Mucopolysaccharidoses

Definition

The mucopolysaccharidoses (MPS) are a number of metabolic disorders that follow a chronic and progressive course and involve many body systems.

Description

Though the symptoms and severity vary for each MPS disorder, common features include enlarged organs (organomegaly), dysostosis multiplex (abnormal bone formation), and a characteristic facial appearance. Hearing, vision, breathing, heart function, joint mobility, and mental capacity may also be affected. As of 2003, seven types of MPS have been classified. The MPS disorders are caused by absent or insufficient production of proteins known as lysosomal enzymes The specific enzyme that is deficient or absent distinguishes one type of MPS from another. However, before these enzymes were identified, the signs and symptoms expressed by an affected individual led to the diagnosis. The discovery of these enzymes resulted in a reclassification of some of the MPS disorders. These conditions are often referred to as MPS I, MPS II, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX and may also referred to by their original names, which are Hurler (MPS I H), Hurler-Scheie (MPS I H/S), Scheie (MPS I S), Hunter (MPS II), Sanfilippo (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX).

Demographics

The MPS syndromes are considered to be rare. Sanfilippo syndrome appears to be the most common MPS with a reported incidence of one in 70,000. The incidence of Hyaluronidase deficiency is not yet known. The incidence of the remaining six classes of MPS are estimated to be: one in 100,000 for Hurler syndrome; one in 500,000 for Scheie syndrome; one in 115,000 for Hurler/Scheie disease; one in 100,000 (male live births) for Hunter syndrome (mild and severe combined); one in 100,000 to one in 300,000 for Morquio syndrome (types A and B included); one in 215,000 for Maroteaux-Lamy syndrome; and less than one in 250,000 for Sly syndrome. These figures are general; more exact figures have been reported for individual MPS disorders in certain countries.

Causes and symptoms

All of the MPS are genetic conditions. MPS I, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX are inherited in an autosomal recessive manner which means that affected individuals have two altered or non-functioning genes, one from each parent, for a specific enzyme that is needed to break down mucopolysaccharides. MPS II (Hunter syndrome) is inherited in an X-linked manner which means that the gene for MPS II is located on the X chromosome, one of the two sex chromosomes. Hunter syndrome primarily affects males because they have only one X chromosome and therefore lack a second, normal copy of the gene responsible for the condition. Carriers for

the autosomal recessive forms of MPS have one normal copy and one non-working copy of the MPS gene in question. Female carriers of the X-linked MPS (MPS II) have one X chromosome with a normal gene for the condition (the IDS gene) and one X chromosome with a non-working IDS gene.

The enzymes that are deficient in the MPS disorders normally break down a type of mucopolysaccharide (a long chain of sugar molecules) in the body known as glycosaminoglycans (GAGs). Glycosaminoglycans are essential for building the bones, cartilage, skin, tendons, and other tissues in the body. Normally, the human body continuously breaks down and builds GAGs. There are several enzymes involved in breaking down each GAG and a deficiency or absence of any of the essential enzymes can cause one or more GAGs to accumulate in the tissues and organs in the body. When too much GAG is stored, organs and tissues can be damaged or not function properly. The accumulating material is stored in cellular structures called lysosomes, and these disorders are also known as lysosomal storage diseases.

MPS I

Mutations in the alpha-L-iduronidase (IDUA) gene located on chromosome 4 cause the MPS I disorders (Hurler, Hurler-Scheie, and Scheie syndromes). Initially, these three disorders 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 recognized that all three were variants of the same disorder.

MPS I H (HURLER SYNDROME) Individuals with Hurler syndrome tend to have the most severe form of MPS I. Hurler syndrome may also be referred to as severe MPS I. Infants with Hurler syndrome appear normal at birth and typically begin to develop normally. Symptoms of Hurler syndrome are often evident within the first year or two after birth. Many of these infants may initially grow faster than expected, but their growth slows and typically stops by age three. Facial features also begin to appear coarse; affected children develop a short nose, flatter face, thicker skin, and a protruding tongue. Additionally, their heads become larger and they develop more hair on their bodies with the hair becoming coarser. Affected children with Hurler syndrome lose previously attained skills (milestones) and eventually suffer from profound mental retardation . Progressive abnormal development of all bones of the body (dysostosis multiplex) occurs in all children with Hurler syndrome. Children usually develop joint contractures (stiff joints), kyphosis (a "hunchback" curve of the spine), and broad hands with short fingers. Many of these children experience breathing difficulties, and respiratory infections are common. Other common problems include heart valve dysfunction, cardiomyopathy (weakness of the heart muscle), hepatosplenomegaly (enlarged spleen and liver), clouding of the cornea, hearing loss, and carpal tunnel syndrome . Children with Hurler syndrome typically die within the first ten years of life.

MPS I H/S (HURLER-SCHEIE SYNDROME) Hurler-Scheie syndrome is felt to be the intermediate form of MPS I, meaning that the symptoms are not as severe as those in individuals who have Hurler syndrome but not as mild as those with Scheie syndrome. Hurler-Scheie syndrome may also be referred to as intermediate MPS I. Individuals with Hurler-Scheie syndrome tend to be shorter than expected and may develop some of the physical features seen in Hurler syndrome, but usually they are not as severe. Intellectual ability varies; individuals have normal or near normal intelligence. The prognosis for children with Hurler-Scheie syndrome is variable with some individuals dying during childhood and others living to adulthood.

MPS I S (SCHEIE SYNDROME) Scheie syndrome is considered the mild form of MPS I. Individuals with Scheie syndrome usually have normal intelligence, but there have been some reports of affected individuals developing psychiatric problems. Common physical problems include corneal clouding, heart abnormalities, and orthopedic difficulties involving the hands and back. Individuals with Scheie syndrome do not develop the facial features seen with severe MPS I. Usually life span is normal.

MPS II (Hunter syndrome)

Mutations in the iduronate-2-sulphatase (IDS) gene cause both forms of MPS II (mild and severe). Nearly all individuals with Hunter syndrome are male, because the gene that causes the condition is located on the X chromosome. The severe form is associated with progressive mental retardation and physical disability, with most individuals dying before age 15. Males with the mild form of Hunter syndrome usually have have normal or near normal intelligence. They tend to develop physical differences similar to males with the severe form, but not as quickly. Most males with Hunter syndrome develop joint stiffness, chronic diarrhea, enlarged liver and spleen, heart valve problems, hearing loss, kyphosis, and tend to be shorter than expected. Men with mild Hunter syndrome can have a normal life span and some have had children.

MPS III (Sanfilippo syndrome)

MPS III is a variable condition with symptoms beginning to appear between ages two and six years of age. The condition is characterized by developmental delay, behavioral problems, and mild physical problems (as compared to other types of MPS). Specific problems include: seizures , sleeplessness, thick skin, joint contractures, enlarged tongues, cardiomyopathy, hyperactivity, and mental retardation. The life expectancy in MPS III is also variable. On average, individuals with MPS III live until adolescence. Initially, the diagnosis of MPS III, like the other MPS conditions, was clinical; the diagnosis was made by observation of certain physical characteristics. It was later discovered that a deficiency in one of four enzymes could lead to the developmental delay and physical symptoms associated with MPS III. Each type of MPS III is now subdivided into four groups, labeled A-D, according to the specific enzyme deficiency. All four of these enzymes help to break down the same GAG, heparan sulfate.

