Mucopolysaccharidosis Type I

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Mucopolysaccharidosis type I

Definition

Mucopolysaccharidosis type I (Hurler syndrome) is a disorder that results when cells cannot break down two by-products of normal metabolism. These by-products, dermatan sulfate and heparan sulfate, build up and disrupt normal cell function, leading to severe disease. The disease affects most body systems, causing progressive deterioration of tissues and organs.

Description

Though present from conception, Hurler syndrome may be undetectable at birth. The newborn often looks healthy and seems to develop normally for the first few months. However, symptoms begin to appear around the age of six months, when dermatan sulfate and heparan sulfate reach dangerous levels.

Individuals with Hurler syndrome lack sufficient amounts of the enzyme needed to break down dermatan sulfate and heparan sulfate. This enzyme, alpha-L-iduronidase, is part of a biochemical pathway which splits complex molecules into smaller, recyclable units. Without alpha-L-iduronidase, the complex molecules cannot be eliminated and deposit themselves in cells, tissues, and organs. Deposits in the soft tissues of the face lead to a typical appearance, causing children with Hurler syndrome to resemble each other more than they resemble their own healthy siblings. The spleen and liver become enlarged early in the course of the disease. Deposits stored in the growth plates of bones lead to dwarfism, scoliosis , joint stiffness, and other skeletal abnormalities. Corneal clouding caused by the deposits results in vision damage. Hearing loss usually occurs as well. Deposits in the brain cause loss of skills gained early in life, and severe mental retardation occurs.

The accumulation of dermatan sulfate and heparan sulfate in the airways leads to frequent respiratory tract and ear infections. Deposits also cause coronary artery obstruction and damage to the heart. In fact, respiratory complications and heart failure are the most frequent causes of death in Hurler syndrome patients. Many children with Hurler syndrome die by the age of 12.

Dermatan sulfate and heparan sulfate belong to a class of complex molecules known as mucopolysaccharides, chains formed by smaller sugar molecules strung together. For this reason, Hurler syndrome is also known as a mucopolysaccharidosis, a name meaning, "too many mucopolysaccharides." To be precise, Hurler syndrome is called mucopolysaccharidosis type I (MPS I); there are several other mucopolysaccharidoses , each resulting from absence or deficiency of a different enzyme.

Sometimes Hurler syndrome is called a lysosomal storage disease. Lysosomes are cell parts which normally contain enzymes needed to break down complex molecules. When the enzymes are absent or deficient, the lysosomes store the complex molecules, expand, and eventually destroy the cells from within.

Hurler syndrome takes its most commonly used name from Gertrud Hurler, the German pediatrician who first described the condition in her patients.

Genetic profile

Researchers have identified the gene responsible for Hurler syndrome and have mapped it to the 4p16.3 site on chromosome 4. The gene is named IDUA, for the iduronidase enzyme which it produces when working properly. Researchers have connected 52 different IDUA mutations to cases of Hurler syndrome.

Hurler syndrome is an autosomal recessive disorder. This means that it occurs only when a person inherits two defective copies of the IDUA gene. If one copy is normal and the other has a mutation, the person does not have Hurler syndrome. However, the person carries the mutated gene and can pass it on to the next generation.

Carriers of IDUA mutations have only one working gene. As a result, these carriers produce less alpha-L-iduronidase enzyme than do people with two normal IDUA genes. Nevertheless, they produce enough enzyme to break down dermatan sulfate and heparan sulfate, so disease does not occur.

Demographics

Hurler syndrome affects males and females of all races and ethnic groups. It is a rare disorder, occurring in about one out of 100,000 people.

Different IDUA gene mutations appear more frequently in certain populations. For instance, two specific mutations account for most Hurler syndrome cases among Northern Europeans, while two other mutations appear most often in Japanese patients.

Signs and symptoms

A child with Hurler syndrome may be born with a hernia. In fact, hernia is often the first sign of this disorder. However, since it can also occur in other conditions or as an isolated event, it does not immediately point to Hurler syndrome.

Other symptoms appear within six to twelve months of birth. Tissue damage in airways leads to breathing difficulties and frequent respiratory and ear infections. The child's face begins to take on the coarse, typical features of Hurler syndrome. The skull appears large and unusually shaped, scalp veins are prominent, and the bridge of the nose is flat. The lips are large and the mouth is frequently open due to an enlarged, protruding tongue. Teeth may be late to emerge and are usually small, short, widely spaced, and somewhat malformed. The earlobes are thick, and the eyelids are full.

