Hurler syndrome

• Hurler syndrome is a rare, inherited disorder in which a hereditary factor, or gene, is defective. The gene affected is one that controls production of an enzyme, called alpha-L-iduronidase. As a result, patients with Hurler syndrome typically experience developmental abnormalities, learning difficulties, intellectual disabilities, and various types of organ dysfunction.
• Enzymes are proteins that bring about chemical reactions in the body. Alpha-L-iduronidase is the enzyme responsible for the breakdown of large, complex sugar molecules called glucosaminoglycans (formerly called mucopolysaccharides). Glucosaminoglycans are found in most of the body's tissues and organs. Like most substances in the body, they are continually produced and broken down in order to maintain constant levels in the body.
• Hurler syndrome is one of eleven disorders that are classified as mucopolysaccaharidoses (MPS). Different classes of MPS syndromes are categorized based on the specific enzyme deficiency involved in the complex chemical breakdown pathway of the glucosaminoglycans. Hurler syndrome is considered MPS type I.
• Because patients with Hurler syndrome have defective alpha-L-iduronidase, glucosaminoglycans build up in abnormally large amounts throughout the body.
• Hurler syndrome is a lysosomal storage disease. Lysosomal storage diseases occur when the enzyme responsible for breaking down a particular substance inside the lysosomes, or sac-like structures within cells, is missing. As a result, the substance builds up inside the lysosomes.
• Both parents must pass down a defective gene for a child to develop Hurler syndrome. However, each parent almost always has one normal copy of the gene, and therefore produce enough alpha-L-iduronidase so that glucosaminoglycans continue to be broken down normally. Thus, neither parent carrying a copy of the defective gene generally exhibits any disease symptoms.
• Without treatment, survival beyond the early teen-aged years is rare. However, with treatments that are currently available, some children with Hurler syndrome have been able to live longer and more comfortable lives.

• Hurler syndrome is strictly a genetic disorder, and there are no specific environmental risk factors known to affect the progression or severity of the disease.
• Because most people with Hurler syndrome do not reach reproductive age, most cases are inherited from parents who each carry only one copy of the mutated gene. Carriers do not actually have the disorder, but they can pass the mutated gene to each of their children.
• If one parent is a carrier, there is a 50% chance with each birth that the child will also be a carrier, and a 0% chance that the child will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, and a 50% chance that each child will be a carrier.
• Male and female children are equally at risk.
• All races and ethnicities have an equal risk of inheriting Hurler syndrome.

Causes

• Hurler syndrome is caused by the hereditary deficiency of an enzyme, called alpha-L-iduronidase. A gene that regulates the production of this enzyme is defective. The enzyme is normally present in many types of cells in nearly all of the body's tissues. It is required for the breakdown of glucosaminoglycans, which make up much of the jelly-like material present between the cells in many tissues. Glucosaminoglycans also make up much of the mucous that is produced at the surface of many tissues, such as those in the digestive and respiratory tracts. They also constitute most of the material found in cartilage and inside of joint capsules.
• Normally, the alpha-L-iduronidase enzyme prevents glucosaminoglycans from building up to harmful levels in the body. Because patients with Hurler syndrome do not have enough alpha-L-iduronidase, glucosaminoglycans build up in abnormally large amounts throughout the body, eventually causing the cells to become severely dysfunctional or die. When the cells die, they release large amounts of glucosaminoglycans.
• The build-up of glucosaminoglycans results in abnormally thick mucus in the respiratory and digestive tracts. It also results in abnormal enlargement, thickening, and malfunction of many tissues and organs. Body parts affected include the heart, spleen, liver, muscles, connective tissues, joints, and the central nervous system. Hence, the normal development and functioning of an extremely wide variety of organs is severely impaired.

• The most common signs and symptoms include abnormally flat appearance of the bridge of the nose (low nasal bridge), arrested growth, abnormally small stature, hunchback, cloudy and impaired vision, deafness, joint abnormalities and stiffness, abnormal bone and cartilage development (particularly in the spine and hands), abnormal heart valves, enlargement of the spleen and liver, and progressive mental retardation.