MPS IIIA (SANFILIPPO SYNDROME TYPE A) MPS IIIA is caused by a deficiency of the enzyme heparan sulfate sulfamidase, due to mutations in the SGSH gene on chromosome 17. Type IIIA is felt to be the most severe of the four types, in which symptoms appear and death occurs at an earlier age.

MPS IIIB (SANFILIPPO SYNDROME TYPE B) MPS IIIB is due to a deficiency in N-acetyl-alpha-D-glucosaminidase due to mutations in the NAGLU gene, also located on chromosome 17. This type of MPS III is not felt to be as severe as Type IIIA and the characteristics vary. Type IIIB is the most common of the four types of MPS III in southeastern Europe.

MPS IIIC (SANFILIPPO SYNDROME TYPE C) A deficiency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase causes MPS IIIC. This is considered 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) MPS IIID is caused by a deficiency in the enzyme N-acetylglucosamine-6-sulfatase, due to mutations in the GNS gene located on chromosome 12. This form of MPS III is also rare.

MPS IV (Morquio syndrome)

Morquio syndrome is characterized by severe skeletal deformities and their secondary effects on the nervous system. Intelligence is usually normal. One of the earliest symptoms seen in this condition is a difference in the way the child walks. Skeletal abnormalities can be extreme and include dwarfism, kyphosis (outward-curved spine), prominent breastbone, flat feet, and genu-valgum (knock-knees). A bone deformity known as odontoid hypoplasia (improper formation of the bones that stabilize the head and neck) can result in compression of the spinal cord, a potentially serious and life-threatening complication. As with several of the MPS disorders, Morquio syndrome was originally diagnosed by the presence of particular signs and symptoms. However, it is now known that the deficiency of two different enzymes can result in MPS IV. These two types of MPS IV are called MPS IV A and MPS IV B. MPS IV is variable in its severity. MPS IV A is the classic (typical) or the severe form of the condition and is caused by a deficiency in the enzyme galactosamine-6-sulphatase. The gene involved with MPS IV A (GALNS) is located on chromosome 16. MPS IV B is considered the milder form of the condition. The enzyme, beta-galactosidase, is deficient in MPS IV B. The gene involved with MPS IV B (GLB1) is located on chromosome 3.

MPS VI (Maroteaux-Lamy syndrome)

MPS VI is caused by deficiency of the enzyme Nacetylglucosamine-4-sulphatase (arylsulfatase B), due to mutations in the ARSD gene located on chromosome 5. Affected individuals may have a mild or severe form of the condition. Typically, the nervous system and intelligence are not affected. Individuals with a more severe form of MPS VI can develop airway obstruction, hydrocephalus (extra fluid accumulating in the brain), and abnormal growth and formation of the bones. Additionally, individuals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the condition, individuals tend to be shorter than expected for their age, develop corneal clouding, and live longer.

MPS VII (Sly syndrome)

MPS VII, an extremely rare form of MPS, results from a deficiency of the enzyme beta-glucuronidase due to mutations in the GUSB gene on chromosome 7. MPS VII is also highly variable, but symptoms are generally similar to those seen in individuals with Hurler syndrome. In severe cases, infants may be born with hydrops fetalis.

MPS IX (Hyaluronidase deficiency)

MPS IX is a condition that was first described in 1996 and has been grouped with the other MPS conditions by some researchers. MPS IX is caused by the deficiency of the enzyme hyaluronidase due to mutations in the HYAL1 gene on chromosome 3. In the few individuals described with this condition, the symptoms are variable, but some develop soft-tissue masses (growths under the skin). Also, these individuals are shorter than expected for their age.

Diagnosis

Identification of symptoms is usually the first step in making an MPS diagnosis. Doctors will then use laboratory tests to establish an accurate diagnosis. They may first use a screening test that looks for glycosaminoglycans in the urine. The definitive diagnosis of an MPS is made using a biochemical test that measures the specific enzyme (known to be reduced or absent) in the individual's tissues or bodily fluids. Genetic testing may also be used to confirm a suspected diagnosis and, in some cases, to provide limited information about potential disease severity. Genetic testing is accomplished by looking for specific changes known as mutations in the gene responsible for the MPS disorder. Genetic testing is available for all of the MPS disorders except MPS IIIC, MPS IVB, and MPS IX. If the gene mutation(s) have been found in an affected individual, the same genetic test may be used for carrier screening in unaffected family members, such as adult siblings, and for prenatal diagnosis. If the DNA mutations are not found or if genetic testing is not available, carrier screening and prenatal diagnosis may be accomplished using biochemical methods. Preimplantation genetic diagnosis (PGD) is available on a research basis for MPS I and MPS II. More information on PGD for these types of MPS can be found by contacting the Reproductive Genetics Institute at (773) 472-4900 or at [email protected].

Treatment team

Treatment of MPS disorders requires a multidisciplinary approach. In addition to the patient's primary health care professionals, medical professionals involved in the care of patients with an MPS usually includes specialists in neurology, neurosurgery, ophthalmology (eyes), otolaryngology (ear-nose-throat), audiology (hearing), cardiology, pulmonology (lungs), anesthesiology, gastroenterology, nutrition, orthopedic surgery, rehabilitation (physical, occupational, and speech therapy) and genetics. Some patients with MPS may receive comprehensive services through a specialty clinic such as metabolic or neurogenetics clinic. A genetic specialist, such as a clinical geneticist or a genetic counselor, may be helpful to the patient and family, especially at the time of diagnosis or prior to genetic testing. Psychological counseling and MPS support groups may also assist families in coping with this condition.

Treatment

Treatment of the MPS disorders primarily consists of supportive care and management of complications. Bone marrow transplant (BMT) and enzyme replacement are two promising therapies that offer the possibility of altering the course of these conditions. Due to the progressive nature of the MPS disorders, regular evaluations by primary care providers and specialists is required to detect problems early. Treatment for the most common problems found in the MPS disorders is listed below.

Symmtomatic care and treatment

HYDROCEPHALUS Hydrocephalus (increased fluid in the ventricles of the brain) commonly occurs in MPS I, MPS II, MPS VI, and MPS VII due to a blocked circulation of cerebral spinal fluid in the brain. If the hydrocephalus is detected early, a surgical procedure known as ventriculoperitoneal shunting or a VP shunt may afford the affected individual with a better outcome. Periodic CT or MRI scans may be recommended to monitor for hydrocephalus in a child with MPS. In MPS III, enlarged ventricles (spaces in the brain) may occur but here the enlargement is thought to be due to cortical atrophy (loss of brain cells). It has been reported that shunting may decrease behavior problems associated with this form of MPS.

SEIZURES Seizures are a problem found in severe forms of MPS and especially in MPS III (Sanfilippo syndrome). Patients with seizures are given a type of prescription medication known as an anticonvulsant.

