NORD gratefully acknowledges Alice Kwak and Ankur Kumar, NORD Editorial Interns from the University of Notre Dame, Barb Calhoun, MSN, RN, NP, Nurse Practitioner and Outreach Coordinator, Boler-Parseghian Center for Rare and Neglected Diseases at the University of Notre Dame, and Laura Adang MD, PhD, Division of Child Neurology, Children's Hospital of Philadelphia, for assistance in the preparation of this report.
Multiple sulfatase deficiency (MSD) is an ultra-rare genetic disorder in which all of the known sulfatase enzymes are unable to be fully activated by formylglycine-generating enzyme (FGE), which is encoded by the SUMF1 gene. Because of the multisystemic importance of sulfatases, this disorder affects many parts of the body. While neurologic impairment is universal, major systemic symptoms can be variable and include bone abnormalities, coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Because of deficient activation of steroid sulfatase, the skin of children affected by MSD can be usually dry and scaly (ichthyosis).
Classically, the subtypes of MSD are defined by the age at symptom onset: neonatal, severe late infantile, mild infantile, and juvenile. The clinical relevance of these divisions is unknown, as subtle symptoms are present in infancy across all types. Because MSD is the result of a variable degree of deficiency across all human sulfatases, the systemic symptoms can be variable.
GASTROINTESTINAL (GI)/ URINARY
Multiple sulfatase deficiency is an autosomal recessive disorder caused by a change (mutation) in the SUMF1 gene. This gene allows cells to make an enzyme called FGE (formylglycine-generating enzyme) that activates all sulfatases within the cell. Without activation, sulfatases are not able to do their jobs in the cell. The missing sulfatases are directly responsible for the changes in the body seen in MSD. More severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the more mild forms are due to mutations that lead to reduced but correctly functioning FGE.
Recessive genetic disorders like multiple sulfatase deficiency occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Multiple sulfatase deficiency is an ultra-rare disorder with a wide spectrum of disease. To date, over one hundred patients have been reported in the literature with 50 of those patients confirmed alive by patient organization registries. This number may be underestimated due under diagnosis or lack of reporting. Males and females are equally affected and no ethnic predisposition has been identified.
MSD should be suspected in any individual with developmental delays, coarse facial features, bone abnormalities, and ichthyosis. MSD can be diagnosed when a child has low levels of at least two sulfatases and elevated sulfatide levels. Additional testing, such as glycosaminoglycan levels, can also be supportive, although can be normal in some individuals affected by MSD. Molecular genetic testing for mutations in the SUMF1 gene can be helpful as well, but with the rarity of the disease, only a limited number of disease-causing variants have been fully characterized.
The MRI associated with MSD can be variable and nonspecific. The images can demonstrate demyelination, perivascular space prominence, and/or hydrocephalus.
There are currently no targeted therapies for MSD, and treatment is supportive and based upon symptoms. Care for patients with MSD requires a multidisciplinary team to evaluate the many body systems that may be affected by this disease. Due to the very broad spectrum of clinical problems a comprehensive approach is recommended. Depending on the needs of the child, important members of the team may include neurology and/or metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry.
The neurologic delay and regression is the most common symptom shared by patients with MSD. Early evaluation and intervention by physical, occupational, and speech therapy can be helpful to manage the symptoms of MSD and maximize mobility and communication.
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