Mucopolysaccharidosis Type III

Mucopolysaccharidosis Type III

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Mucopolysaccharidosis Type III is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • MPS disorder III
  • MPS III
  • mucopolysaccharide storage disease type III
  • oligophrenic polydystrophy
  • polydystrophia oligophrenia

Disorder Subdivisions

  • Sanfilippo disease (types A, B, C, and D)
  • Sanfilippo syndrome (types A, B, C, and D)

General Discussion

The Mucopolysaccharidoses (MPS Disorders) are a group of rare genetic disorders caused by the deficiency of one of the lysosomal enzymes, resulting in an inability to metabolize complex carbohydrates (mucopolysaccharides) into simpler molecules. High concentrations of mucopolysaccharides in the cells of the central nervous system, including the brain, cause the neurological and developmental deficits that accompany these disorders.



Mucopolysaccharides are rather thick jelly-like ("muco") compounds made of long chains ("poly") of sugar-like (saccharides) molecules used to make connective tissues in the body.



Lysosomal enzymes are found in the lysosome, a very small membrane-contained body (organelle) found in the cytoplasm of most cells. The lysosome is often called the "waste disposal plant" of the cell. The accumulation of these large, undegraded mucopolysaccharides in the cells of the body is the cause of a number of physical symptoms and abnormalities.



MPS-III (Sanfilippo Syndrome) is one of seven MPS Disorders. It is an inborn error of metabolism that is transmitted as an autosomal recessive genetic disorder. MPS-lll has been subdivided into four types: MPS-III Type A, MPS-III Type B, MPS-III Type C, and MPS-III Type D. All types are associated with some degree of mental deterioration, but the severity depends on the particular type of MPS-lll. Several physical defects may be present, and the severity of these defects varies with the type of MPS-III. In the case of each type of MPS-III, abnormal amounts of a specific, chemically complex molecule is excreted in the urine. The excreted chemical is the same for each of the four types of MPS-III, since the defective gene involves a different step, and thus a different enzyme, in the deconstruction of the same mucopolysaccharide. By testing for one or another of these enzymes, the variant type may be readily identified.

Symptoms

Patients with Sanfilippo Syndrome (MPS Type III) usually appear normal at birth, but mental retardation and developmental delay is usually evident by age 3-5 years. Mental and motor development reach a peak by 3-6 years of age after which behavioral disturbances and intellectual decline usually occur. However, hyperactivity and irritability may become obvious earlier.



The following symptoms are usually apparent by approximately age 10: neurological deficits and signs, wobbly and erratic gait and difficulty walking (ataxia), hyperactivity (hyperkinetic syndrome), mental retardation, stiff joints, hernias, enlarged liver and/or spleen (hepatosplenomegaly).



Growth is usually minimally affected; the head may be enlarged, and abnormal hairiness (hirsutism) may occur. Mild coarsening of facial features also characterize this disorder. In some cases deafness may also occur.

Causes

All four varieties of MPS-III are autosomal recessive genetic disorders.



The gene abnormalities associated with MSS-IIIA, MPS-IIIB, and MPS-IIID have been identified. The gene abnormality associated with MPS-IIIC has not been identified but has been localized to chromosome 14. The Gene Map Loci are as follows:



MPS-IIIA --------- 17q25.3

MPS-IIIB --------- 17q21

MPS-IIIC --------- Chromosome 14

MPS-IIID --------- 12q14



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17q25.3" refers to band 25.3 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Each of the four types of MPS-III affects males and females equally. There have been three studies of the incidence of this disorder, and its variants, that have been of sufficient size to yield reasonably reliable results.



In The Netherlands the overall incidence of MPS-III was about 1 per 73,000 live births. The relative prevalence of the types of MPS-III in The Netherlands turned out to be A:B:C = 6:2:3.



In British Columbia only the incidence of Type A was reported. The overall incidence of MPS-IIIA was found to be 1 per 324,000 live births.



In Northern Ireland the overall incidence of MPS-III was about 1 per 280,000 live births. The relative prevalence of the types of MPS-III in Northern Ireland turned out to be A:B = 2:1.

Standard Therapies

Diagnosis

The presence of heparan sulfate in the urine is diagnostic for MPS-III. To distinguish between the different forms of MPS-III requires tests designed to identify the presence or absence of a particular enzyme in the cell. For example, MPS-III Type A is characterized by a lack of heparan N-sulfatase; patients with MPS-III Type B lack alpha-N-acetylglucosaminidase. MPS-III Type C is indicated by a deficiency of acetyl CoA:alpha-glucosaminide acetyltransferase and patients with MPS-III Type D lack N-acetylglucosamine 6-sulfatase. Each of these four enzymes is essential to one step in the degradation of heparan sulfate, so that if any one enzyme is lacking, then the heparan sulfate will be excreted.



Treatment

Treatment of Sanfilippo Syndrome is symptomatic and supportive. Genetic counseling may be helpful to the parents of patients with Sanfilippo Syndrome. Prenatal diagnosis is now possible for this disorder.

Investigational Therapies

Preliminary clinical trials designed to gauge the safety and efficacy of enzyme replacement therapy, bone marrow transplantation and gene therapy in the treatment of MPS Disorders have had discouraging results. Early efforts to use gene therapy as a treatment for MPS-III were unsuccessful. Experimental studies, e.g. stem cell transplantation and others, are continuing on MPS Disorders other than MPS-III. If these trials are successful, the principles learned may be applied to MPS-III.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Clarke JTR. The Mucopolysaccharide Storage (MPS) Diseases. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:474-79.



Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2407-09.



Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1610.



Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3421-41.



Rowland LP. Ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:524-26.



Lyon G, Adams RD, Kolodny EH. Eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. McGraw-Hill Companies. New York, NY; 1996:151-61.



REVIEW ARTICLE

Yogalingham G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis typeIIIa and IIIB: Diagnostic, clinical, and biological implications. Human Mutat. 2001;18:264-81.



JOURNAL ARTICLES

Beesley CE, Burke D, Jackson M, et al. Sanfilippo syndrome type D: ientification of the first mutation in the N-acetylglucosamine-6-sulphatase gene. J Med Genet. 2003;40:192-94.



Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): a survey of managing clinicians. Clin Genet. 2002;62:418-21.



Tanaka A, Kimura M, Lan HT, et al. Molecular analysis of the alpha-N-acetylglucosaminidase gene in seven Japanese from six unrelated families with mucopolysaccharidosis IIIB (Sanfilippo type B), including two novel mutations. J Hum Genet. 2002;47:484-87.



Barone R, Fiumara A, Villani GR, et al. Extraneurologic symptoms as presenting signs of Sanfilippo disease. Pediatr Neurol. 2001;25:254-57.



Perkins KJ, Muller V, Weber B, et al. Prediction of Sanfilippo phenotype severity from immunoquantification of heparan-N-sulfamidase in cultured fibroblasts from mucopolysaccharidosis type IIIA patients. Mol Genet Metab. 2001;73.



Tylki-Szymanska A, Czartoryska B, Gorska D, et al. Type III D mucopoly-saccharidosis (Sanfilippo D): clinical course and symptoms. Acta Paediatr Jpn. 1998. 40:492-94.



FROM THE INTERNET

McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIA. Entry Number; 252900: Last Edit Date; 2/25/2002.



McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIB. Entry Number; 252920: Last Edit Date; 10/17/2003.



McKusick VA, Ed. Online Mendelian Inheritance in Man(OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIC. Entry Number; 252930: Last Edit Date; 3/28/2001.



McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIID. Entry Number; 252940: Last Edit Date; 4/28/2003.



MEDLINEplus. Sanfilippo Syndrome. Update Date: 8/6/2003. 3pp.

www.nlm.nih.gov/medlineplus/ency/article/001210.htm



Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes. Muco-polysaccharidosis (MPS) III (A, B, C, D). nd. 5pp.

www.nlm.nih.gov/cgi/jablonski/syndrome_cgi?index=465



NINDS Mucopolysaccharidoses Information Page. Reviewed 12-14-2001. 3pp.

www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm



NashD, Varma S. Mucopolysaccharidosis Type III. Emedicine. Last Updated: June 19, 2003. 7pp.

www.emedicine.com/ped/topic2040.htm



MPS III. The National MPS Society, Inc. nd. 3pp.

www.mpssociety.org/mps3.html



Aufox SA. Mucopolysaccharidoses. HealthAtoZ. Encyclopedia Index M. Gale Encyclopedia of Medicine. December, 2002. 7pp.

www.healthatoz.com/healthatoz/Atoz/ency/mucopolysaccharidoses.html



Characteristics of MPS III. MPS Australia. nd. 2pp.

www.mpssociety.org.au/characteriii.htm



MPS III. Gpnotebook. ©2003.

www.gpnotebook.co.uk



Sanfilippo Syndrome. AllRefer.com. ©2003.

www.health.allrefer.com/health/sanfilippo-syndrome-info.html

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



Vaincre Les Maladies Lysosomales

2 Ter Avenue

Massy, 91300

France

Tel: 0169754030

Fax: 0160111583

Email: accueil@vml-asso.org

Internet: http://www.vml-asso.org



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



National MPS Society, Inc.

PO Box 14686

Durham, NC 27709

Tel: (919)806-0101

Fax: (919)806-2055

Tel: (877)677-1001

Email: info@mpssociety.org

Internet: http://www.mpssociety.org



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



Society for Mucopolysaccharide Diseases

MPS House

Repton Place

White Lion Road

Amersham

Buckinghamshire, HP7 9LP

United Kingdom

Tel: 08453899901

Fax: 08453899902

Email: mps@mpssociety.co.uk

Internet: http://www.mpssociety.co.uk



Canadian Society for Mucopolysaccharide and Related Diseases, Inc.

PO Box 30034

RPO Parkgate

North Vancouver

British Columbia, V7H 2Y8

Canada

Tel: 6049245130

Fax: 6049245131

Tel: 8006671846

Email: info@mpssociety.ca

Internet: http://www.mpssociety.ca



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



Sanfilippo Foundation Switzerland

C/o NAT Services SA

Rue de Jargonnant 2

Genève, 1207

Switzerland

Tel: 41787207317

Email: info@fondation-sanfilippo.ch

Internet: http://www.sanfilippo-foundation.org



Jonahs Just Begun - Foundation to Cure Sanfilippo, Inc.

P. O. Box 150057

Brooklyn, NY 11215

Tel: (347)689-2186

Fax: (347)710-3136

Email: jw.mps3c@yahoo.com

Internet: http://jonahsjustbegun.org/



For a Complete Report

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