VISION AND HEARING Regular evaluation by an ophthalmologist is recommended to look for common eye problems including changes in the retina, glaucoma, and corneal clouding. Retinal degeneration, an eye problem that leads to night blindness and loss of peripheral vision, is common in MPS I, MPS II, and MPS III. Adding a night light to a hall or bedroom may help with this. Glaucoma is especially common in MPS I and is usually treated with medications. Corneal clouding is found in MPS I, MPS IV, MPS VI and MPS VII. People with corneal clouding have photophobia (the inability to tolerate bright light). Caps with a visor or sunglasses may be recommended to help reduce this problem. Corneal transplantation is possible for people with significantly reduced vision yet transplants may not always result in improved vision in the long term.

Hearing problems are common in the MPS disorders. Regular hearing evaluations are important so that children with hearing loss can be treated early. Hearing aids may provide some degree of improvement. Recurrent otitis media (middle ear infections) significantly contribute to hearing loss in individuals with MPS. Prescription medications are used to treat otitis media. Ventilating tubes in the ears may be used to minimize the long term effects of these infections.

CARDIOVASCULAR Many individuals with MPS show some signs of heart disease. Common problems include abnormal heart valves, narrowing of the blood vessels in the heart, and weak heart muscles (cardiomyopathy). Patients with MPS I H and the severe form of MPS II usually have damage to the mitral valve. In MPS I H/S, MPS IS, MPS IV, and MPS VI, aortic valvular disease is more common. Medications may be prescribed for congestive heart failure and hypertension associated with underlying heart disease. Valve replacement surgery is possible and has been reported in the MPS disorders.

AIRWAY DISEASE Obstruction of the airway is a common and significant problem for individuals with MPS. This problem can be due to a narrowed trachea (wind pipe), thickened vocal cords, large adenoids or tonsils, decreased rib movement with breathing, and a large tongue. A condition known as obstructive sleep apnea (temporary cessation of breathing while asleep) is the most common airway problem in MPS. Treatment for sleep apnea may include: removal of adenoids and tonsils, CPAP or BiPAP treatment, or a tracheostomy. CPAP (continuous positive airway pressure) and BiPAP (bilevel positive airway pressure) are treatments that help to keep the airway open at nighttime. A tracheostomy, an permanent opening through the neck into the trachea, may be needed in severe cases of sleep apnea.

FEEDING PROBLEMS For many individuals with MPS, neurological problems eventually lead to significant problems with chewing and swallowing. Surgical placement of gastrostomy tube (G-tube) or a jejunostomy tube (J-tube) may be recommended when feeding problems cause weight loss, choking, gagging, or episodes of pneumonia.

SKELETAL DEFORMITIES Bony problems, especially of the neck, spine, and hips may require orthopedic intervention. Problems of the cervical spine due to odontoid hypoplasia (improper formation bones that stabilize the head and neck) can be quite serious. Odontoid hypoplasia can lead to slippage of the bones in the neck and compression of the spine in the cervical (neck) region. In severe cases, this spinal cord compression may result in nerve damage, paralysis or death. Odontoid hypoplasia is common in MPS IV (Morquio syndrome). Treatment includes regular monitoring with MRI or X-rays and cervical fusion surgery for severe cases. Other bony problems seen in the MPS disorders include progressive scoliosis or kyphosis (curvatures of the spine) and hip dysplasia (abnormal hip joint). Bracing and sometimes surgery may be used to treat spine curvature. A surgical procedure known as spinal fusion may be considered in patients with significant curvature. Patients with hip dysplasia may be given non-steroidal anti-inflammatory medications.

CARPAL TUNNEL SYNDROME Carpal tunnel syndrome is a common problem in MPS. Although many individuals with MPS may not have typical symptoms (numbness, tingling, pain ), the carpal tunnel syndrome can and may be severe. Treatment options include splinting, anti-inflammatory medications and surgery.

Bone marrow transplantation (BMT)

Bone marrow transplants have been used to treat children with MPS I, MPS II, MPS III, and MPS VI. Some success has been achieved with BMT in MPS I and in MPS VI; however, this treatment is not a cure and is considered experimental due to the associated risks, including death. Some children who have undergone BMT have shown reduced progression of some disease symptoms. It remains uncertain whether BMT can prevent brain damage. BMT is not recommended as a treatment for MPS II or MPS III.

Enzyme replacement therapy

Enzyme replacement therapy is available for MPS I. A pharmaceutical form of alpha-L-iduronidase known as laronidase is available in the United States. More information may be obtained at <http://www.aldurazyme.com>. Enzyme therapy may be an option in the future for individuals with MPS IV.

Recovery and rehabilitation

Rehabilitation for the MPS disorders consists of physical, occupational, and possibly speech therapy. For example, physical therapy may help preserve joint function for individuals with joint stiffness. Joint stiffness is present in all of the MPS disorders except MPS IV and MPS IX. In physical therapy, patients may undergo range-of-motion exercises (passive bending and stretching of the arms and legs). Also, physical therapy after neck, spine or knee surgery can help patients (who could walk prior to surgery) to walk again. Occupational therapy can teach patients to use adaptive techniques and devices that may help compensate for loss of mobility and/or for loss of speech. Speech therapy may be indicated for individuals with MPS; however, this intervention may not be useful in cases in which the mental condition is rapidly deteriorating.

Hyperactivity can be a severe problem in individuals with MPS, especially in MPS III and MPS II. Medications may or may not be successful in treating this problem. Behavior modification programs may be helpful for some hyperactive MPS children. It may also be necessary to adapt the house and yard to the child.

Clinical trials

As of December 2003, there were four clinical trials related to the MPS disorders that were recruiting patients. A phase II/II trial to determine whether the administration of iduronate-2-sulfatase enzyme is safe and efficacious in patients with MPS II will be conducted in the United States, Brazil, Germany and England. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting Transkaryotic Therapies at 617-613-4499. A phase III trial to evaluate the ability of recombinant human arylsulfatase B enzyme to enhance endurance in patients with Mucopolysaccharidosis VI (MPS VI) will be conducted in the United States. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting BioMarin Pharmaceuticals at 415-884-6700. A phase II study of allogeneic bone marrow or umbilical cord blood transplantation in patients with mucopolysaccharidosis I will be conducted in the United States. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting the Study Chair at the Fairview University Medical Center in Minneapolis, Minnesota, at 612-624-5407. A phase II study of bone marrow or umbilical cord blood transplantation in patients with lysosomal or peroxisomal inborn errors of metabolism. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting the Study Chair at the Fairview University Medical Center in Minneapolis, Minnesota at 612-624-5407.

Prognosis

Life expectancy for individuals with an MPS is extremely varied. In severe forms of MPS, affected individuals may die in infancy such as in the severe cases of Sly syndrome, or they may die in in childhood or adolescence such as in Hurler syndrome and severe Hunter syndrome. In milder forms of MPS such as Scheie syndrome, mild Hunter syndrome individuals can live well into adulthood. Life spans for individuals with Sanfillipo syndrome, Maroteaux-Lamy syndrome, Morquio syndrome and mild Sly syndrome are quite variable. As more MPS I patients utilize enzyme replacement therapy, new information about prognosis and life span for this disorder will be learned.

Special 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. If general anesthesia is needed, it should be administered by an anesthesiologist experienced in the MPS disorders.

Children and families affected by an MPS may benefit from social services. A social worker may be able to help families obtain Social Security, Medicaid, or other assistance available from agencies that specialize in the care of persons with disabilities. A child with MPS may benefit from an Individual Education Plan (IEP). An IEP provides a framework from which administrators, teachers, and parents can meet the educational needs of a child with MPS.

