A systematic cross-sectional survey of multiple sulfatase deficiency

Multiple Sulfatase Deficiency (MSD) is an inborn error of metabolism caused by pathogenic variants in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE) that activates all known sulfatases. FGE deficiency results in widespread tissue accumulation of multiple sulphated substrates. Through a systematic analysis of published cases, we retrieved 80 MSD cases and reviewed the disease clinical, biochemical, and genetic findings. Leukodystrophy, neurosensorial hearing loss, and ichthyosis were the most frequent findings at diagnosis. Of 51 reported pathogenic variants, 20 were likely gene disruptive and the remaining were missense variants. No correlations between class of variants and clinical severity or degree of enzyme deficiency were detected. However, cases harboring variants located at N-terminal always had severe neonatal presentations. Moreover, cases with neonatal onset showed the lowest overall survival rate compared to late-infantile and juvenile onsets. Using GnomAD, carrier frequency for pathogenic SUMF1 variants was estimated to be ~1/700 and the disease prevalence was approximately 1/2,000,000. In summary, MSD is an ultra-rare multisystem disorder with mainly neurologic, hearing and skin involvements. Although the collected data were retrospective and heterogenous, the quantitative data inform the disease natural history and are important for both counseling and design of future interventional studies.