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Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD . Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis . Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and skin changes as in X-linked ichthyosis . Regeneration of a reduced Cys336/Cys341 pair is accomplished in vivo by a yet unknown reductant of the endoplasmic reticulum or in vitro by DTT . In this article, we describe a non-ichthyotic Neonatal multiple sulfatase deficiency patient with a novel mutation in the SUMF1 gene .
In a severe lysosomal storage disorder, multiple sulfatase Deficiency (MSD), global sulfatase activity is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases . He had coarse facies, appendicular hypertonia, Truncal ataxia and Ichthyosis limited to both lower limbs . Two Chinese cases with Multiple sulfatase deficiency were firstly reported . Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by Mutations in the sulfatase modifying factor 1 (SUMF1) gene . The accumulation of aberrant mitochondria can alter cell homeostasis, thus resulting in tissue degeneration .
In LSDs, autophagic stress has been associated to mitochondrial accumulation and dysfunction . However, the mechanisms underlying mitochondrial aberrations and how these are involved in tissue pathogenesis remain largely unexplored . In normal conditions, mitochondrial clearance occurs by mitophagy, a selective form of autophagy, which relies on a parkin-mediated mitochondrial priming and subsequent sequestration by autophagosomes . Here, we performed a detailed analysis of key steps of mitophagy in a mouse model of multiple sulfatase deficiency (MSD), a severe type of LSD characterized by both neurological and Systemic involvement . We demonstrated that in MSD liver reduced parkin levels resulted in inefficient mitochondrial priming, thus contributing to the accumulation of giant mitochondria that are located outside autophagic Vesicles ultimately leading to cytochrome c release and apoptotic cell death .
Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature . Induction of lysosomal exocytosis by TFEB overexpression rescued pathologic storage and restored normal cellular Morphology both in vitro and in vivo in lysosomal storage diseases (LSDs) . In addition to multiple sulfatase Deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis . There is a paucity of data, however, relating to the mechanisms that link this accumulation with disease Pathology . The gene responsible for the post-translational modification that activates sulfatases, sulfatase modifying factor 1 (SUMF1), is defective in the rare Autosomal recessive disorder Multiple sulfatase Deficiency (MSD) .
However, when we analyzed the iNKT cell compartment in newly tested LSD animal models that accumulate GSL, glycoaminoglycans or both, we observed a defective iNKT cell selection only in animals affected by multiple sulfatase deficiency, in which a generalized aberrant T-cell development, rather than a pure iNKT defect, was present . She presented with primary microcephaly, facial anomalies including depressed Nasal bridge, Nasal hypoplasia, anteverted nostrils, smooth philtrum, limited mobility of Hip and knee Joints, mild ichthyosis, as well as muscular hypotonia . Since biochemical and clinical findings are variable, the diagnosis is difficult in most of the cases . Here, we present clinical findings of two consanguineous patients with Multiple sulfatase deficiency . SUMF1 is mutated in patients affected by multiple sulfatase Deficiency, a rare recessive disorder in which all sulfatase activities are impaired .
While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood . By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase Deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion . MRI demonstrated extensive Diffuse Symmetrical high signal in the deep white matter of both cerebral hemispheres, as well as of the subcortical white matter and the brainstem, while there was additional enlargement of sulci and subdural spaces and mild Atrophy . Assay of arylsulphatase A activity in white blood cell homogenates at the age of 29 months disclosed a marked Deficiency of the enzyme, compatible with the diagnosis of early-infantile metachromatic leukodystrophy . Multiple sulfatase Deficiency (MSD) is a rare Autosomal recessive disorder characterized by the simultaneous Deficiency of all known sulfatases .
MLD (metachromatic leukodystrophy), CDPX (X-linked dominant chondrodysplasia punctata) and MPS (mucopolysaccharidosis) II, IIIA and VI] . All patients with mucopolysaccharidosis type i (MPS I), MPS II, MPS IIIA, MPS VI, metachromatic leukodystrophy, Niemann-Pick disease type A/B, and multiple sulfatase deficiency could be identified by reduced enzyme levels compared to controls . The detection of inclusion bodies in her white blood Cells at 37 months of age led to the appropriate diagnostic workups for lysosomal storage diseases . Sulfatases degrade and remodel sulfate esters, and inactivity of FGE results in multiple sulfatase deficiency, a fatal disease . The previously determined FGE crystal Structure revealed two crucial cysteine residues in the active site, one of which was thought to be implicated in substrate binding .
Several human inherited diseases are caused by the Deficiency of individual sulfatases, while in patients with Multiple sulfatase deficiency mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene cause a defect in the post-translational modification of a cysteine residue into C(alpha)-formylglycine (FGly) at the active site of all sulfatases . Sulfatase activity requires a unique posttranslational modification, which is impaired in patients with multiple sulfatase Deficiency (MSD) due to a Mutation of the sulfatase modifying factor 1 (SUMF1) .
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