Mucopolysaccharidoses



Definition

Mucopolysaccharidosis (MPS) is a general term for many different related inherited disorders that are caused by the accumulation of mucopolysaccharides in body tissues. This accumulation interferes with the individual's development.

Description

Mucopolysaccharides are long chains of sugar molecules that are essential for building the bones, cartilage, skin, tendons, and other tissues in the body. Another name for mucopolysaccharides is glycosaminoglycans (GAGs). Normally, the human body continuously breaks down and rebuilds cells that contain GAGs. There are many different types of GAGs, and different GAGs are unable to be broken down in each of the MPS conditions. Several enzymes are involved in breaking down each GAG, and a deficiency or absence of any of the essential enzymes can cause the GAG not to be broken down completely. This condition results in the accumulation of GAGs in the tissues and organs in the body. The accumulating GAGs are stored in cellular structures called lysosomes, and these disorders are known as lysosomal storage diseases. When too many GAGs accumulate, organs and tissues become damaged or do not function properly.

Before specific deficient enzymes were identified, MPS disorders were diagnosed by the signs and symptoms seen in an individual. The discovery of individual enzyme deficits resulted in a reclassification of some of the MPS disorders. Types of MPS disorders are MPS I, MPS II, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX. However, these conditions are also referred to by their original names, which are Hurler, Hurler-Scheie, Scheie (all MPS I), Hunter (MPS II), Sanfilippo (all MPS III), Morquio (all MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX).

Demographics

MPS disorders are rare, and the frequency with which they occur varies depending on the type of the disorder. For all MPS types combined, the disorder occurs in only about one of every 25,000 people. Except for MPS II, individuals of both genders are affected equally. Because of its inheritance pattern, MPS II is found only in males. All MPS disorders are present at birth, although symptoms appear at different times, depending on the type of disorder. There appears to be no race or ethnic component in the distribution of MPS disorders.

Causes and symptoms

All MPS disorder except MPS II are inherited in an autosomal recessive manner. An individual with an autosomal recessive disorder inherits one non-working genes from each parent. The parents are called carriers of the disorder. If the parent has one good copy of the gene and one defective copy, the parent will not have MPS and may be unaware that he or she has a defective gene. MPS only occurs when both of an individual's genes that produce the same enzyme contain a mutation or defect, causing them not to function properly. As a result, either no enzyme is produced, or the amount produced is inadequate. When two people are carriers for an autosomal recessive disorder, they have a 25 percent chance with each pregnancy to have a child with the disorder. Some individuals who have MPS are able to have children. Children of MPS parents are all carriers of the disorder, because they inherit one bad copy of the gene from the affected parent. However, these children are not at risk to develop the disorder unless the other parent is a carrier or affected with the same autosomal recessive condition.

Unlike the other MPS conditions, MPS II is inherited in an X-linked recessive manner, which means that the gene causing the condition is located on the X chromosome, one of the two sex chromosomes. A male child inherits an X chromosome from his mother and a Y chromosome from his father. He will have the disorder if the X chromosome inherited from his mother carries the defective gene, since he has only one (nonfunctioning) copy of the gene. Females inherit one X chromosome from their mother and a second X chromosome from their father. Because they have two X chromosomes, they are carriers of the disorder if one of their X chromosomes has the gene that causes the condition, while the other X chromosome does not.

Although MPS are all inherited disorders, each type is caused by a deficiency of one particular enzyme involved in breaking down GAGs. The accumulation of the GAGs in the tissues and organs in the body causes the symptoms characteristic of the MPS disorders. Symptoms and their time of onset vary widely depending on which form of the disorder the individual inherits.

MPS I

MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase. Three conditions, Hurler, Hurler-Scheie, and Scheie syndromes, are caused by a deficiency of this enzyme. Initially, these three conditions were believed to be separate, because each was associated with different physical symptoms and prognoses. However, once the underlying cause of these conditions was identified, it was realized that these three conditions are variants of the same disorder.

MPS I H (Hurler syndrome)

About one child in 100,000 is born with Hurler syndrome. This tends to be the most severe form of MPS I. Symptoms of Hurler syndrome are often evident within the first year or two after birth. Often these infants initially grow faster than expected, but then reach a point where they begin to lose the skills that they have learned. Their growth slows and typically stops by age three.

