1/6. Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX.Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hyaluronidase has been thought to be incompatible with life. However, a patient with a deficiency of serum hyaluronidase, now designated as mucopolysaccharidosis IX, was recently described. This patient had a surprisingly mild clinical phenotype, including notable periarticular soft tissue masses, mild short stature, an absence of neurological or visceral involvement, and histological and ultrastructural evidence of a lysosomal storage disease. To determine the molecular basis of mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on human chromosome 3p21.3 and encoding proteins with homology to a sperm protein with hyaluronidase activity. These genes, HYAL1 and HYAL2, encode two distinct lysosomal hyaluronidases with different substrate specificities. We identified two mutations in the HYAL1 alleles of the patient, a 1412G --> A mutation that introduces a nonconservative amino acid substitution (Glu268Lys) in a putative active site residue and a complex intragenic rearrangement, 1361del37ins14, that results in a premature termination codon. We further show that these two hyaluronidase genes, as well as a third recently discovered adjacent hyaluronidase gene, HYAL3, have markedly different tissue expression patterns, consistent with differing roles in HA metabolism. These data provide an explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and predict the existence of other hyaluronidase deficiency disorders.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
2/6. chondroitin 4- and 6-sulfate mucopolysaccharidosis--a morphological study.A 17-year-old patient clinically manifesting gargoyle face, dwarfism, skeletal bone deformity, mild mental retardation and benign course was presented. Biochemically, increased urinary excretion of acidic glycosaminoglycans was confirmed and chondroitin 4-sulfate and chondroitin 6-sulfate were substantiated to be the major components of the acid mucopolysacchariduria. light microscopically, variable numbers of foam cells were observed in the biopsy materials of the lymph nodes, liver and skin, as well as in the smears of bone marrow aspirates. In the liver, the parenchymal cells appeared vacuolated. Histochemically, accumulation of sulfated acid glycosaminoglycans was demonstrated in the cytoplasm of the foam cells proliferating in these tissues, as well as in the liver cells. Electron microscopically, all of these storage cells were found to contain numerous, membrane-bound, vacuolar inclusions filled with flocculent, finely reticulogranular materials of low electron density similar to those seen in the storage cells of Hurler, Hunter or Sanfilippo's syndrome. Empty vacuoles were often coexistent. Accordingly, this case should be termed "chondroitin 4- and 6-sulfate mucopolysaccharidosis", with emphasis on the possibility of a new type of genetic mucopolysaccharidosis.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
3/6. Otolaryngologic manifestations of the mucopolysaccharidoses.A retrospective review of 45 children with mucopolysaccharidoses was performed to determine the frequency of complications related to the head and neck. In this series, every patient had at least one complication involving the head and neck region, and in over half, operative intervention by the otolaryngologist was required. Upper airway obstruction occurred in 17 (38%) and necessitated a tracheostomy in 7 (16%). Cervical spine instability occurred in 8 (18%), making airway management difficult. Recurrent respiratory infections occurred in 17 (38%), and chronic recurrent middle ear effusions were noted in 33 (73%). This review demonstrates that children afflicted with the mucopolysaccharidoses frequently have otolaryngologic-related complications that are common throughout their life span and often the primary management issue in their continuing care. The otolaryngologic management of these patients is outlined based on the results of this study and review of the relevant literature.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
4/6. The management of otolaryngological problems in the mucopolysaccharidoses: a retrospective review.The mucopolysaccharidoses are rare, genetically transmitted metabolic disorders that affect children early in life. These potentially life-threatening diseases almost invariably involve the auditory apparatus and the upper respiratory tract. Thus, the otolaryngologist is frequently involved in the care of these patients. This paper presents a 10-year retrospective review of the management of these patients at the Hospital for Sick Children. Data concerning auditory and upper respiratory pathology are presented. Results indicate that persistent serous otitis, sensorineural hearing loss, and upper respiratory obstruction leading to sleep apnea, are frequent findings in these patients. Specific recommendations are made with regard to appropriate otolaryngologic intervention in children affected with these diseases.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
5/6. First trimester prenatal diagnosis of Sanfilippo disease (MPSIII) type B.Two pregnancies of a family at risk for Sanfilippo disease type B were monitored in the first trimester. In one case an affected fetus was diagnosed on chorionic villi by the assay of N-acetyl-alpha-D-glucosaminidase and confirmed on cultured fibroblasts from the aborted fetus. Pathological findings are also reported and compared with changes observed later in life. The disease was excluded in the second pregnancy.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
6/6. Mucopolysaccharidosis type IIIC (Sanfilippo): early clinical presentation in a large Turkish pedigree.Two sisters from a large consanguineous Turkish family with Sanfilippo C disease presented within the first 2 years of life. They had coarse facial features, organomegaly and discrete radiological signs of dysostosis multiplex. Urinary glycosaminoglycan excretion was elevated, heparan sulfate being the major component. The uptake of radioactive sulfate into fibroblasts from both patients was abnormal. A deficiency of acetylCoA: alpha-glucosamine transferase was demonstrated in fibroblasts from one patient. To our knowledge, this is the first report of the disease presenting in early infancy.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |