Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement

Abstract

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.

Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra‐rare disease

“…5,8,20 The phenotype of MSD is more than a direct summation of individual sulfatase deficiencies as the simultaneous loss of several sulfatases may result in novel pathophysiologic effects. 5 Additionally, several sulfatases have uncharacterized phenotypes, adding to the clinical uncertainty surrounding this rare disorder. 5 The ultra-rare nature of MSD has limited our understanding of clinical features and progression.…”

“…5 Additionally, several sulfatases have uncharacterized phenotypes, adding to the clinical uncertainty surrounding this rare disorder. 5 The ultra-rare nature of MSD has limited our understanding of clinical features and progression.…”

Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient

“…The dysmorphic features in the patient and increased urinary GAG excretion were suspicious for a mucopolysaccharidosis. LSDs, including different forms of mucopolysaccharidosis, are a rare cause of NIHF and MSD is one of the rarest entities . The majority of MSD cases are of the late infantile type, only few neonatal cases have been described.…”

A systematic review and meta‐analysis of published cases reveals the natural disease history in multiple sulfatase deficiency

“…We used published clinical guidelines to identify MSDspecific clinical features. 13 Case descriptions from 137 individuals were searched for key clinical terms (n = 234), then categorized by clinical signs yielding 75 categories, which were then grouped into 11 key clusters of signs. Additionally, nine clinical signs were classified as "other signs" (Table S3).…”

“…5,7,8,10,11 The lack of comprehensive natural disease history studies has limited the full development of potential biomarkers and endpoints for interventional studies. 5,13 It is hypothesized that the same biomarkers that are abnormal in the individual sulfatase deficiency disorders, including measures of sulfatase enzyme activity, glycosaminoglycans, and sulfatides, will be abnormal in MSD. The association of these factors to the clinical phenotype in MSD is unknown.…”