1/27. Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type and mutant recombinant alpha-N-acetylglucosaminidase and relationship with sanfilippo phenotype in an attenuated patient.Mucopolysaccharidosis type IIIB (MPS-IIB) is a lysosomal storage disorder characterised by the defective degradation of heparan sulfate due to a deficiency of alpha-N-acetylglucosaminidase (NAG). The clinical severity of MPS-IIIB ranges from an attenuated to severely affected Sanfilippo phenotype. This paper describes the expression and characterisation of wild-type recombinant NAG and the molecular characterisation of a previously identified R297X/F48L compound heterozygous MPS-IIIB patient with attenuated Sanfilippo syndrome. We have previously shown R297X to be the most common mutation in a cohort of Dutch and Australian patients, occurring at a frequency of approximately 12.5%. To date F48L has only been described in the proband. To determine the contribution of each mutation to the overall clinical phenotype of the patient, both mutant alleles were engineered into the wild-type NAG cDNA and expressed in Chinese hamster ovary cells. The wild-type NAG and F48L mutant alleles were also retrovirally expressed in MPS-IIIB skin fibroblasts. Residual NAG activity and the stability and maturation of immunoprecipitated NAG were determined for wild-type NAG and mutant NAG. The combined biochemical phenotypes of the two NAG mutant alleles demonstrated a good correspondence with the observed attenuated Sanfilippo phenotype of the patient.- - - - - - - - - - ranking = 1keywords = lysosomal storage, storage (Clic here for more details about this article) |
2/27. Sanfilippo syndrome type D: identification of the first mutation in the N-acetylglucosamine-6-sulphatase gene.Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. It is caused by a deficiency of N-acetylglucosamine-6-sulphatase, which is one of the enzymes involved in the catabolism of heparan sulphate. We present the clinical, biochemical, and, for the first time, the molecular diagnosis of a patient with Sanfilippo D disease. The patient was found to be homozygous for a single base pair deletion (c1169delA), which will cause a frameshift and premature termination of the protein. Accurate carrier detection is now available for other members of this consanguineous family.- - - - - - - - - - ranking = 0.00093480867643965keywords = enzyme (Clic here for more details about this article) |
3/27. Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome.Sanfilippo A syndrome, mucopolysaccharidosis type IIIA, is caused by a deficiency of heparan sulphamidase activity, and usually presents in childhood with neurodegeneration leading to death in teenage years. Visceral symptoms are limited to coarsening and diarrhea. We now describe an adult patient who presented with cardiomyopathy. At age 45 years she had hypertension, and the next year she developed a progressively worsening cardiomyopathy with prominent apical hypertrophy and atrial fibrillation. At age 53, she had severe concentric hypertrophic nonobstructive cardiomyopathy in both ventricles. There was no coarsening of features. Neurologic function, skeleton, cornea, liver, and spleen were normal. Percutaneous endomyocardial biopsy showed ballooned cardiomyocytes with storage vacuoles, containing acid mucopolysaccharides. Leucocytes, uterus, and brain biopsy did not show this storage material. There was a slight increase in total urine mucopolysaccharides, with an increased proportion of heparan sulfates. Heparan sulphamidase activity was deficient in leukocytes and heparan sulphamidase protein and activity were reduced in cultured fibroblasts. No mutations were identified after sequencing of the heparan sulphamidase gene at the cDNA and the genomic level. This new clinical presentation expands the clinical spectrum of Sanfilippo A syndrome to include a primary visceral presentation of cardiomyopathy without neurologic symptoms in the adult. The late onset may be related to the residual heparan sulphamidase activity. The genetic basis of this new variant is still unclear. physicians evaluating adults must remain aware of possible new adult presentations of storage conditions.- - - - - - - - - - ranking = 0.075595850304402keywords = storage (Clic here for more details about this article) |
4/27. Sanfilippo B disease: a re-examination of a particular sibship after 12 years.A particular sibship, with mild and severe types of Sanfilippo B disease within the same family, was re-examined after 12 years. The phenotypes of the mild and of the severe patients were maintained, specifically the mental retardation. Cultures of lymphoblasts from the mild patient were established and proteins were electrophoresed in native conditions and then immunoblotted with specific antibody. Two bands of 182,000 and 131,000 Da were found, comigrating with the enzyme from normal lymphoblasts and the enzyme from normal urine. The data are discussed in relationship to the molecular defect underlying alpha-N-acetylglucosaminidase deficiency and to the ability of the antiserum to react with normal, mutant, monomeric and multimeric forms of the enzyme.- - - - - - - - - - ranking = 0.0028044260293189keywords = enzyme (Clic here for more details about this article) |
5/27. Sanfilippo syndrome type D in two adolescent sisters.We report on two adolescent sisters with Sanfilippo syndrome type D with some clinical features different from other cases previously described. They are the oldest cases reported to date and provide new clues about the course of the disease. Enzymatic and immunological characterisation of the patients' fibroblasts indicated deficiency of N-acetylglucosamine-6-sulphate sulphatase (GlcNAc-6S sulphatase). However, Northern blot analysis showed apparently normal mRNA encoding GlcNAc-6S sulphatase. These findings suggest that abnormal translation or premature degradation may be responsible for the enzyme defect in these cases of Sanfilippo syndrome type D.- - - - - - - - - - ranking = 0.00093480867643965keywords = enzyme (Clic here for more details about this article) |