Resources

BOOKS

Neufeld, Elizabeth F. and Joseph Muenzer. "The Mucopolysaccharidoses." Chapter 136. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed., Vol. 3, edited by Charles R. Scriver, Arthur L. Beaudet, William S. Sly, and David Valle. New York: McGraw-Hill Medical Publishing Division, 2001.

Parker, James N., and Philip M. Parker, eds. The Official Parent's Sourcebook on Mucopolysachharidoses: A Revised and Updated Directory for the Internet Age. San Diego, CA: ICON Health Publications, 2002.

PERIODICALS

Froissart, R., I. Moreira da Silva, N. Guffon, D. Bozon, and I. Maire. "Mucopolysaccharidosis type II-genotype/phenotype aspects." Acta Paediatrica Supplement 91 (2002): 82–87.

Gulati, M. S., and M. A. Agin. "Morquio syndrome: a rehabilitation perspective." Journal of Spinal Cord Medicine 19 (January 1996): 12–16.

Kakkis, E. D. "Enzyme replacement therapy for the mucopolysaccharide storage disorders." Expert Opinion on Investigational Drugs 11 (May 2002): 675–685.

Robertson, S. P., G. L. Klug, and J. G. Rogers. "Cerebrospinal fluid shunts in the management of behavioral problems in Sanfilippo syndrome." European Journal of Pediatrics 157 (August 1998): 653–655.

Vougioukas, V. I., A. Berlis, M. V. Kopp, R. Korinthenberg, J. Spreer, and V. van Velthoven. "Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature." Pediatric Neurosurgery 35 (July 2001): 35–38.

WEBSITES

Online Mendelian Inheritance in Man (OMIM). National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Omim/>.

The National Institute of Neurological Disorders and Stroke (NINDS). Mucopolysaccharidoses Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm>.

OTHER

The National MPS Society. MPS Disorder booklets. 45 Packard Drive, Bangor, ME: The National MPS Society, 2001-2003. <http://www.mpssociety.org/lib-health.html>.

ORGANIZATIONS

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, Ontario L3R-OM9, CA. (904) 479-8701 or (800) 667-1846. rldillio@ interlog.com. <http://www.mpssociety.ca>.

National MPS Society, Inc. 45 Packard Drive, Bangor, ME 04401. (207) 947-1445; Fax: (207) 990-3074. [email protected]. <http://www.mpssociety.org>.

Society for Mucopolysaccharide Diseases. 46 Woodside Road, Amersham, Buckinghamshire HP6-6AJ, UK. (149) 443-4252; Fax: (149) 443-4252. [email protected]. <http://www.mpssociety.co.uk>.

Dawn J. Cardeiro, MS, CGC

Mucopolysaccharidoses

Definition

Mucopolysaccharidosis (MPS) is a general term for a number of inherited diseases that are caused by the accumulation of mucopolysaccharides, resulting in problems with an individual's development. With each condition, mucopolysaccharides accumulate in the cells and tissues of the body because of a deficiency of a specific enzyme. The specific enzyme that is deficient or absent is what distinguishes one type of MPS from another. However, before these enzymes were identified, the MPS disorders were diagnosed by the signs and symptoms that an individual expressed. The discovery of these enzymes resulted in a reclassification of some of the MPS disorders. These conditions are often referred to as 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 (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX).

Description

Mucopolysaccharides are long chains of sugar molecules that are essential for building the bones, cartilage, skin, tendons, and other tissues in the body. Normally, the human body continuously breaks down and builds mucopolysaccharides. Another name for mucopolysaccharides is glycosaminoglycans (GAGs). There are many different types of GAGs and specific GAGs are unable to be broken down in each of the MPS conditions. There are several enzymes involved in breaking down each GAG and a deficiency or absence of any of the essential enzymes can cause the GAG to not be broken down completely and result in its accumulation in the tissues and organs in the body. In some MPS conditions, in addition to the GAG being stored in the body, some of the incompletely broken down GAGs can leave the body via the urine. When too much GAG is stored, organs and tissues can be damaged or not function properly.

Genetic profile

Except for MPS II, the MPS conditions are inherited in an autosomal recessive manner. MPS conditions occur when both of an individual's genes that produce the specific enzyme contain a mutation, causing them to not work properly. When both genes do not work properly, either none or a reduced amount of the enzyme is produced. An individual with an autosomal recessive condition inherits one of those non-working genes from each parent. These parents are called "carriers" of the condition. When two people are known carriers for an autosomal recessive condition, they have a 25% chance with each pregnancy to have a child affected with the disease. Some individuals with MPS do have children of their own. Children of parents who have an autosomal recessive condition are all carriers of that condition. These children are not at risk to develop the condition 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. This means that the gene causing the condition is located on the X chromosome, one of the two sex chromosomes. Since a male has only one X chromosome, he will have the disease if the X chromosome inherited from his mother carries the defective gene. Females, because they have two X chromosomes, are called "carriers" of the condition if only one of their X chromosomes has the gene that causes the condition, while the other X chromosome does not.

Causes and symptoms

Each type of MPS is caused by a deficiency of one of the enzymes involved in breaking down GAGs. It is the accumulation of the GAGs in the tissues and organs in the body that cause the wide array of symptoms characteristic of the MPS conditions. The accumulating material is stored in cellular structures called lysosomes, and these disorders are also known as lysosomal storage diseases.

MPS I

MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase. Three conditions, Hurler, Hurler-Scheie, and Scheie syndromes, all are caused by a deficiency of this enzyme. Initially, these three conditions were felt to be separate because each were associated with different physical symptoms and prognoses. However, once the underlying cause of these conditions was identified, it was realized that these three conditions were all variants of the same disorder. The gene involved with MPS I is located on chromosome 4p16.3.

MPS I H (HURLER SYNDROME). It has been estimated that approximately one baby in 100,000 will be born with Hurler syndrome. Individuals with Hurler syndrome tend to have 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 begin to develop as expected, but then reach a point where they begin to loose the skills that they have learned. Many of these infants may initially grow faster than expected, but their growth slows and typically stops by age three. Facial features also begin to appear "coarse." They develop a short nose, flatter face, thicker skin, and a protruding tongue. Additionally, their heads become larger and they develop more hair on their bodies with the hair becoming coarser. Their bones are also affected, with these children usually developing joint contractures (stiff joints), kyphosis (a specific type of curve to the spine), and broad hands with short fingers. Many of these children experience 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 is felt to be the 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 will be born with Hurler-Scheie syndrome. These individuals tend to be shorter than expected, and they can have normal intelligence, however, some individuals with MPS I H/S will 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 living to adulthood.

MPS I S (SCHEIE SYNDROME). Scheie syndrome is considered the mild form of MPS I. It is estimated that approximately one baby in 500,000 will be born with Scheie syndrome. Individuals with MPS I S usually have normal intelligence, but 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 the X chromosome, specifically Xq28. Like many MPS conditions, Hunter syndrome is divided into two groups, mild and severe. It has been estimated that approximately 1 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 is felt to be 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. Men 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, kyphosis, and tend to be shorter than expected. These symptoms tend to progress at a different rate depending on if an 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 characteristics. It was later discovered that the physical symptoms associated with Sanfilippo syndrome could be caused by a deficiency in one of four enzymes. Each type of MPS III is now subdivided into four groups, labeled A-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 are deficient or missing.

