Multiple Sulfatase Deficiency, Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Multiple sulfatase deficiency (MSD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by mutations in the sulfatase-modifying factor 1 (SUMF1) gene. SUMF1 encodes for a formylglycine-generating enzyme (FGE) that performs a critical posttranslational modification of the catalytic residue necessary for activation of all human sulfatases.
MSD is often confused for a single sulfatase deficiency because it is characterized by deficiency of all known sulfatases, which results in tissue accumulation of sulfatides, sulfated glycoaminoglycans, sphingolipids, and steroid sulfates. Indeed, the clinical phenotype encompasses symptoms of every single sulfatase deficiency, including metachromatic leukodystrophy (MLD), the mucopolysaccharidoses, X-linked ichthyosis, and chondrodysplasia punctata type I. Age of onset and clinical severity are variable and correspond with the level of residual FGE enzyme activity. A severe neonatal form of MSD closely overlaps the clinical presentation of the mucopolysaccaridoses but it is often fatal within 1 year. Late-infantile MSD (onset 0-2 years) accounts for most cases and is characterized by a clinical presentation similar to MLD. Patients show progressive cognitive and motor impairment as well as skeletal changes. More rarely, MSD presents in late childhood (juvenile-onset) with more mild symptoms and slower progression. Patients with late-infantile or juvenile-onset MSD may have less severe sulfatase deficiency.
Patients with a clinical suspicion of MLD, a mucopolysaccharidosis, X-linked ichthyosis, or chondrodysplasia should be investigated for possible FGE deficiency. Urine sulfatide analysis is the recommended first tier biochemical test (CTSA / Ceramide Trihexoside/Sulfatide Accumulation in Urine Sediment, Urine). If positive, iduronate sulfatase and arylsulfatase A and B enzyme levels should be assayed and are typically decreased in patients with MSD.
While enzyme replacement therapy has been used to treat a subset of single LSD, its effectiveness is not well established for patients with MSD. Therefore, confirmation or exclusion of a diagnosis of MSD has important implications for patient management as well as prognosis.
Confirmation of multiple sulfatase deficiency for patients with clinical features
Identification of SUMF1 mutation(s) to allow for genetic testing in family members
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of multiple sulfatase deficiency (MSD) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MSD. For carrier testing, it is important to first document the presence of a SUMF1 gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Dierks T, Schlotawa L, Frese MA, et al: Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease-Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta 2009 Apr;1793(4):710-725
2. Schlotawa L, Ennemann EC, Radhakrishnan K, et al: SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet 2011 Mar;19(3):253-261