Skeletal abnormalities begin to appear. The hands are broad, with short, stubby fingers. Joints are often stiff and may limit the child's movement. The neck is very short; the spine is crooked and bends outward, resulting in a hunchback appearance.

Children under the age of one may already show signs of heart disease. This is usually due to tissue damage in the arteries or valves of the heart, caused by accumulation of dermatan sulfate and heparan sulfate. Accumulation also causes the liver and spleen to become severely enlarged, but these organs continue to function normally.

Hurler syndrome has a devastating effect on mental development. By the age of one or two, developmental delay occurs. The child may make slow progress for a few more years, but then actually begins to lose skills gained earlier. The mental capacity of a person with Hurler syndrome is similar to that of a normal three-yearold. Deterioration of the senses makes this situation worse. Corneal clouding damages vision. Hearing loss, narrowed airways, and enlarged tongue contribute to poor language skills.

Many infants with Hurler syndrome grow quickly during their first few months. However, skeletal abnormalities and progressive tissue damage cause growth to slow down and then to stop before it should. As a result, most people with Hurler syndrome do not grow beyond four feet tall.

Diagnosis

Hurler syndrome shares many symptoms with other mucopolysaccharidoses and with different lysosomal storage diseases. For this reason, laboratory tests are used to confirm Hurler syndrome diagnosis based on a physical exam.

The simplest test available is urine screening. People with Hurler syndrome excrete increased amounts of dermatan sulfate and heparan sulfate in their urine. In addition, a blood test reveals deficiency of alpha-L-iduronidase enzyme. White blood cells and skin cells can be microscopically examined for damage caused by deposits of dermatan sulfate and heparan sulfate.

If Hurler syndrome is present in a family, healthy family members could carry a mutated IDUA gene. Several clinical laboratories offer carrier screening to these individuals. A blood sample is all that is required. Most labs screen for carrier status by measuring the level of the alpha-L-iduronidase enzyme. Levels are lower in carriers than they are in people who have two normal IDUA genes. It is also possible to examine the actual genes to see if a Hurler syndrome mutation appears.

Since Hurler syndrome is a rare disorder, most carriers have children with non-carrier partners. Thus there is generally no risk of the disease occurring in the children. However, if two carriers have children together, each child has a 25% chance of having Hurler syndrome. Carrier screening provides an opportunity to assess the risk and consider reproductive options before pregnancy occurs.

Each child born to two carriers has a 50% risk of inheriting one mutated gene and one normal gene. This child, like the parents, is a carrier.

Because a rare autosomal recessive gene can be passed for generations before two carriers have a child together, sometimes an affected child is born into a family with no previous history of Hurler syndrome. This is generally an indication that both parents carry a mutated IDUA gene. These parents worry not only about the health of the affected child, but also about the risk to future children.

Prenatal testing is available to find out if a fetus has Hurler syndrome. This can be done by amniocentesis or chorionic villus sampling. Amniocentesis involves removal of a small amount of amniotic fluid from the uterus. Chorionic villus sampling involves removal of a small sample of placental tissue. In either case, the cells present in the sample are checked for enzyme deficiency or gene mutations.

Treatment and management

Treatment of individual Hurler syndrome symptoms does not cure the disease, but it does offer some relief. Surgical repair is available to correct a hernia. Hearing aids sometimes improve hearing and language skills, and eyeglasses may enhance eyesight. Some children with Hurler syndrome improve communication skills by learning sign language.

Skeletal abnormalities require attention, especially if they affect the upper part of the spine and compress the spinal cord. Spinal cord compression and storage of dermatan sulfate and heparan sulfate in the surrounding membranes cause fluid to accumulate in the brain. Brain damage often occurs unless this condition is corrected. A surgeon can implant a shunt in the brain to remove excess fluid. Once present, the mental retardation caused by Hurler syndrome is generally not reversible.

It is important to protect the upper back and neck of a patient with Hurler syndrome. This area should not be manipulated during chiropractic or physical therapy. If the patient undergoes anesthesia for any reason, care should be taken to support the neck and upper back at all times.

Orthopedic treatment can help reduce joint stiffness and its effects on movement.