6/27. Two cases of mucopolysaccharidosis type III (Sanfilippo). An anatomopathological study.Anatomopathological studies of one case of Sanfilippo disease types A and C, respectively, are presented. The storage phenomenon is very severe in the central as well as in the peripheral nervous system of both patients. light microscopy does not show significant differences between the two cases. Electron microscopy of the nervous system reveals in both cases the presence of variable amounts of zebra bodies and of membrano-granulo-vacuolar inclusions. The presence of larger amounts of zebra bodies in the type A case and of larger quantities of membrano-granulo-vacuolar inclusions in the type C case constitute probably a nondistinctive feature between the two types. light and electron microscopic studies of visceral organs do not disclose significant differences either. It is concluded that no major morphological differences between Sanfilippo disease types A and C can be observed.- - - - - - - - - - ranking = 0.025198616768134keywords = storage (Clic here for more details about this article) |
7/27. Sanfilippo's syndrome type C--the first known case in south africa.The clinical, radiological and biochemical findings in a black girl with a rare, inherited mucopolysaccharide storage disease, Sanfilippo's syndrome (mucopolysaccharidosis (MPS) III) type C, are described. Practical points concerning the biochemical diagnosis of this condition, arising from unusual characteristics of the deficient enzyme acetyl CoA: alpha-glucosaminide N-acetyltransferase, are discussed. Because phenotypic manifestations of mucopolysaccharidosis are mild in all four types of Sanfilippo's syndrome and screening tests for mucopolysacchariduria in these patients may be negative, many cases may be passed unrecognized or simply labelled as cases of nonspecific mental retardation. It is suggested that Sanfilippo's syndrome is grossly underdiagnosed in the RSA and clinicians are urged to develop a greater awareness of the existence, and often subtle presentation, of the condition.- - - - - - - - - - ranking = 0.039167504230744keywords = storage, storage disease, enzyme (Clic here for more details about this article) |
8/27. Hepatic fibrosis in the mucopolysaccharidoses.The mucopolysaccharidoses are a group of clinically progressive, heritable, lysosomal storage disorders. Many organ systems are affected due to widespread accumulation of incompletely degraded mucopolysaccharide. The novel finding of hepatic fibrosis in each of six cases of mucopolysaccharidosis examined at autopsy (including examples of Hurler syndrome, Hunter syndrome, and Sanfilippo syndrome) is described. In each instance, the liver was diffusely involved by fibrosis that outlined the lobules, and there was extensive hepatocyte and Kupffer cell vacuolization. The pattern of hepatic fibrosis is not explained by either cardiac failure or drug toxicity. It is hypothesized that the hepatic fibrosis is due to the abnormal accumulation of a hepatotoxic metabolite. The frequency and severity of liver disease in the mucopolysaccharidoses deserve further study. In particular, with the advent of bone marrow transplantation as therapy for some of the mucopolysaccharidoses, the question of whether cirrhosis develops in these patients and, if so, what its rate of progression is, should be addressed.- - - - - - - - - - ranking = 1keywords = lysosomal storage, storage (Clic here for more details about this article) |
9/27. Deficiency of density-dependent regulation of cell growth in the culture of skin fibroblasts from patients with mucolipidosis III.Cultured skin fibroblast cells were prepared from two patients with mucolipidosis III (ML III), which is a genetic disorder characterized by low activities of multiple lysosomal enzymes in fibroblasts. Genetic complementation analysis of fused fibroblast hybrids revealed that the patients were classified in different complementation groups. growth curves of fibroblasts of ML III patients in culture were compared with those of fibroblasts of Sanfilippo's syndrome patients as well as of the normal fibroblasts. Normal and Sanfilippo fibroblasts gave essentially the same sigmoid curve of cell growth. However, although both ML III cell lines grew at the normal rate in the initial logarithmic phase, they continued to proliferate actively even after the cultures reached confluency. This is the first report to demonstrate the deficiency of density-dependent regulation of cell growth in the culture of nontransformed cell types. Therefore, the culture of skin fibroblasts of ML III patients may serve as a useful experimental model for investigating the regulation of cell proliferation in vitro.- - - - - - - - - - ranking = 0.00093480867643965keywords = enzyme (Clic here for more details about this article) |
10/27. Golgi and computer morphometric analysis of cortical dendrites in metabolic storage disease.Golgi and computer morphometric analysis of neuronal dendrites was done on four cases, one each of tay-sachs disease, infantile type 2 sialidosis, Hurler's syndrome, and Sanfilippo's syndrome. There were large meganeurites on pyramidal neurons in tay-sachs disease, and small ones in Hurler's and Sanfilippo's syndromes. All the meganeurites in these three diseases were predominantly distal to the soma in layer 3, but close to it in layer 5. These findings may be accounted for by different rates of ganglioside accumulation and cortical neuronal morphogenesis. Computer morphometric analysis revealed atrophic or less developed layer 5 dendritic length and branching in tay-sachs disease, sialidosis, and Hurler's syndrome compared with tissues from control patients. These dendritic changes may be secondary to ganglioside accumulation or due to abnormal surface membrane production during dendritic development. This study contributes to an understanding of how enzyme deficiency is translated into abnormal cell structure and, presumably, function.- - - - - - - - - - ranking = 0.15386559089366keywords = storage, storage disease, enzyme (Clic here for more details about this article) |
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