NORD gratefully acknowledges Deborah Marsden, MD, Metabolism Program, Boston Children's Hospital, for assistance in the preparation of this report.
The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits.
Individuals with MPS disorders share many similar symptoms such as multiple organ involvement, distinctive “coarse” facial features, and abnormalities of the skeleton especially joint problems. Additional findings include short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities. The severity of the different MPS disorders varies greatly among affected individuals, even among those with the same type of MPS and even among individuals of the same family.
In most cases of MPS, affected infants appear normal at birth and symptoms become apparent around the age of one or two, however, in MPS VII, approximately 40% of pregnancies with an affected baby are complicated by a condition called non-immune hydrops fetalis that may be detected on routine ultrasound examination. Initial symptoms may include frequent colds, runny nose, infections, growth delays, or mild developmental delays. Mild forms of these disorders may not become apparent until childhood or adolescence. In most cases, the mucopolysaccharidoses are chronic, progressive disorders and, depending upon the type of MPS and severity, affected individuals may experience a decline in physical and mental function, sometimes resulting in life-threatening complications.
There are different types of mucopolysaccharides that are not broken down due to enzyme malfunction or deficiency. Specifically, the mucopolysaccharides known as dermatan sulfate, heparan sulfate, or keratan sulfate may be involved alone or in some combination.
Hurler syndrome (mucopolysaccharidosis type 1-H; MPS 1-H) is the most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme alpha-L-iduronidase, which results in an accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at six months to two years of age. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at about the age of two.
Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the mildest form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. However, in Scheie syndrome the deficiency is specific for accumulation of dermatan sulfate. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and clouding of the cornea that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five.
Hurler-Scheie syndrome (mucopolysaccharidosis type I-H/S; MPS-IH/S) is an extremely rare disorder that refers to individuals who have a less severe form of Hurler syndrome, but a more severe form than Scheie syndrome. Like Scheie syndrome, affected individuals have a deficiency of the alpha-L-iduronidase specific for accumulation of dermatan sulfate. Hurler-Scheie syndrome is not as severe as Hurler syndrome, but more severe than Scheie syndrome. Affected individuals may develop coarse facial features, joint stiffness, short stature, clouding of the corneas, abnormally enlarged liver and/spleen (hepatosplenomegaly), and skeletal and cardiac abnormalities. Intelligence may be normal or mild to moderate intellectual disability may develop. Symptoms usually become apparent between three and six years of age.
Hunter syndrome (mucopolysaccharidosis type II; MPS II) is the only type of MPS disorder inherited as an X-linked trait. Initial symptoms and findings associated with Hunter syndrome usually become apparent between ages two to four years. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Accumulation of heparin sulfate may occur. Two relatively distinct clinical forms of Hunter syndrome have been recognized. In the mild form of the disease (MPS IIB), intelligence may be normal or only slightly impaired. However, in the more severe form (MPS IIA), profound intellectual disability may become apparent by late childhood. In addition, slower disease progression tends to occur in those with the mild form of the disorder.
Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) has four subtypes (A, B, C, and D) that are distinguished by four different enzyme deficiencies. Initial symptoms of the four types of Sanfilippo syndrome include hyperactivity, sleep disorders, and delays in attaining developmental milestones (e.g., crawling and walking). All forms of Sanfilippo syndrome are characterized by varying degrees of intellectual disability, progressive loss of previously acquired skills (e.g., language), and hearing loss. Affected individuals may experience seizures, unsteady gait, and aggressive behavior. Affected individuals may eventually lose the ability to walk. Accumulation of heparan sulfate may occur.
Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively, resulting in accumulation of keratan and chondroitin sulfate in type A and keratan sulfate in type B. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with Morquio syndrome have normal intelligence. The clinical features of MPS IV-B are usually fewer and milder than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). In some cases, hearing loss, weakness of the legs, and/or additional abnormalities also occurs.
Mucopolysaccharidosis type V is the former designation for Scheie syndrome. However when it was discovered that both Hurler and Scheie syndromes occur due to a deficiency of the same enzyme, Scheie syndrome was reclassified as a subtype of mucopolysaccharidosis type I.
Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is characterized by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, resulting in accumulation of dermatan sulfate. This form of MPS varies greatly among affected individuals. Some affected individuals only experience a few mild symptoms, other develop a more severe form of the disorder. Possible symptoms of Maroteaux-Lamy syndrome include coarse facial features, umbilical hernia, a prominent breast bone (pectus carinatum), joint contractures, clouding of the corneas, and an abnormal enlargement of the liver and/or spleen (heptasplenomegaly). Skeletal malformations and heart disease may occur in individuals with this form of MPS. In most cases, intelligence is normal.
Sly syndrome (mucopolysaccharidosis type VII; MPS VII) is characterized by a deficiency of the enzyme beta-glucuronidase, resulting in the accumulation of three glycosaminoglycans: dermatan sulfate, heparan sulfate and chondroitin sulfate. The symptoms may vary greatly from person to person. Individuals may have normal intelligence or mild to severe intellectual disability. Some skeletal abnormalities are often present. Hernias, clouding of the corneas, excessive accumulation of cerebrospinal fluid in the skull (hydrocephalus), short stature, heart disease, and coarse facial features have also been reported. In rare cases, some newborn infants with Sly syndrome may experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis). MPS VII is currently in clinical trial.
DiFerrante syndrome (mucopolysaccharidosis VIII; MPS VIII) is an obsolete term for a form of MPS described in a single individual with clinical and biochemical features of Morquio and Sanfilippo syndromes. The disorder had been reported to be due to a deficiency of glucosamine-6-sulfate sulfatase. Subsequently, this disorder was called MPS VIII (DiFerrante syndrome). Dr. DiFerrante later found that the enzyme was normal in his patient, and the disorder had been misdiagnosed. Therefore, DiFerrante syndrome is not a valid medical disorder.
Hyaluronidase deficiency (mucopolysaccharidosis IX; MPS IX) is an extremely rare form of MPS characterized by a deficiency of the enzyme hyaluronidase, which is needed to breakdown the mucopolysaccharides known as hyaluronan (hyaluronic acid). This form of MPS was first described in 1996. Symptoms may include mild short stature, cysts, frequent ear infections, cleft palate, and the development of soft-tissue masses. However, more cases of this form of MPS must be identified before a clear clinical picture can be established.
All of the MPS disorders result from deficiency or malfunction of a specific lysosomal enzyme necessary in the breaking down of dermatan sulfate, heparan sulfate, or keratan sulfate, either alone or together. Failure to breakdown these mucopolysaccharides results in their accumulation in cells, tissues and organs throughout the body. All of these disorders are inherited as autosomal recessive traits except for Hunter syndrome, which is an X-linked recessive trait.
Genetic diseases are determined by abnormal changes in the gene for enzyme for each disorder, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits an 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 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%.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. A Female who has an abnormal gene present on one of her X chromosomes is a carrier for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.
The prevalence of all forms of mucopolysaccharidosis is estimated to be one in 25,000 births. However, because mucopolysaccharidoses, especially the milder forms of the diseases, often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.
Estimates for the specific types of mucopolysaccharidosis range from: one in 100,000 for Hurler syndrome; one in 500,000 for Scheie syndrome; one in 115,000 for Hurler-Scheie syndrome; one in 70,000 for Sanfilippo syndrome; one in 200,000 for Morquio syndrome; and fewer than one in 250,000 in Sly syndrome. Hunter syndrome occurs predominantly in males. In extremely rare cases, affected females have been reported. The incidence of Hunter syndrome is estimated at one in 100,000-150,000 male births.
More than 40 distinct lysosomal storage diseases have been identified.
A diagnosis of a mucopolysaccharidosis disorder is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., coarse facial features, skeletal malformations, hepatosplenomegaly), and a variety of specialized tests including urine analysis to detect excessive levels of mucopolysaccharides. Tests known as enzyme assays may be performed to detect deficient levels of lysosomal enzymes in cells of the body.
Newborn screening for MPS I has recently been approved for inclusion in the Recommended Universal Screening Panel, although each state decides independently when or if, it will be added to its newborn screening panel MPS II is currently being screened in Illinois. After an abnormal newborn screening result, it would be necessary to follow up with a definitive diagnosis by enzyme assay.
Prenatal diagnosis is possible through the use of amniocentesis and chorionic villus sampling. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During CVS, tissue samples are removed from a portion of the placenta and DNA studies may be performed, primarily in families with a previously affected child, and the abnormal gene mutations are known.
In 2005, The U.S. Food and Drug Administration (FDA) approved galsulfase (Naglazyme) for the treatment of MPS VI, also known as Maroteaux-Lamy syndrome. Naglazyme, an orphan drug, is a product of BioMarin Pharmaceutical Inc.
In 2003, The FDA approved laronidase (Aldurazyme) as a treatment for MPS I Specifically, this enzyme replacement therapy is approved for treating patients with the Hurler and Hurler-Scheie forms of MPS I and those with the Scheie form who exhibit moderate to severe symptoms. Aldurazyme is manufactured by BioMarin Pharmaceutical Inc. and distributed by Sanofi-Genzyme. It is the first treatment approved specifically for MPS I.
The FDA approved idursulfase (Elaprase) for MPS II (July 2006), galsidase (Naglazyme) for MPS VI (May 2005) and elosufase alfa (Vimizin) for MPS IVA (February 2014). Elaprase is manufactured by Shire Pharmaceuticals, and Naglazyme and Vimizin by BioMarin Pharmaceutical Inc.
Otherwise, treatment for the various forms of mucopolysaccharidosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat skeletal problems (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Surgery may be used to treat a variety of symptoms associated with mucopolysaccharidosis, including carpal tunnel syndrome, skeletal malformations, and hernias. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Heart valve replacement may be necessary in some cases.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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:
Toll-free: (800) 411-1222
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Email: [email protected]ih.gov
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Since prenatal diagnosis is possible through the use of amniocentesis and tissue sampling of the embryo, new diagnostic interventions are being developed. Experimental treatments that scientists are trying to develop include replacing defective enzymes via enzyme replacement therapy and/or bone marrow transplants. Scientific study of gene replacement in animal models raises the hope that gene replacement therapy may someday be made available to people with serious genetic disorders.
Bone marrow transplantation as a way to replace defective enzymes has been studied as a treatment for individuals with mucopolysaccharidosis. The effectiveness of BMT has varied greatly. Physical characteristics may improve, such as cloudy corneas may become clear, the size of an abnormally enlarged liver and spleen may decrease, and mucopolysaccharide levels may drop. Skeletal malformations are unaffected, however. The effect on neurological symptoms varies considerably. Because BMT is a procedure that carries significant risks, it should only be considered in selected cases.
Enzyme replacement therapy for MPS III (A), San Filippo syndrome type A and for MPS IV (Morquio syndrome) is currently under investigation.
Gene therapy is under study as a possible treatment for mucopolysaccharidosis. More studies are needed to determine the safety and effectiveness of gene therapy as a possible treatment for Hurler syndrome and other mucopolysaccharidoses.
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