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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.
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.
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.
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.
There are six recognized mucopolysaccharidoses (MPS) each of which is an inborn error of metabolism caused by a deficiency of a specific enzyme s in the lysosome that is essential for the normal degradation of mucopolysaccharides. Without these enzymes mucopolysaccharides accumulate in the cells causing progressive mental and physical deterioration.
MPS-I includes Hurler, Scheie, and Hurler/Scheie syndromes. Each presents during infancy and Hurler syndrome bears with it the more severe set of problems; Scheie presents with the least severe set of symptoms; and Hurler/Scheie presents with symptoms intermediate between the others. Infants with MPS-I usually have clouded corneas and impaired vision, and progressive mental and physical deterioration. Life span is usually under 10 years.
MPS-II (Hunter syndrome) has severe and mild variants and affects juveniles rather than infants. Those with the severe form have short stature (dwarfism), progressive deafness, and mental declines. Patients with the milder form may be shorter than normal but may be taller than those with the severe form. Physical and mental deterioration are less severe and characteristic facial features, such as enlarged forehead lips and tongue may be present. Life span may be normal.
MPS-IV (Morquio syndrome) starts in infancy and symptoms may include severe dwarfing and clouding of the cornea. Intelligence is normal and lifespan may extend into the 30's or 40's.
MPS-VI (Maroteaux-Lamy syndrome) begins in infancy and resembles Hurler syndrome in that intelligence and vision may be impaired. Patients may live into the 20's or 30's.
MPS-VII (Sly disease) presents with impaired vision (corneal clouding) skeletal abnormalities, enlarged liver and spleen (hepatosplenomegaly). Intellectual development varies among those affected.
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 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.
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
For information about clinical trials sponsored by private sources, contact:
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Barone R, Fiumara A, Villani GR, et al. Extraneurologic symptoms as presenting signs of Sanfilippo disease. Pediatr Neurol. 2001;25:254-57.
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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.
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NINDS Mucopolysaccharidoses Information Page. Reviewed 12-14-2001. 3pp.
NashD, Varma S. Mucopolysaccharidosis Type III. Emedicine. Last Updated: June 19, 2003. 7pp.
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Report last updated: 2007/08/17 00:00:00 GMT+0