1/38. bone marrow transplantation in a Hunter patient with P266H mutation.Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a lysosomal disease caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS, EC 3.1.6.13). Affected patients show a wide spectrum of clinical phenotypes, from severe to mild. Mutational analysis on this disease resulted in the identification of more than 200 alterations. bone marrow transplantation (BMT) is considered, at present, an appropriate therapy for MPS II subjects without severe neuropsychological impairment, however molecular analysis in BMT treated patients has been poorly studied. We describe here a patient subjected to BMT in 1995 whose IDS gene alteration, mutation P266H, was identified thereafter. The 4-year follow-up included clinical, biochemical and molecular parameters. dna analysis showed, after BMT, coexisting host mutant and donor normal alleles, ensuring the effectiveness of the therapy and providing a fast and accurate tool to monitor the colonization of donor cells after treatment.- - - - - - - - - - ranking = 1keywords = enzyme (Clic here for more details about this article) |
2/38. enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome.We have assessed the effectiveness of transplanted histocompatible fibroblasts as a long-lived source of lysosomal enzymes for replacement therapy in three patients with Hunter's syndrome, over periods ranging from 2.5 to 3.75 yr. The level of Hunter corrective factor excreted by all three patients increased after transplantation, as did the activity of alpha-L-idurono-2-sulfate sulfatase in serum, when measured directly with a radioactive disulfated disaccharide substrate. Sulfatase activity was also raised in leukocyte homogenates from the two patients that we were able to assess. These increases in enzyme activity were accompanied by corresponding increases in catabolism of heparan and dermatan sulfates, as shown by (a) a decrease in sulfate:uronic ratios of urinary oligosaccharides, (b) an increase in iduronic acid monosaccharide, and (c) a normalization of Bio-Gel P-2 gel filtration profiles. Both the increase in enzyme activity and increased catabolism were maintained during the period of study and were not affected by either a gradual decrease or total withdrawal of immunosuppressive therapy.- - - - - - - - - - ranking = 327.54060097539keywords = lysosomal enzyme, enzyme (Clic here for more details about this article) |
3/38. Analysis of a 43.6 kb deletion in a patient with Hunter syndrome (MPSII): identification of a fusion transcript including sequences from the gene W and the IDS gene.Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked lysosomal storage disorder. A novel mutation is described in an MPS II patient in whom the disorder is caused by a 43.6 kb deletion. Southern blot analysis, PCR analysis and subsequent sequencing of the deletion junction revealed that the deletion spans exons 1-7 of the iduronate-2-sulfatase (IDS) gene, the IDS-2 locus and exons 3-5 of the recently identified gene W. Short direct repeats of 12 bp were identified at both deletion breakpoints, suggesting that the deletion is the result of an illegitimate recombination event. A sequence motif (TGAGGA) which is identical to a consensus sequence frequently associated with deletions in man was identified at both breakpoints. This further supports the notion that this motif is a hot spot for recombination. gene expression studies by RT-PCR analysis of total rna derived from fibroblasts of the patient revealed the presence of a novel fusion transcript. dna sequence analysis of the cDNA demonstrated that it consists of exons derived from both the gene W and the IDS gene. A similar but longer fusion transcript containing exons 2-4 of the gene W and exons 4-9 of the IDS gene could also be detected in rna of normal cell lines originating from different tissues. This result further demonstrates the complex gene expression profile of the IDS region, which may contribute to the observed genomic instability of this region.- - - - - - - - - - ranking = 461.52053867764keywords = lysosomal storage, storage (Clic here for more details about this article) |
4/38. Donor bone marrow from a sibling with inborn error of metabolism for treatment of acute leukaemia - clinical and biochemical consequences in the non-affected recipient.bone marrow transplantation (BMT) is increasingly used in an attempt to correct inborn errors of metabolism (IEM). However, little is known about effects of BMT from patients with IEM donating for non-affected recipients. We present data from a 8.5-year-old girl who underwent BMT in second remission for relapsed acute lymphoblastic leukaemia (ALL) at the age of 7 years from her HLA-identical brother who was severely affected by Hunter syndrome (Mucopolysaccharidosis type II, iduronate-2-sulphatase (IDS) deficiency). After BMT not only leukocyte but also plasma activity of IDS was absent. Mixing experiments and immunoadsorption suggest antibody-mediated enzyme inhibition. However, her urinary glycosaminoglycan excretion has not increased post BMT and clinical signs of mucopolysaccharidosis are absent 20 months after BMT. We conclude that patients with white cell enzyme deficiencies and other IEMs do not have to be excluded from bone marrow donation. Antibody production by the graft may occur and be reflected by a marked reduction in plasma enzyme levels but not tissue activity. Similar antibody responses resulting in enzyme inactivation might also affect other enzyme replacement strategies for individuals with IEM.- - - - - - - - - - ranking = 5keywords = enzyme (Clic here for more details about this article) |
5/38. Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia.This report describes unrelated umbilical cord blood transplantation for a 10-month-old infant boy with mucopolysaccharidosis IIB (Hunter syndrome), an X-linked metabolic storage disorder due to deficiency of iduronate sulfatase. Two years after transplant approximately 55% normal plasma enzyme activity has been restored and abnormal urinary excretion of glycosaminoglycans has nearly completely resolved. The boy has exhibited normal growth and development after transplant. Nine months after transplant he developed severe autoimmune hemolytic anemia and required 14 months of corticosteroid treatment to prevent clinically significant anemia. bone marrow transplantation for Hunter syndrome and post-transplant hemolytic anemia are reviewed. bone marrow transplantation (2000).- - - - - - - - - - ranking = 6.860145790611keywords = storage, enzyme (Clic here for more details about this article) |
