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Maroteaux–Lamy syndrome (also known as mucopolysaccharidosis type VI[1] or polydystrophic dwarfism) is a form of mucopolysaccharidosis caused by a deficiency in arylsulfatase B (ASB),[2] an enzyme responsible for the degradation of glycosaminoglycans in lysosomes. It is named after Pierre Maroteaux (1926-), and his mentor, Maurice Emil Joseph Lamy (1895-1975), both French physicians.[3][4]
History and symptoms
[edit]Children with MPS VI, Maroteaux–Lamy syndrome, usually have normal intellectual development but share many of the physical symptoms found in Hurler syndrome. Caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase, Maroteaux–Lamy syndrome has a variable spectrum of severe symptoms. Neurological complications include clouded corneas, deafness, thickening of the dura (the membrane that surrounds and protects the brain and spinal cord), and pain caused by compressed or traumatized nerves and nerve roots.
Signs are revealed early in the affected child's life, with one of the first symptoms often being a significantly prolonged age of learning how to walk.[5] By age 10 children have developed a shortened trunk, crouched stance, and restricted joint movement. In more severe cases, children also develop a protruding abdomen and forward-curving spine. Skeletal changes (particularly in the pelvic region) are progressive and limit movement. Many children also have umbilical hernia or inguinal hernias. Nearly all children have some form of heart disease, usually involving valve dysfunction.
An enzyme replacement therapy, galsulfase (Naglazyme), was tested on patients with MPS VI and was successful in that it improved growth and joint movement. An experiment was then carried out to see whether an injection of the missing enzyme into the hips would help the range of motion and pain. Costing $350,000 a year, Naglazyme is one of the world's most expensive drugs.[6]
Prevalence
[edit]The epidemiological studies of MPS VI so far have described birth prevalence but not population prevalence. MPS VI birth prevalence ranges from 1 per 43,261 births in Turkish immigrants living in Germany[7] to 1 per 1,505,160 births in Sweden[8]. Although no specific ethnic group has been associated with an increased risk of MPS VI, a common mutation has been found in Brazilian and Portuguese MPS VI patients.[9]
Biochemical features
[edit]MPS VI is determined by mutations in the arylsulfatase B (ARSB) gene located in chromosome 5[10] which result in low or absent activity of the enzyme arylsulfatase B (ASB) also called N-acetylgalactosamine-4-sulfatase (E.C.3.1.6.12). ASB catalyzes the hydrolysis of the 4-sulfate groups of the N-acetyl-D-galactosamine-4-sulfate units of chondroitin sulfate (CS) and dermatan sulfate (DS) glycosaminoglycans (GAG).
Deficiency of ASB leads to incomplete degradation and cellular accumulation of DS and cell injury. Although CS is also a substrate for ASB, it is also hydrolyzed by hyaluronidase and β-glucoronidase into trisaccharides and oligosaccharides that also accumulate but are not recognized as classic storage material.[11]
DS is a glycosaminoglycan composed of linear polysaccharides assembled as disaccharide units containing an uronic acid and a hexosamine. On one hand, three variables can be found at the uronic acid position: D-glucuronate (GlcA), L-iduronate (IdoA) or IdoA-2-sulfate (IdoA2S). On the other hand, four variables can be found at the hexosamine position: N-acetyl-D-galactosamine (GalNAc), GalNAc-4-sulfate (GalNAc4S), GalNAc-6-sulfate (GalNAc-6S) and GalNAc-4,6-disulfate (GalNAc4,6diS).[12]
ASB protein and kinetics in MPS VI
[edit]ASB quantification is measured in cultured skin fibroblasts using an immunoquantification assay and is calculated as amount of enzyme per amount of cell protein. MPS VI patients express 0 to 5 ng/mg, less than 5% of the mean of the ASB protein found in normal controls (105 ng/mg).