MPS III is a variable condition with symptoms beginning to appear between ages two and six years of age. Because of the accumulation of heparan sulfate in the central nervous system, the central nervous system is severely affected. In MPS III, signs that the central nervous system is degenerating usually are evident in most individuals between ages six and 10. Many children with MPS III will 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). MPS IIIA is caused by a deficiency of the enzyme heparan N-sulfatase. Type IIIA is felt to be the most severe of the four types, in which symptoms appear and death occurs at an earlier age. A study in British Columbia estimated that one in 324, 617 live births are 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 (location 17q25).

MPS IIIB (SANFILIPPO SYNDROME TYPE B). MPS IIIB is due to a deficiency in N-acetyl-alpha-D-glucosaminidase (NAG). This type of MPS III is not felt to be as severe as Type IIIA and the characteristics vary. Type IIIB is the most common of the four in southeastern Europe. The gene associated with MPS IIIB is also located on the long arm of chromosome 17 (location 17q21).

MPS IIIC (SANFILIPPO SYNDROME TYPE C). A deficiency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase causes MPS IIIC. This is considered 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). MPS IIID 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 (location 12q14).

MPS IV (Morquio syndrome)

As with several of the MPS disorders, Morquio syndrome was diagnosed by the presence of particular signs and symptoms. However, it is now known that the deficiency of two different enzymes can cause the characteristics of MPS IV. These two types of MPS IV are called MPS IV A and MPS IV B. MPS IV is also variable in its severity. The intelligence of individuals with MPS IV is often completely normal. In individuals with a severe form, skeletal abnormalities can be extreme and include dwarfism, kyphosis (backward-curved spine), prominent breastbone, flat feet, and knock-knees. One of the earliest symptoms seen in this condition usually is a difference in the way the child walks. In individuals with a mild form of MPS IV, limb stiffness, and joint pain are the primary symptoms. MPS IV is one of the rarest MPS disorders, with approximately one baby in 300,000 born with this condition.

MPS IV A (MORQUIO SYNDROME TYPE A). MPS IV A is the "classic" or the severe form of the condition and is caused by a deficiency in the enzyme galactosa-mine-6-sulphatase. The gene involved with MPS IV A is located on the long arm of chromosome 16 (location 16q24.3).

MPS IV B (MORQUIO SYNDROME TYPE B). MPS IV B is considered the milder form of the condition. The enzyme, beta-galactosidase, is deficient in MPS IV B. The location of the gene that produces beta-galactosidase is located on the short arm of chromosome 3 (location 3p21).

MPS VI (Maroteaux-Lamy syndrome)

MPS VI, which is another rare form of MPS, is caused by a deficiency of the enzyme N-acetylglucosa-mine-4-sulphatase. This condition is also variable; individuals may have a mild or severe form of the condition. 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 (extra fluid accumulating in the brain) and have bone changes. Additionally, individuals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the condition, 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 (approximate location 5q11-13).

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 (location 7q21).

MPS IX (Hyaluronidase deficiency)

MPS IX is a condition that was first described in 1996 and has been grouped with the other MPS conditions by some researchers. MPS IX is caused by the deficiency of the enzyme hyaluronidase. In the few individuals described with this condition, the symptoms are variable, but some 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 (possibly 3p21.3-21.2)

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.

Diagnosis

While a diagnosis for each type of MPS can be made on the basis of 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 usually cannot accurately determine if an individual is a carrier for a MPS condition. This is because the enzyme levels in individuals who are not carriers overlaps the enzyme levels seen in those individuals who are carrier for a 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 an MPS condition, prenatal diagnosis is available to them to help determine if a fetus is affected with the same MPS as their other child. This can be accomplished through testing samples using procedures such as an amniocentesis or chorionic villus sampling (CVS). Each of these procedures has its own risks, benefits, and limitations.

Treatment

There is no cure for mucopolysaccharidosis. There are several types of experimental therapies that are being investigated. Typically, treatment involves trying to relieve some of the symptoms. For MPS I and VI, bone marrow transplantation has been attempted as a treatment option. In those conditions, bone marrow transplantation has sometimes been found to help slow down the progression or reverse some of symptoms of the disorder in some children. The benefits of a bone marrow transplantation are more likely to be noticed when performed on children under two years of age. However it is not certain that a bone marrow transplant can prevent further damage to certain organs and tissues, including the brain. Furthermore, bone marrow transplantation is not felt to be helpful in some MPS disorders and there are risks, benefits, and limitations with this procedure. In 2000, ten individuals with MPS I received recombinant human alpha-L-iduronidase every week for one year. Those individuals showed an improvement with some of their 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).

Prevention

No specific preventive measures are available for genetic diseases of this type. For some of the MPS diseases, biochemical tests are available that will identify healthy individuals who are carriers of the defective gene, allowing them to make informed reproductive decisions. There is also the availability of prenatal diagnosis for all MPS disease to detect affected fetuses.

KEY TERMS

Cardiomyopathy— A thickening of the heart muscle.

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

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

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

Lysosome— 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. 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

Caillud, C., and L. Poenaru. "Gene Therapy in Lysosomal Diseases." Biomed & Pharmacother 54 (2000): 505-512.

Kakkis, E. D., et al. "Enzyme-Replacement Therapy in Mucopolysaccharidosis I." The New England Journal of Medicine 344 (2001): 182-188.

ORGANIZATIONS

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, ONT L3R-OM9. Canada (905) 479-8701 or (800) 667-1846. 〈http://www.mpssociety.ca〉.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. 〈http://www.climb.org.uk〉.

Metabolic Information Network. PO Box 670847, Dallas, TX 75367-0847. (214) 696-2188 or (800) 945-2188.

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. [email protected]. 〈http://www.mpssociety.org〉.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. 〈http://www.rarediseases.org〉.

Society for Mucopolysaccharide Diseases. 46 Woodside Rd., Amersham, Buckinghamshire, HP6 6AJ. UK +44 (01494) 434156. 〈http://www.mpssociety.co.uk〉.

Zain Hansen MPS Foundation. 23400 Henderson Rd., Covelo, CA 95420. (800) 767-3121.

OTHER

National Library of Medicine. National Institutes of Health. 〈http://www.nlm.nih.gov/〉.

"NINDS Mucopolysaccharidoses Information Page." The National Institute of Neurological Disorders and Stroke. National Institutes of Health. 〈http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm〉.

Online Mendelian Inheritance in Man (OMIM). National Center for Biotechnology Information. 〈http://www.ncbi.nlm.nih.gov/Omim/〉.

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: <www.mpsspciety.org>.

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

WEB SITES

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

McGovern, Margaret. "Mucopolysaccharidosis Type VI." eMedicine.com October 15, 2003. Available online at <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 <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 <www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm> (accessed January 13, 2005).

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

Mucopolysaccharidoses

Definition

Mucopolysaccharidosis (MPS) is a general term for a number of inherited diseases that are caused by the accumulation of mucopolysaccharides, resulting in problems with an individual's development. With each condition, mucopolysaccharides accumulate in the cells and tissues of the body because of a deficiency of a specific enzyme. The specific enzyme that is deficient or absent is what distinguishes one type of MPS from another. However, before these enzymes were identified, the MPS disorders were diagnosed by the signs and symptoms that an individual expressed. The discovery of these enzymes resulted in a reclassification of some of the MPS disorders. These conditions are often referred to as 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 (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX).