• Two types of hernia are among the most common early signs and symptoms. Inguinal hernia arises when a loop of intestine bulges into the sac containing the testicles in males. It may result in pain, nausea, or vomiting. Umbilical hernia arises when a loop of intestine bulges into the mid-abdominal region near the navel, or umbilicus. This may occur when the opening for the umbilical cord, which normally closes before birth, doesn't close completely. It may result in pain, especially when coughing, sneezing, or standing. Both types of hernia are readily detectable in infants with Hurler syndrome by physical examination, and may usually be corrected by surgery.
• A protruding abdomen, caused by liver and/or spleen enlargement, is a common symptom.
• Joint and skeletal abnormalities may lead to difficulty walking.
• The cornea, or protective membrane on the front surface of the eye, often appears cloudy, resulting in impaired vision.
• Mongolian spots, which are bluish birth marks on the skin, are common.
• "Claw hand," in which the fingers are permanently bent into a claw-like configuration, is often present.
• Abnormal curvature of the lower spine, resulting in a hunchbacked appearance called the Gibbus deformity, is common.
• An abnormally large tongue, sometimes protruding from the mouth, is often present. The enlarged tongue, deafness, and mental retardation may all contribute to the speech difficulties generally experienced by children with Hurler syndrome.
• Hair is often courser and more abundant than in normal children.
• The head generally has an elongated appearance, and due to the unusually low nasal bridge, the face usually appears flattened. The forehead often bulges, and the neck is usually short and stiff, giving the overall impression that the head is abnormally large. This impression is often magnified by the short stature of children with Hurler syndrome. These characteristic facial features were formerly described in the older medical literature by the term "gargoylism."
• Signs and symptoms are not usually evident at birth, but generally become obvious when a child reaches two to four years of age. However, in some cases, facial abnormalities and frequent respiratory infections may be present much earlier.
• There is considerable variability in the order of appearance of the various signs and symptoms during development, as well as in their severity.

• General: Babies with Hurler syndrome often appear normal or nearly normal at birth. Warning signs in babies that most often alert a physician to the possibility of Hurler syndrome include chronic upper respiratory problems and hernias. These warning signs are indications that laboratory diagnostic tests for Hurler syndrome should be performed.
• Urine test: If a physician suspects Hurler syndrome on the basis of signs, symptoms, and physical examination, a simple and rapid diagnostic test that may be performed is a urine test. A urine test will show abnormally high amounts of glucosaminoglycans if any of the mucopolysaccharidosis type I (MPH I) diseases are present. Hurler syndrome is the most severe form of three closely related subtypes of MPH I, which are all caused by the same enzyme deficiency, but differ in severity. However, increased glucosaminoglycans in the urine may also be caused by other types of unrelated diseases and enzyme deficiencies. Therefore, if the urine test is positive, a blood test must also be performed.
• Blood test: In this test, the amount of alpha-L-iduronidase enzymes in white blood cells from the blood sample is measured. Abnormally low amounts of the alpha-L-iduronidase enzyme in the blood, along with characteristic skeletal abnormalities detectable by physical examination and by X-rays, is considered definitive for a diagnosis of MPH I.
• Analysis of DNA, obtained during blood tests, may also be used to determine the exact structure of the defective gene, and this may be used to verify the diagnosis of MPH I.
• By using a blood test for alpha-L-iduronidase and/or DNA analysis, it is sometimes possible to distinguish Hurler syndrome from the other closely related MPH I subclasses, Hurler-Scheie syndrome and Scheie syndrome. However, distinguishing among these three MPS I subtypes is often difficult, and factors such as symptom severity and age of onset are generally used to establish a specific diagnosis. Inability to distinguish Hurler syndrome from the other MPH I subclasses does not affect treatment options, since these are the same for all three subclasses.
