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

Abstract

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden.

Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

“…For the assessment of language‐, swallowing‐ and gross motor function, standardized tools were used (expressive‐language‐function‐classification [ELFC‐MLD], 16 eating‐and‐drinking‐ability‐classification‐system [EDACS], 28 GMFC‐MLD, 17,18 gross‐motor‐function‐measure [GMFM‐88] 29 ) (Supplementary Material S1). Neurologic and somatic exam features and medical complications of MSD according to Adang et al 7 are shown in Supplementary Material S2. Long‐term disease course was followed up until the present (15 years, patient 1) or death (20 years, patient 2) by regular (non‐standardized) telephone contacts.…”

“…Confirmation of the identified SUMF1 variant in patient 1, diagnostic testing in patient 2, and carrier testing was done by Sanger sequencing. Genotype data and some clinical aspects of the two patients are published in a larger MSD cohort 7 …”

“…FGE deficiency influences the clinical MSD picture by effects of the respective affected sulfatases. Correlation with their remaining activity is missing, and even normal activity of single sulfatases occurs 1,2,7‐9 . Deficiency of arylsulfatase A (ARSA) (EC 3.1.6.8) (also due to pathogenic variants in ARSA or PSAP revealing metachromatic leukodystrophy [MLD; OMIM #250100] or SAP‐B deficiency [SAP‐B; OMIM #249900]) leads to accumulation of sulfatides causing neurodegeneration 10 .…”

“…Clinical MSD spectrum ranges from severe neonatal presentation to severe/mild‐infantile and milder juvenile types 1,2,5,11,13 . Genotype‐phenotype‐correlation in MSD is discussed controversially 1‐3,7,13‐15 . MSD spectrum of the age of onset, clinical signs, and genotypes is described in recent systematic literature reviews and natural history study 1,2,7 .…”

View from inside: When multiple sulfatase deficiency changes everything about how you live and becomes your life

“…I put a really big effort into encouraging enrolment in this study as did others (see Acknowledgements). I am delighted to say that robust natural history data on MSD has been published now 4 . Subsequently, some of the key authors of the care guidelines document and natural history study also extended their commitment to MSD research by writing a very important GeneReviews article on MSD which was also published 5 .…”