Development of Sensory, Motor and Behavioral Deficits in the Murine Model of Sanfilippo Syndrome Type B

BACKGROUND: Mucopolysaccharidosis (MPS) IIIB (Sanfilippo Syndrome type B) is caused by a deficiency in the lysosomal enzyme N-acetyl-glucosaminidase (Naglu). Children with MPS IIIB develop disturbances of sleep, activity levels, coordination, vision, hearing, and mental functioning culminating in early death. The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes. PRINCIPAL FINDINGS: To more thoroughly assess MPS IIIB in mice, alterations in circadian rhythm, activity level, motor function, vision, and hearing were tested. The suprachiasmatic nucleus (SCN) developed pathologic changes and locomotor analysis showed that MPS IIIB mice start their daily activity later and have a lower proportion of activity during the night than wild-type controls. Rotarod assessment of motor function revealed a progressive inability to coordinate movement in a rocking paradigm. Purkinje cell counts were significantly reduced in the MPS IIIB animals compared to age matched controls. By electroretinography (ERG), MPS IIIB mice had a progressive decrease in the amplitude of the dark-adapted b-wave response. Corresponding pathology revealed shortening of the outer segments, thinning of the outer nuclear layer, and inclusions in the retinal pigmented epithelium. Auditory-evoked brainstem responses (ABR) demonstrated progressive hearing deficits consistent with the observed loss of hair cells in the inner ear and histologic abnormalities in the middle ear. CONCLUSIONS/SIGNIFICANCE: The mouse model of MPS IIIB has several quantifiable phenotypic alterations and is similar to the human disease. These physiologic and histologic changes provide insights into the progression of this disease and will serve as important parameters when evaluating various therapies

Glycobiology of cell death: when glycans and lectins govern cell fate

Although one typically thinks of carbohydrates as associated with cell growth and viability, glycosylation also has an integral role in many processes leading to cell death. Glycans, either alone or complexed with glycan-binding proteins, can deliver intracellular signals or control extracellular processes that promote initiation, execution and resolution of cell death programs. Herein, we review the role of glycans and glycan-binding proteins as essential components of the cell death machinery during physiologic and pathologic settings.Fil: Lichtenstein, Rachel. Ben-Gurion University of the Negev. Faculty of Engineering. Department of Biotechnology Engineering; IsraelFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Cs.exactas y Naturales. Departamento de Quimica Biologica; Argentin

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality

Expression and characterization of wild type and mutant recombinant human sulfamidase - Implications for Sanfilippo (mucopolysaccharidosis IIIA) syndrome

Mucopolysaccharidosis IIIA (MPS-IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of sulfamidase (NS; EC 3.10.1.1), resulting in defective degradation and storage of heparan sulfate. This paper reports the production and characterization of monoclonal and polyclonal antibodies against recombinant human sulfamidase (rhNS) to quantitate and characterize normal and mutant sulfamidase produced from the wild type NS expression vector. Glycosylation and phosphorylation studies of immunoprecipitated rhNS show that all five potential glycosylation sites are utilized, with three high mannose/hybrid oligosaccharides and two simpler chains, with at least one functional mannose 6-phosphate group. An NS quantification system was developed to determine the effect of the three most common and severe patient mutations: S66W (Italy), R74C (Poland), and R245H (The Netherlands). The quantity and specific activity of expressed mutant rhNS was significantly lower than expressed normal rhNS, with 0.3, 0.2, and 0.05% of normal rhNS produced and 15, 17, and 83% of normal specific activity for S66W, R74C, and R245H observed, respectively. The recent structural elucidation of N-acetylgalactosamine-4-sulfatase was utilized to postulate the effect on the structure-function relationship of NS. The characterization of normal and mutated rhNS has relevance for efficient diagnosis and therapeutic developments for MPS-IIIA patients

Experiences of Crisis Pregnancy among Irish and Non-Irish adults living in Ireland: Findings from the Irish Contraception and Crisis Pregnancy Survey 2010 (ICCP-2010)

Background: Using nationally representative data, this paper investigates the experience of crisis pregnancy (CP) among Irish and non-Irish adults living in Ireland in 2010. Aims: To generate a detailed profile of Irish and non-Irish adults living in Ireland who have had an experience of CP and to investigate the differences in the experiences of CP between Irish and non-Irish adults. Method: A national cross-sectional telephone survey methodology recruited 3002 adult(18-45 years) participants (69% response). Descriptive statistics and chi square analysis were used to compare the differences between the Irish (n=334) and non-Irish sample (n=57) with an experience of CP. Results: The majority of respondents with an experience of CP had a higher education level and were aged between 18-25 years. Significant differences, in terms of outcome of CP, were also found between groups; with more Irish respondents choosing parenthood over abortion, compared with their non-Irish counterparts. Conclusion: This paper presents a unique profile of Irish and non-Irish adults living in Ireland with an experience of CP. Enhanced promotion of longer-acting contraceptives to all younger adults, and targeted awareness raising of post-abortion services among the non-Irish community, is recommended

Primary culture of neural cells isolated from the cerebellum of newborn and adult mucopolysaccharidosis type IIIA mice

The original publication can be found at www.springerlink.comIn order to evaluate the mechanisms leading to neuropathology in Mucopolysaccharidosis type IIIA (MPS-IIIA, Sanfilippo syndrome), we have harvested and cultured primary neural cells isolated from the cerebellum of newborn and adult MPS-IIIA and unaffected mice. Cell viability and plating efficiency were comparable for brain tissue obtained from either newborn or adult MPS-IIIA and unaffected mice. Cultures (newborn and adult) comprised a mixed brain cell population including astrocytes, oligodendrocytes, and neurons. Newborn MPS-IIIA cells contained inclusions and vacuoles consistent with the pathology present in affected brain tissue. Newborn and adult MPS-IIIA brain cells had approximately 5–7% of the sulfamidase activity present in primary neural cells cultured from unaffected newborn and adult mice. In addition, high levels of glucosamine-N-sulfate[α-1,4]hexuronic acid, a heparan sulfate-derived disaccharide, were detected in both newborn and adult MPS-IIIA brain cells. These results suggest that the primary MPS-IIIA brain cells exhibit characteristics of MPS-IIIA phenotype at the histopathological and biochemical level in culture.L. M. Sutherland, K. M. Hemsley and J. J. Hopwoo