Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lowe (oculocerebrorenal) syndrome (LS) is an X-linked disorder characterized by congenital cataracts, generalized hypotonia, mental retardation, and renal Fanconi syndrome. The basic defect remains unknown, but the possibility that fibroblasts express reduced sulfation of glycosaminoglycans has been studied in several laboratories. A mechanism involving overproduction of an enzyme (nucleotide pyrophosphatase) active against adenosine 3'-phosphate, 5'-phosphosulfate (PAPS) has been postulated. Decreased synthesis of normally sulfated glycosaminoglycans was also reported. We measured the synthesis of proteoglycans and glycosaminoglycans by incorporation of [3H]glucosamine and Na2(35)SO4 into cultured fibroblasts from four LS patients and related it directly to the synthesis in six normal fibroblast cultures. We found that the rate of synthesis varied greatly among the normal cultures (cv, 30%), but not significantly between LS and the normal. The LS fibroblasts' ability to sulfate glycosaminoglycans was assayed as the amount of 3H-glycosaminoglycan eluting at low ionic strength on anion exchange chromatography, the amount of non-sulfated disaccharide present in chondroitinase digests of labeled proteoglycans, and the ratio of 35S to 3H incorporation into proteoglycans. Each parameter suggested that the LS cells were synthesizing normally sulfated glycosaminoglycans (e.g. % delta Di-0S, 21 +/- 6 in normal; 27 +/- 6 in LS). The cells' ability to sulfate glycosaminoglycans was tested under conditions of markedly stimulated glycosaminoglycan synthesis, by treating the cultures with a beta-D-xyloside. LS and normal cells responded to the treatment by elevating the rate of synthesis of normally sulfated glycosaminoglycans (3.5-6-fold in normal, 3-7-fold in LS). Nucleotide pyrophosphatase activities were found to be elevated in each of our four LS cell strains as in the previous studies, excluding genetic heterogeneity as an explanation for our findings. We conclude that LS fibroblasts do not express defects in sulfation of glycosaminoglycans or in synthesis of proteoglycans.
 ...
PMID:Proteoglycan synthesis in normal and Lowe syndrome fibroblasts. 357 Dec 27

Costello syndrome is characterized by mental retardation, loose skin, coarse face, skeletal deformations, cardiomyopathy, and predisposition to numerous malignancies. The genetic origin of Costello syndrome has not yet been defined. Using immunohistochemistry and metabolic labeling with [3H]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin-binding protein (EBP), which is normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. Metabolic pulse labeling of the 67-kD EBP with radioactive serine and further chase of this tracer indicated that both normal fibroblasts and fibroblasts from patients with Costello syndrome initially synthesized comparable amounts of this protein; however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugar-bearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. This was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. We also present evidence that loss of EBP from fibroblasts of Costello syndrome patients is associated with an unusually high rate of cellular proliferation.
 ...
PMID:Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein. 1071 2

Galsulfase [Aryplase, arylsulfatase B, BM 102, Naglazyme, rhASB, recombinant human N-acetylgalactosamine-4-sulfatase, recombinant human arylsulfatase B] is under development with BioMarin Pharmaceutical as an enzyme replacement therapy for the treatment of mucopolysaccharidosis (MPS) VI. MPS VI (also known as Maroteaux-Lamy syndrome) is a progressive, debilitating genetic disease resulting in early death. Patients with MPS VI have a deficiency in the arylsulfatase B (ASB) enzyme that is essential for the progressive breakdown of certain complex carbohydrates. The deficiency in ASB results in the build-up of carbohydrate residues in the lysosomes in all cells of the body. Patients are usually diagnosed at 6-24 months of age, and the symptoms include deceleration of growth, enlarged liver and spleen, skeletal and joint deformities, and upper airway obstruction. Patients do not survive past 20-30 years of age in the more severe cases, but may live longer with the milder cases, but with significant medical problems. While the symptoms of MPS VI are similar to those of MPS I, mental retardation associated with the severe forms of MPS I had not been reported for patients with MPS VI. For some patients, bone marrow transplantation is a treatment, albeit risky, option. MPS VI afflicts approximately 1100 patients in the world. In November 2004, BioMarin announced that it has filed a Biologics License Application (BLA) with the the US FDA for galsulfase for the treatment of MPS VI. The company has requested a priority review as part of the BLA submission, which, if granted, is expected to be completed within 6 months of submission. The FDA accepted the filing of the BLA for galsulfase for MPS VI in February 2005, and granted it a 6-month priority review period. The FDA's decision is due on 31 May 2005. The FDA has granted galsulfase orphan drug status and fast-track designation. Orphan drug status will provide BioMarin Pharmaceutical with 7 years of marketing exclusivity for galsulfase in the US providing that galsulfase is the first agent to gain approval in the US for MPS VI. BioMarin received an orphan drug designation from the EC for galsulfase for the treatment of MPS VI. Following positive safety and efficacy results from the phase I study with galsulfase, BioMarin Pharmaceutical commenced and successfully completed a phase II trial with rhASB in ten patients with MPS VI. This 24-week, open-label, multicentre trial was conducted at two sites, in the US and Australia (at the Lysosomal Diseases Research Unit, Women's and Children's Hospital, Adelaide, Australia, by Dr John Hopwood), and evaluated the safety, efficacy and pharmacokinetics of weekly intravenous infusions of galsulfase at a dose of 1.0 mg/kg. BioMarin Pharmaceutical completed a phase I/II clinical trial of galsulfase in six patients with MPS VI in the Children's Hospital, Oakland, CA, USA, with Dr Paul Harmatz as a principal investigator. This randomised, double-blind study evaluated the safety and efficacy of two doses of galsulfase administered by weekly intravenous infusions for 24 weeks. Five patients from the phase I study had completed the 24-week, open-label extension study. Data from this study confirmed safety and good tolerability of both doses of galsulfase with the 1.0 mg/kg dose producing greater sustained effects. The patients will continue receiving therapy in the future. Seven preclinical trials with galsulfase were conducted in a naturally occurring feline model of MPS VI disease at the Lysosomal Diseases Research Unit, Women's and Children's Hospital, Adelaide, Australia, by Dr John Hopwood. The company manufactures galsulfase at a GMP facility licensed from the State of California.
 ...
PMID:Galsulfase: arylsulfatase B, BM 102, recombinant human arylsulfatase B, recombinant human N-acetylgalactosamine-4-sulfatase, rhASB. 1612 2