• Amniocentesis: When there is a family history of any of the three MPH I diseases, testing for MPH I may be performed on a fetus during pregnancy. The procedure used is called amniocentesis, and may be performed after fifteen weeks of pregnancy. During this procedure, a needle is inserted through the mother's abdomen, and fluid from the cavity surrounding the fetus is withdrawn. The amount of alpha-L-iduronidase enzyme is then measured in cells grown from the amniocentesis fluid sample. In some women, this procedure may cause some discomfort, irritation at the needle insertion site, fluid leakage, and cramping. There is a significant (one out of 200-400) risk of miscarriage associated with amniocentesis. Another commonly used fetal sampling technique, called chorionic villi sampling, may be performed as early as nine weeks into pregnancy. However, chorionic villi sampling is not often used for detection of MPH I in the fetus, since contamination with maternal tissue has been shown to result in inaccurate measurements of the alpha-L-iduronidase enzyme required for the diagnosis.
• Genetic testing: Family members who want to avoid having children because they may carry the gene for Hurler syndrome might wish to undergo genetic testing. To determine if a family member is a carrier of the defective gene, a blood test may be performed. In general, carriers will exhibit less alpha-L-iduronidase in their white blood cells than normal individuals who do not carry the faulty gene. However, there is considerable variability in the amount of alpha-L-iduronidase in MPH I gene carriers, so that it may not always be possible to determine carrier status using a standard blood test. In that case, DNA analysis may be used to determine if a person is a carrier. DNA testing for Hurler syndrome is performed only in certain specialized genetics laboratories. Generally, people who have DNA testing first meet with a genetic counselor, who will explain the testing in detail, answer questions, and explain the test results.

• Behavioral and neurological problems: Children with Hurler syndrome usually exhibit noticeable delays in the development of their learning abilities, beginning between one and two years of age. This developmental delay is progressive and may cause children to lose previously learned skills. The nervous system exhibits a variety of other severe abnormalities in children with Hurler syndrome that adversely affect their quality of life.
• Glucosaminoglycans are substances that are produced in excessive quantities in Hurler syndrome. These excess glucosaminoglycans are deposited in the membranes that surround and protect the brain and spinal cord. Therefore, these membranes tend to become thicker than normal, blocking the regular outflow of the fluid (called cerebrospinal fluid) that surrounds the brain and spinal cord. As cerebrospinal fluid builds up, the child may develop a condition called hydrocephalus, or "water on the brain," which may exert pressure on the brain tissue, resulting in convulsions and contributing to mental retardation.
• Abnormally high pressure on the spinal cord, which is considered a medical emergency, may occur. The abnormally high pressure on the spinal cord is caused by the increase in cerebrospinal fluid and/or by structural abnormalities during development of the bones in the neck. The resulting damage to the nerves in the spinal cord may cause loss of functioning of internal organs. Depending upon which part of the spinal cord is damaged, loss of control of urination and bowel function may occur. Pain and loss of the ability to move the limbs is also common.
• Breathing problems: The increased amount of glucosaminoglycans in the tissues of children with Hurler syndrome causes thickening of the mucous in the respiratory passages and enlargement of tonsils and adenoids, which are the immune tissues in the back of the throat. These changes may result in noisy breathing during waking hours and at night, as well as excessive snoring. It may also cause sleep apnea, a serious condition that occurs when the individual stops breathing for short periods of time during sleep.
• Breathing difficulties may also be caused by the unusually small volume of the chest cavity, narrowing of the small airway passages, and compression of the lungs by an enlarged liver or spleen. As the disease progresses, these breathing problems may worsen and may become life-threatening.
• Hearing problems: Children with Hurler syndrome are prone to ear infections. This is because built-up glucosaminoglycans may block the tubes in the middle ear, preventing them from draining properly. In severe cases, conduction of sound waves is also affected, resulting in hearing loss. In addition, auditory nerve damage is common, also resulting in hearing loss.
• Heart and circulatory problems: Abnormalities of the heart wall and heart valves due to build-up of glucosaminoglycans are common, and these often become life-threatening. Glucosaminoglycan build-up may also lead to thickening and blockage of blood flow in the coronary arteries, which are the sole source of blood for the heart's muscle tissue. The aorta, or large blood vessel that carries oxygen-rich blood from the heart, may become thickened. As a result, heart failure and death may occur before age 10 in the most severe cases.
• Skeletal, muscular, and joint problems: Children with Hurler syndrome suffer from extensive skeletal abnormalities that may affect the use of their hands and their ability to walk normally. Reduced range of motion in many different joints throughout the body is a common problem, and joint abnormalities may also cause pain and symptoms of arthritis.
• One characteristic that is very common in Hurler syndrome is "claw hand." This occurs when the fingers are permanently bent into a claw-like shape. It may result in the inability to write or to hold small objects.
• Carpal tunnel syndrome, caused by the compression of the medium nerve by a tendon in the wrist, is also a frequent problem in individuals with Hurler syndrome. This can lead to pain, tingling, and difficulties in the use of the hands.
• Swallowing may also become difficult due to glucosaminoglycans building up in the muscle tissue of the tongue, resulting in its enlargement. Tongue enlargement may also impair speech.
• Another common finding is a type of abnormal lower spinal curvature, known as the Gibbus deformity, which results in a humpbacked appearance. It may result in back pain and difficulty in walking.
• In many children with Hurler syndrome, abnormal skeletal development in the facial bones results in a characteristic appearance known as "gargoylism," which is characterized by an abnormally protruding forehead, coarse facial features, full lips, flared nostrils, and an abnormally low nasal bridge. Gum and tooth abnormalities are also often present.
• Vision problems: The main eye problem in children with Hurler syndrome is clouding of the cornea, which is the membranous structure that protects the outer surface of the eyeball. In one study, 16% of children with Hurler syndrome and 25% with the closely-related Hurler-Scheie syndrome, were found to have clouding of the cornea that was so extensive as to be classified as "severe," resulting in partial or even complete blindness. Other structural abnormalities of the eye are often present that may severely impair vision or cause blindness. These include glaucoma, which happens when the fluid pressure inside the eyeball increases, damaging the optic nerve. Damage to the retina, which is the portion of the back of the eye that contains the eye's light receptors, may also occur.

• General
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• At present, Hurler syndrome is considered to be incurable, since, for a cure, replacement of the faulty gene with a normal one in nearly all the cells in the body would most likely be required. This is a theoretical possibility, and research investigating the feasibility of this approach is ongoing. However, this type of treatment is not currently available as an option for Hurler syndrome.
• There are currently two different well-established approaches to the treatment of Hurler syndrome. Both approaches involve supplying children with the alpha-L iduronidase enzyme that they need in order to break down excess glucosaminoglycans that are responsible for the syndrome's complications.
• One approach to accomplish this consists of supplying the missing alpha-L-iduronidase enzyme in the form of a drug, which must be regularly injected. This type of approach is called enzyme replacement therapy. Enzyme replacement therapy may improve a child's problems with growth and bone development, breathing, joints, and heart complications. However, there is little evidence that it has any effect on neurological complications and mental development.
• The second approach to supplying the missing enzyme is to provide the child with normal bone marrow cells, donated from a healthy individual. This type of procedure is called bone marrow transplantation (BMT). In BMT, the child's own bone marrow cells are destroyed, and replaced with those from a healthy donor. These foreign bone marrow cells then provide a source of the missing enzyme. BMT is the only procedure currently available that has been shown to be capable of halting the progression of neurological complications, as well as many of the other complications associated with Hurler syndrome. Several studies have also shown significant improvement in tests of mental abilities in some children following BMT. However, regardless of whether enzyme replacement therapy, BMT, or both, are utilized, early diagnosis and treatment are essential, since it is difficult or impossible for any form of treatment to reverse damage already done during a child's development.
• Enzyme replacement therapy
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• Aldurazyme® (laronidase), a man-made version of the deficient alpha-L-iduronidase enzyme, has been approved by the U.S. Food and Drug Administration (FDA) for use in therapy for Hurler syndrome. The enzyme is administered weekly, by slow injection (infusion), into a vein. The procedure for laronidase infusion takes several hours and must be performed weekly. Significant improvement in lung function and walking ability in children with Hurler syndrome after long-term treatment with laronidase has been reported. However, laronidase administered by intravenous infusion cannot enter the brain, since the brain is normally protected by mechanisms that prevent entry of drugs and other foreign substances from the bloodstream. Therefore, improvement in brain and central nervous system functioning is neither observed nor expected. Direct injection of laronidase into the brain has also been attempted, with promising results, but this treatment remains experimental.