Facial features begin to coarsen. These children develop a short nose, flatter face, thicker skin, and a protruding tongue. Their heads become larger, and they develop more hair on their bodies, with the hair becoming coarser. Their bones are also affected, and they usually develop joint contractures (stiff joints), kyphosis (a specific type of curve to the spine), and broad hands with short fingers. Many of these children have breathing difficulties, and respiratory infections are common. Other common problems include heart valve dysfunction, thickening of the heart muscle (cardiomyopathy), enlarged spleen and liver, clouding of the cornea, hearing loss, and carpal tunnel syndrome. These children typically do not live past age 12.

MPS I H/S (Hurler-Scheie syndrome)

Hurler-Scheie syndrome an intermediate form of MPS I, meaning that the symptoms are not as severe as those in individuals who have MPS I H but not as mild as those in MPS I S. Approximately one baby in 115,000 is born with Hurler-Scheie syndrome. These individuals tend to be shorter than expected. They can have normal intelligence ; however, some individuals with MPS I H/S experience learning difficulties. These individuals may develop some of the same physical features as those with Hurler syndrome, but usually they are not as severe. The prognosis for children with MPS I H/S is variable with some individuals dying during childhood, while others live to adulthood.

MPS I S (Scheie syndrome)

Scheie syndrome is the mild form of MPS I. About one baby in 500,000 is born with Scheie syndrome. Individuals with MPS I S usually have normal intelligence, although there have been some reports of individuals with MPS I S developing psychiatric problems. Common physical problems include corneal clouding, heart abnormalities, and orthopedic difficulties involving their hands and back. Individuals with MPS I S do not develop the facial features seen with MPS I H and usually these individuals have a normal life span.

MPS II (Hunter syndrome)

Hunter syndrome is caused by a deficiency of the enzyme iduronate-2-sulphatase. All individuals with Hunter syndrome are male, because the gene that causes the condition is located on their single X chromosome. Like many MPS conditions, Hunter syndrome is divided into two forms, mild and severe. About one in 110,000 males are born with Hunter syndrome, with the severe form being three times more common than the mild form.

The severe form of MPS II is associated with progressive mental retardation and physical disability, with most individuals dying before age 15. In the milder form, most of these individuals live to adulthood and have normal intelligence or only mild mental impairments. Males with the mild form of Hunter syndrome develop physical differences similar to the males with the severe form, but not as quickly. Males with mild Hunter syndrome can have a normal life span and some have had children. Most males with Hunter syndrome develop joint stiffness, chronic diarrhea , enlarged liver and spleen, heart valve problems, hearing loss, and kyphosis. They also tend to be shorter than expected. These symptoms progress at different rates depending on whether the individual has the mild or severe form of MPS II.

MPS III (Sanfilippo syndrome)

MPS III, like the other MPS conditions, was initially diagnosed by the individual having certain physical signs and symptoms. It was later discovered that the physical symptoms associated with Sanfilippo syndrome could be caused by a deficiency in one of four enzymes. MPS III is in the early 2000s subdivided into four groups, labeled A through D, based on the specific enzyme that is deficient. All four of these enzymes are involved in breaking down the same GAG, heparan sulfate. Heparan sulfate is mainly found in the central nervous system and accumulates in the brain when it cannot be broken down because one of those four enzymes is deficient or missing.

MPS III is a variable condition, with symptoms beginning to appear between two and six years of age. Because of the accumulation of heparan sulfate in the central nervous system (CNS), the CNS is severely affected. In MPS III, signs that the CNS is degenerating usually become evident between six and ten years of age. Many children with MPS III develop seizures, sleeplessness, thicker skin, joint contractures, enlarged tongues, cardiomyopathy, behavior problems, and mental retardation. The life expectancy in MPS III is also variable. On average, individuals with MPS III live until they are teenagers, with some living longer and others not that long.

MPS IIIA (Sanfilippo syndrome type A) is caused by a deficiency of the enzyme heparan N-sulfatase. Type IIIA is the most severe of the four types of MPS III. Symptoms appear and death occurs at an earlier age than in other subtypes. A study in British Columbia estimated that one in every 325,000 babies is born with MPS IIIA. MPS IIIA is the most common of the four types in Northwestern Europe. The gene that causes MPS IIIA is located on the long arm of chromosome 17.

