1/47. Identification and characterization of -3c-g acceptor splice site mutation in human alpha-L-iduronidase associated with mucopolysaccharidosis type IH/S.dna screening for mutations in the alpha-L-iduronidase (IDUA) gene was performed in a Chinese mucopolysaccharidosis type IH/S patient. The patient had two different mutations: the maternal allele has L346R (t-g transversion in codon 346) and the paternal allele has 388-3c-g (c-g transversion at position -3 of the 3' splice site of intron 2). In transfected COS-7 cells, L346R showed no appreciable IDUA activity (0.4% of normal activity), although it did not cause an apparent reduction in IDUA mRNA or protein level. The 388-3c-g mutation profoundly affects normal splicing leading to a very unstable mRNA. Expression of the IDUA cDNA containing the mutated acceptor splice site showed trace amounts of enzyme activity (1.6% of normal activity). The results provide further support for the importance of cytosine at the -3 position in rna processing.- - - - - - - - - - ranking = 1keywords = enzyme (Clic here for more details about this article) |
2/47. White matter changes mimicking a leukodystrophy in a patient with Mucopolysaccharidosis: characterization by MRI.Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.- - - - - - - - - - ranking = 3.8495466573849keywords = storage (Clic here for more details about this article) |
3/47. Mucopolysaccharidosis type I: Identification and characterization of mutations affecting alpha-L-iduronidase activity.Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). MPS I covers a broad spectrum of clinical severity ranging from severe Hurler syndrome through intermediate Hurler/Scheie syndrome to mild Scheie syndrome. mutation screening was performed in two unrelated Taiwanese MPS I patients. A Hurler/Scheie patient had A79V (C to T transition in codon 79) in exon 2 and R619G (C to G transversion in codon 619) in exon 14. R619G has been shown to cause disease. Expression of A79V in COS-7 cells showed trace amounts of IDUA activity, demonstrating the deleterious nature of the mutation. A79V mutation did not cause a reduction in IDUA mRNA levels. The reduced level of IDUA protein suggests increased degradation of the mutant enzyme. A Hurler patient had 134del12 (in-frame deletion of codons 16-19 in signal peptide) in exon 1 and Q584X (C to T transition in codon 584) in exon 13. transfection of COS-7 cells with Q584X did not yield active enzyme. Q584X mutation caused an apparent reduction in the IDUA mRNA level and no IDUA protein was detected. Conversely, 134del12 showed 124.6% of normal activity in transfected cells and a 77-kDa precursor protein was observed on Western blot, suggesting biologic activity of precursor IDUA without posttranslational cleavage. These findings provide further evidence of the molecular heterogeneity in mutations in MPS I.- - - - - - - - - - ranking = 415.23578705077keywords = lysosomal enzyme, enzyme (Clic here for more details about this article) |
4/47. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis i.bone marrow transplantation (BMT) has been shown to reverse or stabilize some manifestations of mucopolysaccharidosis i (Hurler syndrome). Idiopathic hyperammonemia (IHA) is a rare complication of solid organ and BMT that is characterized by elevated serum ammonia, normal liver enzymes, and abrupt onset of neurologic deterioration. We present the case of a 14-month-old male patient with Hurler syndrome who developed fatal IHA (ammonia = 2297 micromol/L) 31 days after a cord blood transplant. A complete autopsy was performed, with examination of both frozen and formalin-fixed paraffin-embedded (FFPE) tissues using a variety of special stains and electron microscopy. hyperammonemia was documented by analysis of antemortem serum and postmortem cerebrospinal and vitreous fluid. Other causes of hyperammonemia, including reye syndrome, were excluded. Histologic changes included centrilobular microvesicular steatosis of the liver and storage product present in multiple organs. The highly water-soluble mucopolysaccharide (MPS) storage product was best identified by colloidal iron staining of FFPE and unfixed air-dried fresh frozen liver sections. alcian blue stains failed to convincingly demonstrate MPS in any of the liver sections. This is the first published report, to our knowledge, of IHA in a posttransplant patient younger than 18 years old or following transplantation for Hurler syndrome. Demonstration of the hepatic centrilobular microvesicular steatosis characteristic of IHA was complicated by the diffuse storage of MPS within the liver. MPS storage can be best detected in the liver using colloidal iron staining. Oil-red-O staining may be useful to document microvesicular steatosis in cases with a clinical history of hyperammonemia following solid organ or BMT. Determining if certain subsets of children are at increased risk for IHA requires further study.- - - - - - - - - - ranking = 16.39818662954keywords = storage, enzyme (Clic here for more details about this article) |
5/47. life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.- - - - - - - - - - ranking = 4.8495466573849keywords = storage, enzyme (Clic here for more details about this article) |
6/47. Proliferation of abnormal bone marrow histiocytes, an undesired effect of granulocyte macrophage-colony-stimulating factor therapy in a patient with Hurler's syndrome undergoing bone marrow transplantation.Granulocyte macrophage-colony-stimulating factor (GM-CSF) has shown promise as a means of alleviating leukopenia associated with a wide variety of disorders. It is currently undergoing evaluation as an adjunct to bone marrow transplantation but its use in patients with metabolic disorders, such as Hurler's syndrome (HS), has not been explored. We followed bone marrow morphology in a 2-year-old male with HS who received up to 8 micrograms/kg GM-CSF per day because of failure of allogeneic bone marrow engraftment. Both premortem and postmortem bone marrow sampling revealed almost complete replacement of the marrow space by sheets of histiocytes demonstrating metachromatic cytoplasmic granules. Such cells were present in far greater numbers than are usually seen in untreated patients with HS or patients with HS undergoing successful bone marrow transplantation without GM-CSF. Moreover, the in vitro culture of bone marrow from a second HS patient showed a GM-CSF dose-related increase in colony formation up to a dose of 250 units/ml. Microscopic examination of these colonies showed a high percentage of histiocytes identical to those seen in the patient's bone marrow. These observations suggest that caution should be exercised when considering administration of CSFs to patients with HS and similar metabolic storage diseases.- - - - - - - - - - ranking = 13.851839372569keywords = storage disease, storage (Clic here for more details about this article) |
7/47. airway management in mucopolysaccharide storage disorders.mucopolysaccharidoses (MPS), a group of disorders caused by a genetic disruption, create a special challenge for the otolaryngologist. With the rare types of MPS IV and MPS 1 S, a skilled practitioner is required to abate airway management complications. The erratic deposits of mucopolysaccharides throughout the trachea should be taken into account when decisions to stent the airway are made. Proper management requires to provide an airway that is custom-made to meet the patient's needs. This is a case-by-case presentation of 3 patients with MPS who presented to the Children's Hospital of michigan with progressive respiratory embarrassment. Discussed are the various issues revolving around our ability to provide proper airway management, from intubation to tracheostomy tube placement.- - - - - - - - - - ranking = 15.39818662954keywords = storage (Clic here for more details about this article) |
8/47. light and electron microscopy of the cornea in systemic mucopolysaccharidosis type I-S (Scheie's syndrome).A 37-year-old man with coarse facies, stiff joints, corneal clouding, and normal intelligence sought medical attention. The diagnosis of a systemic mucopolysaccharidosis (MPS) type I-S (Scheie's syndrome) was confirmed by the presence of lysosomal alpha-L-iduronidase deficiency and excessive urinary dermatan and heparan sulfate excretion. The corneal button after perforating keratoplasty of the right eye demonstrated mucopolysaccharides consisting of numerous vacuoles containing fibrillogranular and partly membranebound material in epithelial cells, histiocytes, keratocytes, and extracellular matrix. endothelial cells were distinctly free of storage material. The epithelial basement membrane showed frequent breaks, whereas Bowman's layer was only slightly attenuated. Irregular collagen fibrils and fibrous long-spacing collagen were noted near degenerating distended keratocytes. The Descemet's membrane was normal. The literature of six reported histopathological examinations of the cornea in Scheie's syndrome is reviewed. Detection of fibrous long-spacing collagen seems to be a typical abnormality of the cornea in MPS I-S.- - - - - - - - - - ranking = 3.8495466573849keywords = storage (Clic here for more details about this article) |
9/47. Animal models for lysosomal storage diseases: a new case of feline mucopolysaccharidosis vi.Two long-haired Siamese cats are reported with clinical manifestations of human mucopolysaccharidosis vi (Maroteaux-Lamy disease): facial dysmorphia, dysostosis multiplex, paralysis. urine of the two affected animals contained a high concentration of glycosaminoglycans, as detected by the dimethylmethylene blue test. Qualitative analysis, performed by thin-layer chromatography of the cetylpyridinium chloride-precipitable material, showed dermatan sulphate. Excessive incorporation of [35S]sulphate in the intracellular mucopolysaccharide of cultured fibroblasts and deficiency of arylsulphatase B in such cells indicate that these cats are affected by Maroteaux-Lamy disease. They should thus be considered the first European case of feline mucopolysaccharidosis vi.- - - - - - - - - - ranking = 2739.8406028541keywords = lysosomal storage disease, lysosomal storage, storage disease, storage (Clic here for more details about this article) |
10/47. Atypical microbial infections of digestive tract may contribute to diarrhea in mucopolysaccharidosis patients: a MPS I case study.BACKGROUND: mucopolysaccharidoses are heritable, metabolic diseases caused by deficiency in an activity of one of specific lysosomal enzymes involved in degradation of mucoplysaccharides (glycosaminoglycans). Among many medical problems of patients with mucopolysaccharidoses, there are frequent episodes of diarrhea of unknown etiology. CASE PRESENTATION: A girl, diagnosed enzymatically for mucopolysaccharidosis type I (deficiency of alpha-L-iduronidase) at the age of 3 years and 9 months, was investigated until the age of 5 years and 4 months. Frequent loose stools and episodes of diarrhea, often accompanied by vomiting, were encountered. Detailed microbiological analyses were performed and atypical microbial infections (most often enetropathogenic escherichia coli, but also other species, like pseudomonas aeruginosa or staphylococcus aureus, as well as adenoviruses) of the digestive tract were found in most severe diarrhea episodes. Often, isolations of pathogenic bacterial strains from stools of the investigated patient suffering from diarrhea were not obvious during the first screening, and only detailed microbiological studies, including re-isolation of colonies, gave the results of isolation of particular pathogenic strains (especially in the case of enetropathogenic E. coli). CONCLUSION: We conclude that atypical microbial infections of digestive tract may contribute significantly to diarrhea in mucopolysaccaridosis patients. Since isolated strains were not typical and their isolation was often possible only after detailed investigation (not during a standard screening), such atypical microbial infections of digestive tract of mucopolysaccharidosis patients could be usually overlooked to date. Importantly, these atypical infections could be effectively treated with antimicrobial agents.- - - - - - - - - - ranking = 413.23578705077keywords = lysosomal enzyme, enzyme (Clic here for more details about this article) |
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