• Risks of enzyme replacement therapy:
  There are many uncomfortable, but relatively non-serious side effects associated with the infusion procedure, including flushing, fever, headache, nausea, and rash. The most frequently reported side effects of laronidase are chills, vomiting, nausea, rapid heartbeat, blood pressure increase, and decreased amounts of oxygen in the blood. Other possible side effects include upper respiratory tract infection and soreness at the injection site.
• There are also some serious and potentially life-threatening allergic reactions associated with this type of intravenous infusion, the most serious of which is called anaphylaxis. Anaphylaxis is a severe allergic reaction to the drug, or, in some cases, to other components in the infusion mixture. Anaphylaxis may result in constriction of the narrow air passages in the lungs, resulting in loss of the ability to breath. This may happen within minutes after the drug is administered, unless emergency treatment is available. Thus, laronidase infusion is usually performed in a hospital or clinic. Patients are also generally given anti-fever drugs and antihistamines immediately prior to the infusion to help reduce complications caused by these types of reactions.
• Bone marrow transplantation (BMT)
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• In bone marrow transplantation (BMT), the child's own bone marrow cells are destroyed by drugs and/or radiation, and replaced with those from a healthy donor. Radiation treatments are typically performed with the patient lying on his or her side. They take about 30 minutes, and are administered twice a day for several days prior to the BMT. The radiation treatment itself is painless. BMT may require up to six months in the hospital. Drugs that are used to destroy the patient's own bone marrow cells are called cytotoxic, or "cell-killing" drugs. Many of these drugs are the same as those used to kill cancer cells, and may include busulfan, melphalan, or methotrexate. After the patient's own bone marrow cells are destroyed using these treatments, the patient is supplied with new bone marrow cells from one of two different sources.
• One possible source of normal bone marrow cells is a healthy adult donor. In order to reduce the possibility of rejection reactions and to maximize the chances that the donor's cells will be able to function in their new environment, it is usually best if the donor is a close family member. The donor's cells are injected into a vein, and then migrate to the child's bone marrow, where they divide and replace the child's own defective cells.
• Another possible source of normal bone marrow cells is cord blood from an unrelated donor. Cord blood cells are cells obtained from a newborn's blood present in the umbilical cord after birth. Since cells from cord blood banks are now widely available, it is generally possible to find a "match" of the correct tissue type. This type of matching is necessary to enable the new bone marrow cells to function, and to reduce the possibility of rejection reactions. When injected into a vein, cord blood cells are capable of migrating to the bone marrow, dividing, and replacing the child's own defective bone marrow cells. Immune cells called macrophages are present in most tissues in the body. These cells are normally produced in the bone marrow, and then migrate into many different kinds of tissues throughout the body. Macrophages derived from the transplanted bone marrow are believed to be the main source of alpha-L-iduronidase that leads to clinical improvement after BMT in Hurler syndrome. The choice of whether to use cord blood cells from a blood blank, or to use bone marrow cells obtained from a healthy relative, is determined by the availability of a suitable donor, and how close of a "match" to the patient's tissue type can be found.
• In some children with Hurler syndrome who received a BMT, there was improvement in hearing, reduction in size of the abnormally large spleen and liver, improvement in lung functioning, and improvement of nervous system abnormalities. In some cases, there was also improvement in mental functioning and learning ability. Thus, in some, but not all, Hurler syndrome patients receiving BMT at a sufficiently early age, the possibility for long term survival is considered good. However, vision problems associated with corneal clouding and bone development abnormalities cannot be reversed by BMT. Surgical treatment for those problems is therefore often necessary.
• Risks of BMT: BMT is a highly complex and specialized medical procedure that requires advanced preparation for several common, but life threatening reactions. Graft-versus-host disease (GVHD) is a very common risk of BMT. In GVHD, the foreign bone marrow cells or cord blood cells from the donated marrow or cord blood (the graft) attack and damage the tissues of the transplant patient (the host). GVHD may affect many different parts of the body. The skin, eyes, stomach, and intestines are affected most often. GVHD can range from mild to life-threatening. GVHD can occur with any BMT, except when the donor is an identical twin. Drugs that suppress the immune system, such as corticosteroids, cyclosporine, and methotrexate may be used to try to halt GVHD, but these often have severe side effects, and can interfere with wound healing and normal immune defenses.