MPS IIIB( Sanfilippo syndrome type B) is due to a deficiency in N-acetyl-alpha-D-glucosaminidase (NAG). This type of MPS III is not as severe as type IIIA, and the characteristic signs and symptoms vary. Type IIIB is the most common of the type III disorders in southeastern Europe. The gene associated with MPS IIIB is also located on the long arm of chromosome 17.

MPS IIIC (Sanfilippo syndrome type C) is caused by a deficiency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase. This is a rare form of MPS III. The gene involved in MPS IIIC is believed to be located on chromosome 14.

MPS IIID (Sanfilippo syndrome type D) is caused by a deficiency in the enzyme N-acetylglucosamine-6-sulfatase. This form of MPS III is also rare. The gene involved in MPS IIID is located on the long arm of chromosome 12.

MPS IV A (Morquio syndrome type A)

MPS IV A is the severe form of the disorder and is caused by a deficiency in the enzyme galactosamine-6-sulphatase. The gene involved with MPS IV A is located on the long arm of chromosome 16. The major organs affected by MPS IV are the cornea and the cartilage, particularly the cartilage of the neck. Bowel and bladder function also can be impaired. Respiratory problems and sleep apnea are common. Individuals with MPS IV appear healthy at birth but show skeletal deformities and growth retardation by age three. Death often occurs early in individuals with the severe form of this disorder.

MPS IV B (Morquio syndrome type B) is the milder form of the disorder. The enzyme, beta-galactosidase, is deficient in MPS IV B. The gene that produces beta-galactosidase is located on the short arm of chromosome 3. Individuals with the MPS IV B can have normal lifespans (into their 70s).

MPS VI (Maroteaux-Lamy syndrome)

MPS VI, which is another rare form of MPS, is caused by a deficiency of the enzyme N-acetylglucosamine-4-sulphatase. This condition is also variable; individuals may have a mild or severe form of the disorder. Typically, the nervous system or intelligence of an individual with MPS VI is not affected. Individuals with a more severe form of MPS VI can have airway obstruction, develop hydrocephalus (accumulation of fluid in the brain), and exhibit bone changes. Individuals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the disorder, individuals tend to be shorter than expected for their age, develop corneal clouding, and live longer. The gene involved in MPS VI is believed to be located on the long arm of chromosome 5.

MPS VII (Sly syndrome)

MPS VII is an extremely rare form of MPS and is caused by a deficiency of the enzyme beta-glucuronidase. It is also highly variable, but symptoms are generally similar to those seen in individuals with Hurler syndrome. The gene that causes MPS VII is located on the long arm of chromosome 7.

MPS IX (Hyaluronidase deficiency)

MPS IX, a condition first described in 1996, is caused by a deficiency of the enzyme hyaluronidase. In the few individuals described with this condition, the symptoms are variable. Some individuals develop soft tissue masses (growths) under the skin. Also, these individuals are shorter than expected for their age. The gene involved in MPS IX is believed to be located on the short arm of chromosome 3.

When to call the doctor

Parents should inform the doctor immediately if MPS runs in their family , so that early testing can be done on their children. In addition, any time they have questions about their child's growth and development, they should talk to their pediatrician.

Diagnosis

While a diagnosis for each type of MPS can be made based on the physical signs described above, several of the conditions have similar features. Therefore, enzyme analysis is used to determine the specific MPS disorder. Enzyme analysis often cannot accurately determine if an individual is a carrier for an MPS disorder, because the enzyme levels in individuals who are not carriers overlaps the enzyme levels seen in those individuals who are carrier for MPS. With many of the MPS conditions, several mutations have been found in each gene involved that can cause symptoms of each condition. If the specific mutation is known in a family, DNA analysis may be possible.

Once a couple has had a child with MPS, prenatal testing is available to them to help determine if another fetus is affected with the same MPS as their previous other child. This can be accomplished using procedures such as an amniocentesis or chorionic villus sampling (CVS), after which parents can explore their options relating to the pregnancy.

