort differs from previous cohorts because of the absence of organomegaly and skeletal abnormalities. Keywords multiple sulfatase deficiency, mucosulfatidosis, Austin disease, lysosomal storage disorders, SUMF1, sulfatases Received March 10, 2018. Received revised May 19, 2018. Accepted for publication July 2, 2018. Multiple sulfatase deficiency is an autosomal recessive lysoso- mal storage disorder that was first described by Austin et al in 1964. 1 Other names for this disorder include mucosulfatidosis and Austin disease (OMIM 272200). It is due to a deficiency in formylglycine-generating enzyme (FGE), which is encoded by the Sulfatase Modifying Factor 1 (SUMF1) gene. This protein is essential in the posttranslational modification of all sulfatase enzymes in the endoplasmic reticulum. Formylglycine- generating enzyme catalyzes a cysteine residue shared by all known sulfatases to form formylglycine. This step is critical and required by all sulfatases to promote their enzymatic func- tions. 2,3 A formylglycine-generating enzyme defect leads to a deficiency in the sulfatase enzyme family and causes increased sulfated lipids and mucopolysaccharides. The sulfatase family consists of 17 sulfatases in humans, 17 in dog, and 14 in rodent species. In humans, these include arylsulfatase A-K, galactosa- mine (N-acetyl)-6-sulfate sulfatase (GALNS), N-acetylglucosa- mine-6-sulfatase, iduronate 2-sulfatase (IDS), heparan sulfate sulfatase, sulfatase 1 (SULF1), and sulfatase 2 (SULF2). 4 A deficiency in arylsulfatase A causes metachromatic leukodystro- phy (OMIM 250100), an arylsulfatase B deficiency is associated with mucopolysaccharidosis type VI (Maroteaux-Lamy) (OMIM 253200), an arylsulfatase C (steroid sulfatase) defi- ciency leads to X-linked ichthyosis (OMIM 308100), a defi- ciency in arylsulfatase E causes X-linked recessive chondrodysplasia punctate (OMIM 302950), a galactosamine (N-acetyl)-6-sulfate sulfatase (GALNS) deficiency leads to mucopolysaccharidosis IVA (Morquio A disease) (OMIM253000), an N-acetylglucosamine-6-sulfatase deficiency causes mucopolysaccharidosis IIID (OMIM252940), an IDS deficiency leads to mucopolysaccharidosis II (Hunter syndrome) (OMIM 309900), and a heparan sulfate sulfatase deficiency causes mucopolysaccharidosis IIIA (OMIM 252900). No other diseases are associated with other sulfatase family members. Multiple sulfatase deficiency is considered to be quite rare, as approximately 50 cases have been reported in the literature. 5 Clinically, multiple sulfatase deficiency can be classified into the following 3 types: (1) neonatal, (2) late infantile, and (3) juvenile. The neonatal type is considered to be the most 1 King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard–Health Affairs (NGHA), Riyadh, Saudi Arabia 2 Department of Medical Imaging, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard–Health Affairs (NGHA), Riyadh, Saudi Arabia 3 Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard–Health Affairs (NGHA), Riyadh, Saudi Arabia Corresponding Author: Majid Alfadhel, Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, PO Box 22490, Riyadh 11426, Saudi Arabia. Email: dralfadhelm@gmail.com Journal of Child Neurology 1-5 ª The Author(s) 2018 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0883073818790851 journals.sagepub.com/home/jcn