• Another major risk of BMT is graft failure, which is the term applied to any situation in which the donor cells fail to grow, and therefore cannot make new blood cells required for survival. Thus, graft failure may be life-threatening. Moreover, if the child's own cells were not successfully killed off during the preparatory drug and/or radiation treatments, then these enzyme-deficient cells may begin to re-grow in the bone marrow, as if there had been no transplant. In that case, the child may survive, but the progression of the disease would resume, and continue to worsen. Thus, graft failure is considered to carry a more significant risk for children being treated for Hurler syndrome than for many other diseases that are also treated using BMT.
• In addition, because BMT may disrupt the blood clotting mechanism, another potentially fatal risk of BMT is internal bleeding from the lungs.
• All of these risks occur frequently, and must therefore be weighed carefully. A child's age, severity of signs and symptoms, and their individualized progression of disease complications must all be considered, before BMT is attempted in any particular case.
• Surgery for complications
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• Surgery to remove tonsils and adenoids, which are the immune tissues in the back of the throat, may improve breathing among affected individuals with obstructive airway disorders and abnormal breathing during sleep. Sleep studies can assess airway status and the possible need for nighttime oxygen. Some patients may require surgical insertion of a tube into the windpipe to aid breathing. Surgery may also be required to correct hernias, and to help drain excessive cerebrospinal fluid from the brain. Surgical intervention may also be beneficial to free nerves and nerve roots trapped as a result of skeletal and other developmental abnormalities. Corneal transplants may improve vision among patients with significant corneal clouding. However, surgery in Hurler syndrome patients often presents special problems for anesthesiologists, since abnormalities in breathing may prevent the utilization of standard anesthetic procedures.
• Advice for caregivers
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• Because the complications of Hurler syndrome may vary widely from one person to the next, and because those complications may be severe, it is essential for a variety of specialists to be involved in the care and treatment of a child with this type of disorder. Thus, in addition to the primary care physician, physical therapists, orthopedic surgeons, otolaryngologists, ophthalmologists, neurologists, cardiologists, lung specialists, dentists, psychiatric specialists, social workers, and parents play a role in the care and management of children with this condition.
• Parents of children with Hurler syndrome can obtain up-to-date, detailed information about caring for their children from the National MPS Society. This organization provides regular newsletters and can direct parents and caregivers to the appropriate sources for knowledgeable, experienced help with family support issues, new therapies, clinical trials, and other topics that might help them better cope with the many complex tasks associated with the social as well as medical aspects of caring for a child with Hurler syndrome.

• Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or prevention of Hurler syndrome.

• Diet and lifestyle: Dietary modifications or lifestyle adjustments that can prevent or reverse Hurler syndrome have not been reported in the available literature. However, there is some evidence that limiting sugar intake and dairy products has helped reduce the severity of problems associated with excessive mucus production in some individuals. Increased fiber in the diet has also been shown to be helpful in some children with digestive system complications, such as constipation and diarrhea.
• Physical therapy and exercise: Physical therapy and daily exercise may delay joint problems and improve the ability to move. However, the developmental problems associated with Hurler syndrome are highly variable and extremely individualized, and excessive extension of affected joints can actually be harmful. Therefore, orthopedic doctors and physical therapists who are experienced with the mobility problems of Hurler syndrome patients should be consulted before any exercise program is undertaken.
• Genetic testing: If a blood or tissue sample from a blood relative with Hurler syndrome is available, DNA testing may be utilized to determine if a person is a carrier. Prenatal DNA testing may be performed if there is a family history of Hurler syndrome. However, there are serious risks associated with prenatal testing, including miscarriage. Therefore, patients should discuss the potential health risks and benefits before making any health-related decisions.
• Genetic counseling: People with family histories of Hurler syndrome can meet with genetic counselors. These professionals can help patients understand the risks of having a child with Hurler syndrome. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits.