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

Schlotawa, Lars; Dierks, Thomas; Christoph, Sophie; Cloppenburg, Eva; Ohlenbusch, Andreas; Korenke, Georg Christoph; Gärtner, Jutta

doi:10.1002/jmd2.12074

Cited by 11 publications

(15 citation statements)

References 17 publications

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“…Only nonsense mutations completely abrogate FGE function [52]. All previously analyzed mutations demonstrated reduced intracellular protein levels and excretion supporting the hypothesis that most variants result in early degradation and/or reduced stability of FGE [45][46][47][48]50,52]. In fact, the majority of FGE variants analyzed demonstrate a half-life of less than 2 h [45,[49][50][51].…”

Section: Sumf1 Mutations and Functional Consequencessupporting

confidence: 53%

“…The majority of SUMF1 mutations are of hypomorphic nature resulting in expression of FGE with residual activity [46]. Only nonsense mutations completely abrogate FGE function [52]. All previously analyzed mutations demonstrated reduced intracellular protein levels and excretion supporting the hypothesis that most variants result in early degradation and/or reduced stability of FGE [45][46][47][48]50,52].…”

Section: Sumf1 Mutations and Functional Consequencesmentioning

confidence: 81%

“…Group II fibroblasts show more than 15% of residual activity, sometimes reaching normal values. Group I fibroblasts derive from severe MSD cases whereas group II fibroblasts originate from attenuated MSD cases [52,56,[61][62][63]. Interestingly, and in contrast to group I fibroblasts, group II fibroblasts were reported to show variable sulfatase activity over time in the same cell line.…”

Section: Biomarkers and Diagnosismentioning

confidence: 99%

“…There is emerging evidence for a genotype-phenotype correlation in the homozygous form of the disease. Patients with biallelic nonsense mutations have the most severe symptoms and often have absent sulfatase activities (severe or neonatal very severe form) [52]. Attenuated patients often harbor variants that result in a highly unstable variant FGE with low residual activity.…”

Section: Biomarkers and Diagnosismentioning

confidence: 99%

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Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

Schlotawa

Adang

Radhakrishnan

et al. 2020

IJMS

Self Cite

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Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.

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Section: Sumf1 Mutations and Functional Consequencessupporting

confidence: 53%

Section: Sumf1 Mutations and Functional Consequencesmentioning

confidence: 81%

Section: Biomarkers and Diagnosismentioning

confidence: 99%

Section: Biomarkers and Diagnosismentioning

confidence: 99%

See 2 more Smart Citations

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

Schlotawa

Adang

Radhakrishnan

et al. 2020

IJMS

Self Cite

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Multiple sulfatase deficiency (MSD) is a lysosomal storage disease caused by a deficiency of formylglycine‐generating enzyme due to SUMF1 defects. MSD may be misdiagnosed as metachromatic leukodystrophy (MLD), as neurological and neuroimaging findings are similar, and arylsulfatase A (ARSA) deficiency and enhanced urinary sulfatide excretion may also occur. While ARSA deficiency seems a cause for neurological symptoms and later neurodegenerative disease course, deficiency of other sulfatases results in clinical features such as dysmorphism, dysostosis, or ichthyosis. We report on a girl and a boy of the same origin presenting with severe ARSA deficiency and neurological and neuroimaging features compatible with MLD. However, exome sequencing revealed not yet described homozygosity of the missense variant c.529G > C, p.Ala177Pro in SUMF1. We asked whether dynamics of disease course differs between MSD and MLD. Comparison to a cohort of 59 MLD patients revealed different disease course concerning onset and disease progression in both MSD patients. The MSD patients showed first gross motor symptoms earlier than most patients with juvenile MLD (<10th percentile of Gross‐Motor‐Function in MLD [GMFC‐MLD] 1). However, subsequent motor decline was more protracted (75th and 90th percentile of GMFC‐MLD 2 (loss of independent walking) and 75th percentile of GMFC‐MLD 5 (loss of any locomotion)). Language decline started clearly after 50th percentile of juvenile MLD and progressed rapidly. Thus, dynamics of disease course may be a further clue for the characterization of MSD. These data may contribute to knowledge of natural course of ultra‐rare MSD and be relevant for counseling and therapy.

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Fetal Hydrops

Nagy

Malcomson

2022

Keeling's Fetal and Neonatal Pathology

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

Cited by 11 publications

References 17 publications

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification

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

Fetal Hydrops

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