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

Abstract

Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra-rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE). FGE is necessary for the activation of sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally impaired FGE and individuals with MSD demonstrate clinical signs of single sulfatase deficiencies, including metachromatic leukodystrophy (MLD) and several mucopolysaccharidosis (MPS) subtypes. Comprehensive information related to the natural history of MSD is missing. We completed a systematic literature review and a meta-analysis on data from published cases reporting on MSD. As available from these reports, we extracted clinical, genetic, biochemical, and brain imaging information. We identified 75 publications with data on 143 MSD patients with a total of 53 unique SUMF1 mutations. The mean survival was 13 years (95% CI 9.8-16.2 years). Seventy-five clinical signs and 11 key clusters of signs were identified. The most frequently affected organs systems were the nervous, skeletal, and integumentary systems. The most frequent MRI features were abnormal myelination and cerebral atrophy. Individuals with later onset MSD signs and survived longer than those with signs at birth. Less severe mutations, low disease burden and achievement of independent walking positively correlated with longer survival. Despite the limitations of our approach, we were able to define clinical characteristics and disease outcomes in MSD. This work will provide the foundation of natural disease history data needed for future clinical trial design. Jutta Gärtner and Tim Friede contributed equally to this work.

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

“…Adang et al 7 report on poor outcome and decreased survival in MSD patients bearing two “severe”‐labeled variants (severe‐missense/nonsense‐alleles). In a recent meta‐analysis (75 publications including 143 MSD patients and 53 SUMF1 mutations) Schlotawa et al 1 demonstrated a correlation of survival and mutation severity but not sulfatase activities. Correlation of phenotype and enzyme deficiency seems lacking so far 1,2,7 …”

“…Ultra‐rare multiple sulfatase deficiency (MSD; OMIM #272200) is caused by pathogenic variants in SUMF1 1‐5 . SUMF1 encodes formylglycine‐generating enzyme (FGE) (EC 1.8.3.7), which is essential for sulfatase activation 6 .…”

“…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 .…”

“…X‐linked ichthyosis (OMIM #308100) and chondrodysplasia punctata‐1 (OMIM #302950) are associated with deficiency of steroid sulfatase (EC 3.1.6.2) 12 and arylsulfatase E (EC 3.1.6.1), respectively. 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 .…”

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

“…Some preliminary findings were presented at WORLD Symposium in Orlando in 2019 and I am glad to say this has now been published also. 6 I anticipate that all of this data and hard work will make a major contribution, in tandem with the natural history study data, in the design of future MSD clinical trials.…”