Treatment

As of 2004 there was no cure for MPS, although several types of experimental therapies are being investigated in the early 2000s. Typically, treatment involves trying to relieve the symptoms and improve quality of life. For MPS I and VI, bone marrow transplantation has been attempted as a treatment option. For those types of MPS, bone marrow transplantation has sometimes helped slow down the progression or reverse some of symptoms of the disorder in some children. The benefits of bone marrow transplantation are more likely to be noticed when performed on children less than two years of age. However, bone marrow transplantation is not thought to be helpful in other MPS disorders. Availability of donors is limited, and as a result, very few bone marrow transplantations are done for MPS. There are risks as well as benefits with this procedure, and mortality resulting from the procedure is high.

Another experimental treatment for MPS I involves extended treatment with recombinant human alpha-L-iduronidase. Some individuals treated with this technique show an improvement in some symptoms. Additionally, there is ongoing research involving gene replacement therapy (the insertion of normal copies of a gene into the cells of patients whose gene copies are defective), although this was as of 2004 still highly experimental.

Prognosis

The course of this disorder varies with the specific type of MPS the individual has. MPS I H is often fatal in childhood, with individuals rarely living past age 12. Individuals with MPS I H/S may die in childhood or live to adulthood. Individuals with MPS I H have health problems but usually have a normal lifespan. Individuals with mild MPS II live relatively normal lives, while individuals with the severe form of the disorder usually die in their teens. The life expectancy in MPS III and MPS IV is also variable, depending on the severity of the disorder. Individuals with MPS VI often have shorter than average life spans. As of 2004 MPS IX had been diagnosed so recently that little information is available.

Prevention

No specific measures can prevent the gene mutations that cause MPS. For some of the MPS diseases, biochemical tests may be able to identify healthy individuals who are carriers of the defective gene, allowing them to make informed reproductive decisions. Prenatal testing can also diagnose MPS in the fetus, but this testing is normally done only when there is some reason to expect to find the disorder (e.g. family history of the disease).

Parental concerns

Many individuals with an MPS condition have problems with airway constriction. This constriction may be so serious as to create significant difficulties in administering general anesthesia. Therefore, it is recommended that surgical procedures be performed under local anesthesia whenever possible.

KEY TERMS

Cardiomyopathy —A disease of the heart muscle.

Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.

Joint contractures —Stiffness of the joints that prevents full extension.

Kyphosis —An extreme, abnormal outward curvature of the spine, with a hump at the upper back.

Lysosome —A membrane-enclosed compartment in cells, containing many hydrolytic enzymes, where large molecules and cellular components are broken down.

Mucopolysaccharide —A complex molecule made of smaller sugar molecules strung together to form a chain. It is found in mucous secretions and intercellular spaces.

Recessive gene —A type of gene that is not expressed as a trait unless inherited by both parents.

X-linked gene —A gene carried on the X chromosome, one of the two sex chromosomes.

Resources

PERIODICALS

Kakkis, E. D., et al. "Enzyme-Replacement Therapy in Mucopolysaccharidosis I." The New England Journal of Medicine 344 (2001): 182–8.

ORGANIZATIONS

National MPS Society. PO Box 736, Bangor, ME 04402–0736. Web site: http://www.mpsspciety.org.

National Organization for Rare Disorders Inc. 55 Kenosia Ave, PO Box 1968, Danbury, CT 06813–1968. Web site: http://www.rarediseases.org.

WEB SITES

Braverman, Nancy, and Julie Hoover-Fong. "Mucopolysaccharidosis Type IV." eMedicine.com , March 28, 2003. Available online at http://www.emedicine.com/ped/topic1477.htm (accessed January 13, 2005).

McGovern, Margaret. "Mucopolysaccharidosis Type VI." eMedicine.com October 15, 2003. Available online at http://www.emedicine.com/ped/topic1373.htm (accessed January 13, 2005).

Nash, Donald, and Surendra Vama. "Mucopolysaccharidosis Type I H/S." eMedicine.com , June 19, 2003. Available online at http://www.emedicine.com/ped/topic1032.htm (accessed January 13, 2005).

"NINDS Mucopolysaccharidoses Information Page." National Institute of Neurological Disorders and Stroke , December 4, 2004. Available online at http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm (accessed January 13, 2005).

Tish Davidson, A.M. Sharon A. Aufox, MS, CGC



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