Several options are available to correct breathing difficulties. Some patients respond well to oxygen treatments. Others require tonsillectomy, adenoidectomy or tracheostomy to remove upper airway obstruction. Medications are available to treat common respiratory infections.

If heart disease is limited to valve damage, valve replacement may be an option for some patients with Hurler syndrome.

Children with Hurler syndrome are generally easygoing and affectionate. They benefit greatly from safe and caring environments. Community support and social services can improve the quality of life for the entire family unit. The family of a child with Hurler syndrome experiences grief and loss throughout the lifetime and upon the death of the child. Genetic counseling is available to offer support, educate families about the disease, and assess the risk to other family members. The National MPS Society provides additional support and information.

Bone marrow transplant (BMT) is the only treatment that appears to improve the long-term outcome of children with Hurler syndrome. BMT replaces the child's entire blood system with the blood system of a healthy person. The healthy bone marrow contains stem cells, cells from which other cells and tissues arise. These cells produce enough alpha-L-iduronidase to break down dermatan sulfate and heparan sulfate.

Bone marrow transplant is a complicated procedure. If the donated bone marrow is not compatible with the child's own body tissues, the child's immune system will destroy it. BMT is most successful if the donor is a close relative of the patient, since this increases the chance of compatibility between donor and patient bone marrow. To reduce the risk of donor bone marrow rejection, the patient receives drugs and radiation to suppress the immune system, leaving the patient vulnerable to infection.

Research indicates that children with Hurler syndrome do better if BMT takes place before the age of two. Beyond that point, prevention or correction of brain damage is unlikely, and other body tissues may be so severely affected that the child would not survive BMT.

Prognosis

Bone marrow transplant is the only treatment that can prevent or reduce the effects of Hurler syndrome. However, bone marrow transplant is not an option for every patient. Some patients with severe disease are too weak to survive the transplant procedure or recovery period. For some, a donor match is not available. Others don't have access to the technological or medical expertise needed for the procedure. In addition, some patients who have bone marrow transplants reject the donor cells.

Research into long-term therapies is underway. Two which appear promising are enzyme replacement therapy and gene therapy .

Enzyme replacement involves giving the patient a substitute for the deficient enzyme. The patient would receive regular enzyme injections, similar to insulin injections used by people with diabetes . Enzyme replacement is complicated in a disorder which affects many different tissues, as Hurler syndrome does. Each tissue interacts differently with the enzyme. For this reason, it is difficult to design a substitute which works with various tissues. Furthermore, the brain has a natural barrier against outside substances. This is called the blood-brain barrier, and it stops the enzyme substitute from reaching brain cells. Therefore, an enzyme substitute injected into the blood would not prevent or reduce the brain damage caused by Hurler syndrome. The substitute might, however, reduce damage to other tissues of the body.

Gene therapy attempts to introduce a normal gene into the patient's cells. In theory, the cells would then incorporate the gene, copy it, and produce enough enzyme to break down complex molecules.

Until these or other therapies become available, patients who cannot undergo BMT can receive treatment for individual Hurler syndrome symptoms. While treatment provides temporary relief, it cannot prevent the progressive damage caused by accumulation of dermatan sulfate and heparan sulfate. Death due to respiratory complications or heart failure usually occurs by age 12.

Resources

BOOKS

Beighton, Peter, ed. McKusick's Heritable Disorders of Connective Tissue. Fifth Edition. St. Louis: Mosby, 1993.

Jones, Kenneth L. "Hurler Syndrome." Smith's Recognizable Patterns of Human Malformation. Fifth Edition. Philadelphia: W.B. Saunders Company, 1997, pp. 456-457.

Jorde, Lynn, et al. Medical Genetics. Second Edition. St. Louis: Mosby, 2000, pp. 147-149.

Scriver, Charles, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. Seventh Edition. New York: McGraw-Hill, 1995.

PERIODICALS

Peters, Charles, et al. "Hurler Syndrome: II. Outcome of HLA Genotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in Fifty-Four Children." Blood 91, no. 7 (April 1998): 2601-2608.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 [email protected] <http://www.geneticalliance.org>.

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

WEBSITES

GeneClinics. <http://www.geneclinics.org>. 2001.

GeneTests. <http://www.genetests.org>. 2001.

New York University School of Medicine. <http://www.med.nyu.edu>. 2001.

Avis L. Gibons