Description

Mucopolysaccharides are long chains of sugar molecules that are essential for building the bones, cartilage, skin, tendons, and other tissues in the body. Normally, the human body continuously breaks down and builds mucopolysaccharides. Another name for mucopolysaccharides is glycosaminoglycans (GAGs). There are many different types of GAGs and specific GAGs are unable to be broken down in each of the MPS conditions. There are several enzymes involved in breaking down each GAG and a deficiency or absence of any of the essential enzymes can cause the GAG to not be broken down completely and results in its accumulation in the tissues and organs in the body. In some MPS conditions, in addition to the GAG being stored in the body, some of the incompletely broken down GAGs can leave the body via the urine. When too much GAG is stored, organs and tissues can be damaged or not function properly.

Genetic profile

Except for MPS II, the MPS conditions are inherited in an autosomal recessive manner. MPS conditions occur when both of an individual's genes that produce the specific enzyme contain a mutation, causing them to not work properly. When both genes do not work properly, either none or a reduced amount of the enzyme is produced. An individual with an autosomal recessive condition inherits one non-working gene from each parent. These parents are called "carriers" of the condition. When two people are known carriers for an autosomal recessive condition, they have a 25% chance with each pregnancy to have a child affected with the disease. Some individuals with MPS do have children of their own. Children of parents who have an autosomal recessive condition are all carriers of that condition. These children are not at risk to develop the condition 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. This means that the gene causing the condition is located on the X chromosome, one of the two sex chromosomes . Since a male has only one X chromosome, he will have the disease if the X chromosome inherited from his mother carries the defective gene. Females will be carriers of the condition if only one of their two X chromosomes has the gene that causes the condition.

Causes and symptoms

Each type of MPS is caused by a deficiency of one of the enzymes involved in breaking down GAGs. It is the accumulation of the GAGs in the tissues and organs in the body that cause the wide array of symptoms characteristic of the MPS conditions. The accumulating material is stored in cellular structures called lysosomes, and these disorders are also known as lysosomal storage diseases.

MPS I

MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase. Three conditions, Hurler, Hurler-Scheie, and Scheie syndromes, are all 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 were all variants of the same disorder. The gene involved with MPS I is located on chromosome 4p16.3.

MPS I H (HURLER SYNDROME) It has been estimated that approximately one baby in 100,000 will be born with Hurler syndrome . Individuals with Hurler syndrome tend to have the most severe form of MPS I. Symptoms of Hurler syndrome are often evident within the first year or two after birth. These infants often begin to develop as expected, but then reach a point where they begin to loose the skills that they have learned. Many of these infants may initially grow faster than expected, but their growth slows and typically stops by age three. Facial features also begin to appear "coarse." They develop a short nose, flatter face, thicker skin, and a protruding tongue. Additionally, their heads become larger and they develop more hair on their bodies with the hair becoming coarser. Their bones are also affected, with these children usually developing joint contractures (stiff joints), kyphosis (a "hunchback" curve of the spine), and broad hands with short fingers. Many of these children experience 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 is felt to be the 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 will be born with Hurler-Scheie syndrome. These individuals tend to be shorter than expected, and they can have normal intelligence, however, some individuals with MPS I H/S will 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 living to adulthood.

MPS I S (SCHEIE SYNDROME) Scheie syndrome is considered the mild form of MPS I. It is estimated that approximately one baby in 500,000 will be born with Scheie syndrome. Individuals with MPS I S usually have normal intelligence, but 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 the X chromosome, specifically Xq28. Like many MPS conditions, Hunter syndrome is divided into two groups, mild and severe. It has been estimated that approximately 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 is felt to be 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 males with the severe form, but not as quickly. Men 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, kyphosis, and tend to be shorter than expected. These symptoms tend to progress at a different rate depending on if an 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 characteristics. It was later discovered that the physical symptoms associated with Sanfilippo syndrome could be caused by a deficiency in one of four enzymes. Each type of MPS III is now subdivided into four groups, labeled AD, 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 are deficient or missing.

MPS III is a variable condition with symptoms beginning to appear between ages two and six years of age. Because of the accumulation of heparan sulfate in the central nervous system, the central nervous system is severely affected. In MPS III, signs that the central nervous system is degenerating are usually evident in most individuals between ages six and 10. Many children with MPS III will 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) MPS IIIA is caused by a deficiency of the enzyme heparan N-sulfatase. Type IIIA is felt to be the most severe of the four types, in which symptoms appear and death occurs at an earlier age. A study in British Columbia estimated that one in 324,617 live births are 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 (location 17q25).

MPS IIIB (SANFILIPPO SYNDROME TYPE B) MPS IIIB is due to a deficiency in N-acetyl-alpha-D-glucosaminidase (NAG). This type of MPS III is not felt to be as severe as Type IIIA and the characteristics vary. Type IIIB is the most common of the four in southeastern Europe. The gene associated with MPS IIIB is also located on the long arm of chromosome 17 (location 17q21).

MPS IIIC (SANFILIPPO SYNDROME TYPE C) A deficiency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase causes MPS IIIC. This is considered 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) MPS IIID 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 (location 12q14).

MPS IV (Morquio syndrome)

As with several of the MPS disorders, Morquio syndrome was diagnosed by the presence of particular signs and symptoms. However, it is now known that the deficiency of two different enzymes can cause the characteristics of MPS IV. These two types of MPS IV are called MPS IV A and MPS IV B. MPS IV is also variable in its severity. The intelligence of individuals with MPS IV is often completely normal. In individuals with a severe form, skeletal abnormalities can be extreme and include dwarfism, kyphosis (outward-curved spine), prominent breastbone, flat feet, and knock-knees. One of the earliest symptoms seen in this condition usually is a difference in the way the child walks. In individuals with a mild form of MPS IV, limb stiffness and joint pain are the primary symptoms. MPS IV is one of the rarest MPS disorders, with approximately one baby in 300,000 born with this condition.

MPS IV A (MORQUIO SYNDROME TYPE A) MPS IV A is the "classic" or the severe form of the condition 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 (location 16q24.3).

MPS IV B (MORQUIO SYNDROME TYPE B) MPS IV B is considered the milder form of the condition. The enzyme, beta-galactosidase, is deficient in MPS IV B. The location of the gene that produces beta-galactosidase is located on the short arm of chromosome 3 (location 3p21).

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 condition. 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 (extra fluid accumulating in the brain) and have bone changes. Additionally, individuals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the condition, 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 (approximate location 5q11-13).

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 (location 7q21).

MPS IX (Hyaluronidase deficiency)

MPS IX is a condition that was first described in 1996 and has been grouped with the other MPS conditions by some researchers. MPS IX is caused by the deficiency of the enzyme hyaluronidase. In the few individuals described with this condition, the symptoms are variable, but some 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 (possibly 3p21.3-21.2)

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.

