Two novel mutations of the arylsulfatase B gene in two Italian patients with the severe form of mucopolysaccharidosis VI

Mutation in Brief no 127, On-lin

Molecular pathology of mucopolysaccaridosis IIIB

Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase. The disease is characterized, clinically, by profound neurological deterioration but relatively mild somatic manifestations. The pathogenetic bases of the neurological disease remain obscure; however, a murine model of the MPS IIIB disease is available and suitable both for therapeutic approaches and pathogenesis studies. A first report on the reduction of brain function in this model showed important alterations in the maintenance of neuroplasticity, associated to drastic induction of reactive astrocytes (1). A subsequent study on brain cortex highlighted the involvement of microglia and neuroinflammation in the brain pathology (2). We hypothesized that a pathway focused quantitative analysis of gene expression in the whole brain and in cerebellum of MPS IIIB affected mice, performed at several times from birth (1, 3 and 7 months) would contribute to better illuminate the molecular mechanisms underlying the neuropathology in the MPS IIIB disease. Therefore, we used filter microarrays designed to probe apoptotic-related, neurotrophic signaling molecules, and inflammatory cytokines and receptors. Moreover, we extended the analysis and enhanced the sensitivity of our approach with reverse transcription real time PCR using several gene-specific primer sets. From these combined analyses the Bdnf gene resulted to be down-regulated in the brain but up-regulated in the cerebellum. Cbln1 presented a 2 fold increase in the brain while resting unaltered in the cerebellum of MPS IIIB mice. All the other analysed genes, namely Ccl3, Casp3, Casp11, gp91phox, p67 and p47, showed an increased expression in both brain and cerebellum at every time from birth; particularly, Ccl3 exhibited in both organs and at all times tested approximately a ten-fold increase of its expression. Interestingly, p47, p67 and gp91phox are all components of the phagocyte NADPH oxidase that catalyzes the superoxide production; these results seem to suggest the possible involvement of the reactive oxygen species in the genesis of neurodegeneration for the MPS IIIB mice. The NADPH oxidase-derived superoxide made by the activated microglia could play an important role in the inflammation-mediated damage to neurons

"Classical organic acidurias": diagnosis and pathogenesis.

Organic acidurias are inherited metabolic diseases due to the deficiency of an enzyme or a transport protein involved in one of the several cellular metabolic pathways devoted to the catabolism of amino acids, carbohydrates or lipids. These deficiencies result in abnormal accumulation of organic acids in the body and their abnormal excretion in urine. More than 65 organic acidurias have been described; the incidence varies, individually, from 1 out of 10,000 to[1 out of 1000,000 live births. Collectively, their incidence approximates 1 out of 3000 live births. Among these disorders, methyl malonic aciduria, propionic aciduria, maple syrup urine disease and isovaleric aciduria are sometimes referred to as classical organic acidurias. In this review, we focused on the basic GC–MS-based methodologies employed in the diagnosis of classical organic acidurias and provided updated reference values for the most common involved organic acids. We also attempted to provide the most recent updates on the pathogenetic bases of these diseases

Unfolded Protein Response is not activated in the mucopolysaccharidoses but protein disulfide isomerase 5 is deregulated

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases (LSDs) caused by defects in lysosomal enzymes involved in the catabolism of glycosaminoglycans. The pathogenesis of these disorders is still not completely known, although inflammation and oxidative stress appear to be common mechanisms, as in all LSDs. Recently, it was hypothesized that endoplasmic reticulum (ER) stress followed by an unfolded protein response (UPR) could be another common pathogenetic mechanism in LSDs. The aim of the present study was to verify if the UPR was elicited in the mucopolysaccharidoses and if the mechanism was MPS type- and mutation-dependent. To this end, we analyzed the UPR in vitro, in fibroblasts from patients with different types of mucopolysaccharidoses (MPS I, II, IIIA, IIIB, IVA) and in vivo, in the murine MPS IIIB model. In both cases we found no changes in mRNA levels of several UPR-related genes, such as the spliced or unspliced form of Xbp-1, Bip, Chop, Edem1, Edem2, Edem3. Therefore, we report here that the unfolded protein response of the ER is not triggered either in vitro or in vivo; accordingly, cytotoxicity assays indicated that affected fibroblasts are no more sensitive to apoptosis induction than normal cells. However, our results show that in most of the analysed MPS fibroblasts the expression of a poorly known protein belonging to the family of the protein disulfide isomerases, namely Pdia5, is upregulated; here we discuss if its upregulation could be an early event of ER stress possibly related to the severity of the damage induced in the mutant proteins

Gene symbol: SGSH. Disease: Sanfilippo type A syndrome, mucopolysaccharidosis IIIA.

We report a female patient with heparan N-sulphatase deficiency (MPS IIIA) whose genotype (P293T/R304L; V387M) was investigate