6/38. Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome).Hunter syndrome is an X-linked metabolic storage disorder arising from deficiency of iduronate sulfatase enzyme activity. Despite the successful use of hematopoietic cell transplantation for a variety of lysosomal and peroxisomal storage diseases, limited benefit occurs following transplantation in either the severe or mild forms of Hunter syndrome. A brief ethical commentary is provided on the case of a boy with mucopolysaccharidosis IIB (ie the mild form) who received an unrelated umbilical cord blood transplant to improve his future quality of life. bone marrow transplantation (2000).- - - - - - - - - - ranking = 20.128406246723keywords = storage disease, storage, enzyme (Clic here for more details about this article) |
7/38. anesthesia of CO2 laser surgery in a patient with Hunter syndrome: case report.Hunter syndrome (mucopolysaccharidosis, type II; MPS II) is one of a heterogeneous group of recessively inherited mucopolysaccharide storage diseases. patients with mucopolysaccharidosis show progressive involvement and derangement of many organs, especially upper airway anomalies, which are the major cause of perioperative death. In recent years, a CO2 laser is often applied to upper airway lesions. A 16-year-old patient suffering from Hunter syndrome was scheduled for CO2 laser surgery because of sleep apnea and respiratory stridor. Otolaryngological examination revealed bulging of the bilateral false cord with stenosis of the glottis. We adopted sevoflurane mask induction and high-frequency jet ventilation to overcome the perioperative airway problems. The anesthetic course was uneventful, and the patient was discharged 2 days after the operation.- - - - - - - - - - ranking = 13.268260456112keywords = storage disease, storage (Clic here for more details about this article) |
8/38. Lumbar kyphosis in Hunter's disease (MPS ii).Although radiological involvement of the lower dorsal and upper lumbar vertebrae is common in the severe form of Hunter's disease (MPS II), there are reports in the literature that clinical kyphosis does not occur. We report a boy with marked clinical kyphosis in whom the diagnosis of MPS II was proved by demonstrating a severe deficiency of serum and leucocyte iduronate-sulphate sulphatase and an accelerated incorporation of radiosulphate into his cultured fibroblast glycosaminoglycans, which could not be corrected by the product of other typed reference MPS II cells. The existence of several other genetic diseases, sometimes complicated by kyphosis, was excluded by assay of fibroblast lysosomal enzymes.- - - - - - - - - - ranking = 1keywords = enzyme (Clic here for more details about this article) |
9/38. An Alu-mediated rearrangement as cause of exon skipping in Hunter disease.Hunter syndrome (Mucopolysaccharidosis type II), a rare X-linked lysosomal storage disorder, results from deleterious mutations in the iduronate-2-sulfatase ( IDS) gene located on Xq27.3-q28. Partial or complete deletions and large rearrangements have been extensively reported in the IDS gene as the basis of Hunter disease. The present report, however, is the first report on a Hunter patient in which Alu-mediated recombinations are implicated. Our patient showed the skipping of exon 8 at the cDNA level, without any splice-junction defects at the genomic level, where a new large rearrangement was identified instead. This new mutant allele consisted of an extensive deletion of IDS sequence of about 3 kb, as well as an additional inserted sequence of 157 bp. Two different computer programs were necessary to elucidate the nature of the insert. NCBI-BLAST query detected a single match for 126 bp out of 157 of the fragment that aligned exactly with a specific chromosomal region, Xq25-27.1, where an AluSg sequence is adjacent to an L1. Instead, the Repeat Masker program identified only 83 bp out of 157 of the insert, which was confirmed as an AluS. The observed homology between the AluSc sequence in the IDS intron 8 and the inserted AluS element, as well as the closeness of 26 bp Alu core sequence, considered to be a recombination hotspot, made us hypothesise upon the fact that both an Alu retrotransposition and an Alu-mediated deletion underlie the disease-producing rearrangement. We, therefore, now propose a mechanism that led to the large genomic deletion causing the production of the aberrant mRNA splicing.- - - - - - - - - - ranking = 461.52053867764keywords = lysosomal storage, storage (Clic here for more details about this article) |
10/38. Expression studies of two novel in CIS-mutations identified in an intermediate case of Hunter syndrome.Hunter syndrome (Mucopolysaccharidosis type II) is a rare X-linked recessive lysosomal storage disorder caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS). To date, more than 200 different mutations have been reported in the IDS gene, located on Xq27.3-q28. Here, we report two new mutations (M488I and G489A) identified in hemizygosity in an Italian Hunter patient. Their "in vitro" expression by COS 7 cells was carried out in order to evaluate their functional consequence on enzyme activity as well as their possible cumulative effect on the malfunctioning of the protein. The results obtained enabled us to confirm the G489A mutation as causative. The M488I mutation, however, could not be unequivocally considered as causing disease because of its residual activity. Although a cumulative effect of the two mutations can be excluded "in vitro," we are cautious about drawing a conclusion with regard to the possible role that the two mutations could have played "in vivo" in modulating the phenotype of the patient. Finally, the knowledge of the molecular defect of the patient has enabled us to identify the carriers, providing reliable genetic counselling to the females of the family.- - - - - - - - - - ranking = 463.52053867764keywords = lysosomal storage, storage, enzyme (Clic here for more details about this article) |
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