Ultrastructural studies of parallel tubular arrays in human lymphocytes.
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Parallel tubular inclusions were found in peripheral blood lymphocytes from 18 patients with various hematologic disorders, primarily lymphoproliferative processes, and 1 apparently healthy individual. The inclusions varied in size from 1000 to 6000 A and were usually membrane bounded. The microtubule-like structures comprising the inclusions ranged in size from 150 to 300 A and were packed in wall-to-wall contact with each other. Dense amorphous material and small dark crystalloids were frequently noted in the inclusions. There appeared to be a spatial and structural relationship of the inclusions with the centriole. The highest percent of lymphocytes with inclusionss (greater than 90%) were found in a patient with a lympho-proliferative disorder in whom 95% of the peripheral blood lymphocytes typed as T cells by spontaneous rosette formation with sheep red blood cells. (Am J Pathol 78:59-70, 1975) (+info)
Hepatic storage of glycosaminoglycans in feline and canine models of mucopolysaccharidoses I, VI, and VII.
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Livers from normal cats and dogs, cats with mucopolysaccharidoses (MPS) I and VI, and dogs with MPS VII were analyzed biochemically and morphometrically to determine the lysosomal storage of glycosaminoglycans (GAG) in these animal models of human genetic disease. Analyses were performed on liver samples from seven normal cats ranging in age from 13 weeks to 15 months; six MPS I-affected cats ranging in age from 10 weeks to 26 months; four MPS VI-affected cats ranging in age from 9 months to 32 months; four normal dogs ranging in age from 1 month to 47 months; and three MPS VII-affected dogs, 5 days, 11 days, and 14 months of age. All of the animals were from the breeding colony at the University of Pennsylvania School of Veterinary Medicine and were maintained in accordance with national standards for the care and use of laboratory animals. Each GAG subclass was quantitated, and total GAG concentration was determined. Liver from cats with MPS I had the highest total GAG concentration (5.7 times that of the control), followed by liver from dogs with MPS VII (1.8 times) and cats with MPS VI (1.5 times). These data were very closely correlated (R2 = 0.982) with the results of the morphometric analyses of hepatocyte and Kupffer cell vacuolation associated with lysosomal storage and support the validity of both methods. This is particularly important for the quantification of total and individual GAG concentrations in tissue preparations. The values obtained should prove useful in future assessments of therapeutic regimes, such as enzyme replacement, bone marrow transplantation, and gene therapy, for these genetic diseases. (+info)
Mucolipidosis IV: ocular, systemic, and ultrastructural findings.
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The ocular and systemic findings in four children with mucolipidosis IV (ML IV), a new variant of mucolipidosis, are described. Corneal clouding from birth or early infancy is a prominent feature in all of the patients and in two of them, this was the presenting symptom. Psychomotor retardation usually does not become apparent until the end of the first year of life. Conjunctival biopsies revealed two types of abnormal inclusion bodies: (1) single-membrane-limited cytoplasmic vacuoles containing both fibrillogranular material and membranous lamellae, and (2) lamellar and concentric bodies similar to those found in Tay-Sachs disease. The abnormal cytoplasmic organelles were present in both the stromal fibroblasts and the epithelial cells. The electroretrinogram performed in one patient was subnormal. (+info)
Bone marrow transplantation in patients with storage diseases: a developing country experience.
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Bone marrow transplantation (BMT) is a therapeutic option for patients with genetic storage diseases. Between 1979 and 2002, eight patients, four females and four males (1 to 13 years old) were submitted to this procedure in our center. Six patients had mucopolysaccharidosis (MPS I in 3; MPS III in one and MPS VI in 2), one had adrenoleukodystrophy (ALD) and one had Gaucher disease. Five patients had related and three unrelated BMT donor. Three patients developed graft versus host disease (two MPS I and one MPS VI) and died between 37 and 151 days after transplantation. Five patients survived 4 to 16 years after transplantation. Three patients improved (one MPS I; one MPS VI and the Gaucher disease patient), one patient had no disease progression (ALD) and in one patient this procedure did not change the natural course of the disease (MPS III). (+info)
Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses.