ASB kinetics are analyzed in isolated leukocytes or cultured skin fibroblasts homogenates using a radiolabeled trisaccharide substrate.[13] MPS VI fibroblasts have a Km and a catalytic efficiency close to the normal range. However, they present less than 1.5% of the catalytic capacity (calculated as the product of catalytic efficiency and the cellular content of ASB) observed in fibroblasts from normal controls. Fibroblasts from mildly affected patients have significant catalytic capacity, whereas fibroblasts from severely affected patients have undetectable catalytic capacity.
This data suggests that structurally altered enzyme is synthesized but rapidly degraded soon after insertion into the endoplasmatic reticulum. Very small amounts of enzyme, although with relatively normal catalytic efficiency, appear to reach the lysosome. Thus, only those mutations affecting structure or conformation of the enzyme are seen in MPS VI patients.[14]
Further Reading
[edit]See also
[edit]References
[edit]- ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Garrido E, Cormand B, Hopwood JJ, Chabás A, Grinberg D, Vilageliu L (July 2008). "Maroteaux-Lamy syndrome: functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase B gene". Mol. Genet. Metab. 94 (3): 305–12. doi:10.1016/j.ymgme.2008.02.012. PMID 18406185.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ synd/1619 at Who Named It?
- ^ MAROTEAUX P, LEVEQUE B, MARIE J, LAMY M (1963). "A New Dysostosis with Urinary Elimination of Chondroitin Sulfate B". Presse Med (in French). 71: 1849–52. PMID 14091597.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Chicago Tribune http://www.chicagotribune.com/news/local/breaking/chibrknews-web-wonder-kid-its-keenans-world-for-now-20110414,0,2983797,print.story.
{{cite news}}: Missing or empty|title=(help) - ^ Health Care: The World's Most Expensive Drugs, Matthew Herper, Forbes, Feb. 22, 2010
- ^ Baehner F, Schmiedeskamp C, Krummenauer F; et al. (2005). "Cumulative incidence rates of the mucopolysaccharidoses in Germany". J Inherit Mertab Dis. 28 (6): 1011–1017. doi:10.1007/s10545-005-0112-z. PMID 16435194.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ "Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence". Acta Paediatr. 97 (11): 1577–1581. 2008. doi:10.1111/j.1651-2227.2008.00965.x. PMID 18681890.
{{cite journal}}: Cite uses deprecated parameter|authors=(help) - ^ "Identification of a novel mutation in the ARSB gene that is frequent among Brazilian MPSVI patients". Genet Test. 7 (4): 347–349. 2003. doi:10.1089/109065703322783743. PMID 15000815.
{{cite journal}}: Cite uses deprecated parameter|authors=(help) - ^ Litjens T, Baker EG, Beckmann KR, Morris CP, Hopwood JJ, Callen Df (1989). "Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulfatase". Hum Genet. 82 (1): 67–68. doi:10.1007/BF00288275. PMID 2714781.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Valayannopoulos V, Nicely H, Harmatz P, Turbeville S (2010). "Mucopolysaccharidosis VI". Orphanet Journal of Rare Diseases. 5: 5. doi:10.1186/1750-1172-5-5. PMC 2873242. PMID 20385007.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Trowbridge JM, Gallo RL (2002). "Dermatan sulfate: new functions from an old glycosaminoglycan". Glybobiology. 12: 117–125.
- ^ Hopwood Jj, Elliott H, Muller VJ, Saccone GT (1986). "Diagnosis of Maroteaux-Lamy syndrome by the use of radiolabelled oligosaccharides as substrates for the determination of arylsulphatase B activity". Biochem J. 234 (3): 507–514. doi:10.1042/bj2340507. PMC 1146600. PMID 3087346.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Brooks DA, McCourt PAG, Gibson GJ, Ashton LJ, Shutter M, Hopwood JJ (1991). "Analysis of N-Acetylgalactosamine-4-Sulfatase Protein and Kinetics in Mucopolysaccharidosis Type VI Patients". Am J Hum Genet. 48: 710–719.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
Category:Proteoglycan metabolism disorders Category:Skin conditions resulting from errors in metabolism
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