Diagnosis

While a diagnosis for each type of MPS can be made on the basis of 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 usually cannot accurately determine if an individual is a carrier for a MPS condition. This is because the enzyme levels in individuals who are not carriers overlaps the enzyme levels seen in those individuals who are carrier for a 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 an MPS condition, prenatal diagnosis is available to them to help determine if a fetus is affected with the same MPS as their other child. This can be accomplished through testing samples using procedures such as an amniocentesis or chorionic villus sampling (CVS). Each of these procedures has its own risks, benefits, and limitations.

Treatment

There is no cure for mucopolysaccharidosis, however, several types of experimental therapies are being investigated. Typically, treatment involves trying to relieve some of the symptoms. For MPS I and VI, bone marrow transplantation has been attempted as a treatment option. In those conditions, bone marrow transplantation has sometimes been found to help slow down the progression or reverse some of symptoms of the disorder in some children. The benefits of a bone marrow transplantation are more likely to be noticed when performed on children under two years of age. However, it is not certain that a bone marrow transplant can prevent further damage to certain organs and tissues, including the brain. Furthermore, bone marrow transplantation is not felt to be helpful in some MPS disorders and there are risks, benefits, and limitations with this procedure. In 2000, ten individuals with MPS I received recombinant human alpha-L-iduronidase every week for one year. Those individuals showed an improvement with some of their 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).

Prevention

No specific preventive measures are available for genetic diseases of this type. For some of the MPS diseases, biochemical tests are available that will identify healthy individuals who are carriers of the defective gene, allowing them to make informed reproductive decisions. There is also the availability of prenatal diagnosis for all MPS disease to detect affected fetuses.

Resources

PERIODICALS

Bax, Martin C. O. and Gillian A. Colville. "Behaviour in mucopolysaccharide disorders." Archives of Disease in Childhood 73 (1995): 77–81.

Caillud, C. and L. Poenaru. "Gene therapy in lysosomal diseases." Biomedical & Pharmacotherapy 54 (2000): 505–512.

Dangle, J. H. "Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders-clinical and echocardiographic findings in 64 patients." European Journal of Pediatrics 157 (1998): 534–538.

Kakkis, E. D. et al. "Enzyme-Replacement Therapy in Mucopolysaccharidosis I." The New England Journal of Medicine 344 (2001): 182–188.

Wraith, J. E. "The Mucopolysaccharidoses: A Clinical Review and Guide to Management." Archives of Disease in Childhood 72 (1995): 263–267.

ORGANIZATIONS

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, ONT L3R-OM9. Canada (905) 479-8701 or (800) 667-1846. <http://www.mpssociety.ca>.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

Metabolic Information Network. PO Box 670847, Dallas, TX 75367-0847. (214) 696-2188 or (800) 945-2188.

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. info @mpssociety.org. <http://www.mpssociety.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Society for Mucopolysaccharide Diseases. 46 Woodside Rd., Amersham, Buckinghamshire, HP6 6AJ. UK +44 (01494)434156. <http://www.mpssociety.co.uk>.

Zain Hansen MPS Foundation. 23400 Henderson Rd., Covelo, CA 95420. (800) 767-3121.

WEBSITES

National Library of Medicine. National Institutes of Health. <http://www.nlm.nih.gov/>

"NINDS Mucopolysaccharidoses Information Page." The National Institute of Neurological Disorders and Stroke. National Institutes of Health. <http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm>

Online Mendelian Inheritance in Man (OMIM). National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Omim/>

Sharon A. Aufox, MS, CGC

Mucopolysaccharidoses

Definition

Mucopolysaccharidosis (MPS) is a general term for a number of inherited diseases that are caused by the accumulation of mucopolysaccharides, resulting in problems with an individual's development. With each condition, mucopolysaccharides accumulate in the cells and tissues of the body because of a deficiency of a specific enzyme. The specific enzyme that is deficient or absent is what distinguishes one type of MPS from another. However, before these enzymes were identified, the MPS disorders were diagnosed by the signs and symptoms that an individual expressed. The discovery of these enzymes resulted in a reclassification of some of the MPS disorders. These conditions are often referred to as 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 (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly (MPS VII), and Hyaluronidase deficiency (MPS IX).

Description

Mucopolysaccharides are long chains of sugar molecules that are essential for building the bones, cartilage, skin, tendons, and other tissues in the body. Normally, the human body continuously breaks down and builds mucopolysaccharides. Another name for mucopolysaccharides is glycosaminoglycans (GAGs). There are many different types of GAGs and specific GAGs are unable to be broken down in each of the MPS conditions. There are several enzymes involved in breaking down each GAG and a deficiency or absence of any of the essential enzymes can cause the GAG to not be broken down completely and results in its accumulation in the tissues and organs in the body. In some MPS conditions, in addition to the GAG being stored in the body, some of the incompletely broken down GAGs can leave the body via the urine. When too much GAG is stored, organs and tissues can be damaged or not function properly.

Genetic profile

Except for MPS II, the MPS conditions are inherited in an autosomal recessive manner. MPS conditions occur when both of an individual's genes that produce the specific enzyme contain a mutation, causing them to not work properly. When both genes do not work properly, either none or a reduced amount of the enzyme is produced. An individual with an autosomal recessive condition inherits one non-working gene from each parent. These parents are called "carriers" of the condition. When two people are known carriers for an autosomal recessive condition, they have a 25% chance with each pregnancy to have a child affected with the disease. Some individuals with MPS do have children of their own. Children of parents who have an autosomal recessive condition are all carriers of that condition. These children are not at risk to develop the condition 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. This means that the gene causing the condition is located on the X chromosome , one of the two sex chromosomes. Since a male has only one X chromosome, he will have the disease if the X chromosome inherited from his mother carries the defective gene. Females will be carriers of the condition if only one of their two X chromosomes has the gene that causes the condition.

Causes and symptoms

Each type of MPS is caused by a deficiency of one of the enzymes involved in breaking down GAGs. It is the accumulation of the GAGs in the tissues and organs in the body that cause the wide array of symptoms characteristic of the MPS conditions. The accumulating material is stored in cellular structures called lysosomes, and these disorders are also known as lysosomal storage diseases.

MPS I

MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase. Three conditions, Hurler, Hurler-Scheie, and Scheie syndromes, are all 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 were all variants of the same disorder. The gene involved with MPS I is located on chromosome 4p16.3.

MPS I H (HURLER SYNDROME) It has been estimated that approximately one baby in 100,000 will be born with Hurler syndrome. Individuals with Hurler syndrome tend to have the most severe form of MPS I. Symptoms of Hurler syndrome are often evident within the first year or two after birth. These infants often begin to develop as expected, but then reach a point where they begin to loose the skills that they have learned. Many of these infants may initially grow faster than expected, but their growth slows and typically stops by age three. Facial features also begin to appear "coarse." They develop a short nose, flatter face, thicker skin, and a protruding tongue. Additionally, their heads become larger and they develop more hair on their bodies with the hair becoming coarser. Their bones are also affected, with these children usually developing joint contractures (stiff joints), kyphosis (a "hunchback" curve of the spine), and broad hands with short fingers. Many of these children experience 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 is felt to be the 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 will be born with Hurler-Scheie syndrome. These individuals tend to be shorter than expected, and they can have normal intelligence, however, some individuals with MPS I H/S will 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 living to adulthood.