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Mucopolysaccharidoses (MPS) are inherited, severe, progressive, metabolic disorders caused by deficiencies in different enzymes involved in degradation of glycosaminoglycans (GAGs). Although enzyme replacement therapy (ERT) has recently been available for MPS type I, and clinical trials have been performed in ERT for MPS II and MPS VI, there is little chance that this kind of treatment may be effective for neurodegenerative forms of MPS (due to inefficient delivery of enzymes to central nervous system through the blood-brain barrier), hence currently there is no effective therapy available for them. Therefore, we aim to develop an alternative therapy for these diseases. We found that genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) inhibits synthesis of GAGs considerably in cultures of fibroblasts of MPS patients (types I, II, IIIA and IIIB were tested). Prolonged cultivation of these cells in the presence of genistein resulted in reduction of GAG accumulation and normalization of cells as estimated by biochemical tests and electron microscopic analysis, respectively. As genistein inhibits kinase activity of epidermal growth factor receptor, which is required for full expression of genes coding for enzymes involved in GAG production, we propose to consider a substrate reduction therapy for MPS, which is referred to as 'gene expression-targeted isoflavone therapy'. (+info)
A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.
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OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format. (+info)
Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity.
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We identified two different exonic point mutations causing beta-glucuronidase (beta G1) deficiency in two Japanese patients with mucopolysaccharidosis type VII (MPSVII). Enzyme assay of lysates of the lymphocytes and cultured fibroblasts showed little residual activity. The beta G1-specific mRNA levels were normal, as determined by northern blot analysis. Mutated cDNA clones, including the entire coding sequence, were isolated using the polymerase chain reaction (PCR) products derived from beta G1-deficient fibroblasts. Sequence analysis of the full-length mutated cDNAs showed C----T transitions, which resulted in a single Ala619----Val change (case 1, a 24-year-old male) and a Arg382----Cys change (case 2, a 7-year-old female). The former change was revealed by a loss of the cleavage site for the Fnu4HI in the mutated cDNA. On the basis of the loss of Fnu4HI restriction site, the patient (case 1) was a homozygote with this mutation. The mutational change in patient 2 was confirmed by direct sequencing and by demonstrating heterozygosity for the mutation in her parents. The Ala619----Val and Arg382----Cys mutations each disrupt a different domain which is highly conserved among human, rat, and Escherichia coli beta G1s. Each of these two amino acid changes reduced the beta G1 activity of the corresponding mutant beta G1 expressed following transfection of COS cells with expression vectors harboring the mutated cDNAs. (+info)
Animal models for mucopolysaccharidosis disorders and their clinical relevance.
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Progress in understanding how a particular genotype produces the phenotype of an inborn error of metabolism, such as a mucopolysaccharidosis, in human patients has been facilitated by the study of animals with mutations in the orthologous genes. These are not just animal models, but true orthologues of the human genetic disease, with defects involving the same evolutionarily conserved genes and the same molecular, biochemical, and anatomic lesions as in human patients. These animals are often domestic species because of the individual medical attention paid to them, particularly dogs and cats. In addition, naturally occurring mouse models have also been found in breeding colonies. Within the last several decades, advances in molecular biology have allowed the production of knockout mouse models of human genetic disease, including the lysosomal storage diseases. The ability to use both inbred strains of a small, prolific species together with larger out-bred animals found because of their disease phenotype provides a powerful combination with which to investigate pathogenesis, develop approaches to therapy, and define biomarkers to evaluate therapeutic success. This has been true for the inborn errors of metabolism and, in particular, the mucopolysaccharidoses. CONCLUSION: Animal models of human genetic disease continue to play an important role in understanding the molecular and physiological consequences of lysosomal storage diseases and to provide an opportunity to evaluate the efficacy and safety of therapeutic interventions. (+info)