Hunter's syndrome and associated sleep apnoea cured by CPAP and surgery.
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A 42-yr-old male with Hunter's syndrome presented with severe obstructive sleep apnoea syndrome (OSAS) and daytime respiratory failure. Continuous positive airway pressure (CPAP) therapy was initially ineffective and produced acute respiratory distress. Extensive Hunter's disease infiltration of the upper airway with a myxoma was confirmed. Following surgery to remove the myxoma at the level of the vocal cords, CPAP therapy was highly effective and well tolerated. This report demonstrates the necessity of evaluating fully the upper airway in patients with unusual variants of OSAS, particularly where the disease is not adequately controlled by CPAP. (+info)
Elimination of lysosomal storage in brains of MPS VII mice treated by intrathecal administration of an adeno-associated virus vector.
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Mucopolysaccharidosis type VII (MPS VII) is an inherited lysosomal storage disease caused by insufficient beta-glucuronidase (GUS). To provide gene therapy in a mutant mouse model of this disease, we have used a recombinant adeno-associated virus (rAAV) vector to deliver GUS cDNA to a variety of tissues. Although intravenous administration of vector produced therapeutic levels of GUS in the liver, delivery to the brain was inadequate. To improve delivery to the brain intrathecal injection of the vector into the cerebrospinal fluid was employed. This route of administration to either neonatal or adult mutant mice resulted in therapeutic levels of GUS in the brain and the elimination of storage granules in brain tissue. (+info)
The 2.1-, 5.4- and 5.7-kb transcripts of the IDS gene are generated by different polyadenylation signals.
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Deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS) is responsible for mucopolysaccharidosis type II (OMIM 309900). The IDS gene (Xq28) has been completely sequenced (accession number L35485). Northern blot analysis of poly(A(+)) RNA from different tissues, hybridized with the total IDS cDNA, has revealed three major species of 2.1, 5.4 and 5.7 kb and one minor of 1.4 kb. The 1.4-kb mRNA has been previously described and we show that the three major IDS mRNA are the result of alternative polyadenylation site selection: a non-canonical ATTAAA signal at genomic position 23631 for the 2.1-kb mRNA, a AATAAA signal at position 27156 for the 5.4-kb mRNA and a AATAAA signal at position 27399 for the 5.7-kb mRNA. The different IDS mRNA encode for the same polypeptide and the most abundant transcripts have a long 3'-untranslated region (3'-UTR). The absence of obvious correlation between transcripts content and size, IDS protein amount and IDS activity in the four human fetal tissues tested suggests that it is IDS protein processing that may be regulated rather than IDS gene transcription. (+info)
Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome.
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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. (+info)
Iduronate sulfatase analysis of hair roots for identification of Hunter syndrome heterozygotes.
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Iduronate sulfatase, the enzyme deficient in Hunter syndrome, can be readily measured in individual hair roots. Samples from Hunter syndrome hemizygotes had activities at or near the limits of detection. Samples from two mothers of Hunter syndrome patients, one an obligate heterozygote, had lower average iduronate sulfatase activity than the normal mean, and a significant number of hair roots had activity in the pathognomic range. A third mother showed a normal distribution of enzyme activity, and no hair roots were in the range of those from an affected individual. These results are similar to studies on the distribution of other X-linked enzymes in individual hair root samples from heterozygotes. This suggests that hair root iduronate sulfatase assessment is useful in the detection of Hunter syndrome carrier status, but further refinement of the test system is necessary. (+info)
Detection of hunter heterozygotes by enzymatic analysis of hair roots.
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We have developed a procedure for testing iduronate sulfatase, the enzyme deficient in Hunter syndrome, in single hair roots. Beta-Hexosaminidase was used as the reference enzyme. The ratio of iduronate sulfatase to beta--hexosaminidase, expressed in arbitrary units of activity, is near zero for Hunter patients and greater than 0.6 in almost all roots of normal individuals. Hair roots of Hunter heterozygotes show a characteristic continuum of activity ratios, ranging from totally deficient up to and including the normal range. The results are consistent with the origin of hair roots from a small number of progenitor cells which obey the Lyon hypothesis. The proportion of roots with low activity can be used to discriminate between normal and heterozygous individuals. (+info)
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.
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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. (+info)
Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia.
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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). (+info)