MPS I S (SCHEIE SYNDROME) Scheie syndrome is considered the mild form of MPS I. It is estimated that approximately one baby in 500,000 will be born with Scheie syndrome. Individuals with MPS I S usually have normal intelligence, but 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 the X chromosome, specifically Xq28. Like many MPS conditions, Hunter syndrome is divided into two groups, mild and severe. It has been estimated that approximately 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 is felt to be 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 males with the severe form, but not as quickly. Men 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, kyphosis, and tend to be shorter than expected. These symptoms tend to progress at a different rate depending on if an 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 characteristics. It was later discovered that the physical symptoms associated with Sanfilippo syndrome could be caused by a deficiency in one of four enzymes. Each type of MPS III is now subdivided into four groups, labeled A-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 are deficient or missing.

MPS III is a variable condition with symptoms beginning to appear between ages two and six years of age. Because of the accumulation of heparan sulfate in the central nervous system, the central nervous system is severely affected. In MPS III, signs that the central nervous system is degenerating usually are evident in most individuals between ages six and 10. Many children with MPS III will 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) MPS IIIA is caused by a deficiency of the enzyme heparan Nsulfatase. Type IIIA is felt to be the most severe of the four types, in which symptoms appear and death occurs at an earlier age. A study in British Columbia estimated that one in 324,617 live births are 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 (location 17q25).

MPS IIIB (SANFILIPPO SYNDROME TYPE B) MPS IIIB is due to a deficiency in N-acetyl-alpha-D-glucosaminidase (NAG). This type of MPS III is not felt to be as severe as Type IIIA and the characteristics vary. Type IIIB is the most common of the four in southeastern Europe. The gene associated with MPS IIIB is also located on the long arm of chromosome 17 (location 17q21).

MPS IIIC (SANFILIPPO SYNDROME TYPE C) A deficiency in the enzyme acetyl-CoA-alpha-glucosaminide acetyltransferase causes MPS IIIC. This is considered 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) MPS IIID 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 (location 12q14).

MPS IV (Morquio syndrome)

As with several of the MPS disorders, Morquio syndrome was diagnosed by the presence of particular signs and symptoms. However, it is now known that the deficiency of two different enzymes can cause the characteristics of MPS IV. These two types of MPS IV are called MPS IV A and MPS IV B. MPS IV is also variable in its severity. The intelligence of individuals with MPS IV is often completely normal. In individuals with a severe form, skeletal abnormalities can be extreme and include dwarfism, kyphosis (outward-curved spine), prominent breastbone, flat feet, and knock-knees. One of the earliest symptoms seen in this condition usually is a difference in the way the child walks. In individuals with a mild form of MPS IV, limb stiffness and joint pain are the primary symptoms. MPS IV is one of the rarest MPS disorders, with approximately one baby in 300,000 born with this condition.

MPS IV A (MORQUIO SYNDROME TYPE A) MPS IV A is the "classic" or the severe form of the condition 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 (location 16q24.3).

MPS IV B (MORQUIO SYNDROME TYPE B) MPS IV B is considered the milder form of the condition. The enzyme, beta-galactosidase, is deficient in MPS IV B. The location of the gene that produces beta-galactosidase is located on the short arm of chromosome 3 (location 3p21).

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 condition. 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 (extra fluid accumulating in the brain) and have bone changes. Additionally, individuals with a severe form of MPS VI are more likely to die while in their teens. With a milder form of the condition, 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 (approximate location 5q11-13).

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 (location 7q21).

MPS IX (Hyaluronidase deficiency)

MPS IX is a condition that was first described in 1996 and has been grouped with the other MPS conditions by some researchers. MPS IX is caused by the deficiency of the enzyme hyaluronidase. In the few individuals described with this condition, the symptoms are variable, but some 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 (possibly 3p21.3-21.2)

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.

Diagnosis

While a diagnosis for each type of MPS can be made on the basis of 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 usually cannot accurately determine if an individual is a carrier for a MPS condition. This is because the enzyme levels in individuals who are not carriers overlaps the enzyme levels seen in those individuals who are carrier for a 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 an MPS condition, prenatal diagnosis is available to them to help determine if a fetus is affected with the same MPS as their other child. This can be accomplished through testing samples using procedures such as an amniocentesis or chorionic villus sampling (CVS). Each of these procedures has its own risks, benefits, and limitations.

Treatment and management

There is no cure for mucopolysaccharidosis, however, several types of experimental therapies are being investigated. Typically, treatment involves trying to relieve some of the symptoms. For MPS I and VI, bone marrow transplantation has been attempted as a treatment option. In those conditions, bone marrow transplantation has sometimes been found to help slow down the progression or reverse some of symptoms of the disorder in some children. The benefits of a bone marrow transplantation are more likely to be noticed when performed on children under two years of age. However, it is not certain that a bone marrow transplant can prevent further damage to certain organs and tissues, including the brain. Furthermore, bone marrow transplantation is not felt to be helpful in some MPS disorders and there are risks, benefits, and limitations with this procedure. In 2000, ten individuals with MPS I received recombinant human alpha-L-iduronidase every week for one year. Those individuals showed an improvement with some of their 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).

Prevention

No specific preventive measures are available for genetic diseases of this type. For some of the MPS diseases, biochemical tests are available that will identify healthy individuals who are carriers of the defective gene, allowing them to make informed reproductive decisions. There is also the availability of prenatal diagnosis for all MPS disease to detect affected fetuses.

Resources

PERIODICALS

Bax, Martin C. O., and Gillian A. Colville. "Behaviour in mucopolysaccharide disorders." Archives of Disease in Childhood 73 (1995): 77–81.

Caillud, C., and L. Poenaru. "Gene therapy in lysosomal diseases." Biomedical & Pharmacotherapy 54 (2000): 505–512.

Dangle, J. H. "Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders-clinical and echocardiographic findings in 64 patients." European Journal of Pediatrics 157 (1998): 534–538.

Kakkis, E. D., et al. "Enzyme-Replacement Therapy in Mucopolysaccharidosis I." The New England Journal of Medicine 344 (2001): 182–188.

Wraith, J. E. "The Mucopolysaccharidoses: A Clinical Review and Guide to Management." Archives of Disease in Childhood 72 (1995): 263–267.

ORGANIZATIONS

Canadian Society for Mucopolysaccharide and Related Diseases. PO Box 64714, Unionville, ONT L3R-OM9. Canada (905) 479-8701 or (800) 667-1846. <http://www.mpssociety.ca>.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

Metabolic Information Network. PO Box 670847, Dallas, TX 75367-0847. (214) 696-2188 or (800) 945-2188.

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. [email protected]. <http://www.mpssociety.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Society for Mucopolysaccharide Diseases. 46 Woodside Rd., Amersham, Buckinghamshire, HP6 6AJ. UK +44 (01494) 434156. <http://www.mpssociety.co.uk>.

Zain Hansen MPS Foundation. 23400 Henderson Rd., Covelo, CA 95420. (800) 767-3121.

WEBSITES

National Library of Medicine. National Institutes of Health. <http://www.nlm.nih.gov/>

"NINDS Mucopolysaccharidoses Information Page." The National Institute of Neurological Disorders and Stroke. National Institutes of Health. <http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm>

Online Mendelian Inheritance in Man (OMIM). National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Omim/>

Sharon A. Aufox, MS, CGC