Hunter syndrome

Hunter syndrome, or mucopolysaccharidosis Type II, is a lysosomal storage disease caused by a deficient (or absent) enzyme, iduronate-2-sulfatase (I2S). The syndrome is named after physician Charles A. Hunter (1873–1955), who first described it in 1917. Born in Scotland, Hunter emigrated to Canada and had a medical practice in Winnipeg, Manitoba.

Overview
Hunter syndrome, or mucopolysaccharidosis II (MPS II), is a serious genetic disorder that primarily affects males (X-linked recessive). It interferes with the body's ability to break down and recycle specific mucopolysaccharides, also known as glycosaminoglycans or GAG. Hunter syndrome is one of several related lysosomal storage diseases.

In Hunter syndrome, GAG builds up in cells throughout the body due to a deficiency or absence of the enzyme iduronate-2-sulfatase (I2S). This buildup interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical manifestations for some people with Hunter syndrome include distinct facial features and large head. In some cases of Hunter syndrome, central nervous system involvement leads to developmental delays and nervous system problems. Not all people with Hunter syndrome are affected by the disease in exactly the same way, and the rate of symptom progression varies widely. However, Hunter syndrome is always severe, progressive, and life-limiting.

Diagnosis
The visible signs and symptoms of Hunter syndrome (MPS II) in younger people are usually the first clues leading to a diagnosis. In general, the time of diagnosis usually occurs from about 2 to 4 years of age. Doctors may use laboratory tests to provide additional evidence that an MPS disorder is present, before making a definitive diagnosis by measuring the iduronate-2-sulfatase (I2S) enzyme activity. The most commonly used laboratory screening test for an MPS disorder is a urine test for GAG. It is important to note that the urine test for GAG can occasionally be normal and yet the child still may have an MPS disorder. A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum, white blood cells, or fibroblasts from skin biopsy. In some people with Hunter syndrome, analysis of the I2S gene can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or in chorionic villus tissue.

Genetics
Since Hunter syndrome is an inherited disorder (X-linked recessive) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell in the human body has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father. If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. Alternatively, during egg and sperm formation, a mutation can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected.

Biochemistry
The human body depends on a vast array of biochemical reactions to support critical functions, including the production of energy, growth and development, communication within the body, and protection from infection. Another critical function is the breakdown of large biomolecules, which is the underlying problem in Hunter syndrome (MPS II) and related storage disorders. The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue of the body known as the extracellular matrix. This matrix is made up of a variety of sugars and proteins and helps to form the architectural framework of the body. The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together. One of the parts of the extracellular matrix is a complex molecule called a proteoglycan. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides, otherwise known as GAG. There are several types of GAG, each found in certain characteristic places in the body In Hunter syndrome, the problem concerns the breakdown of two GAG: dermatan sulfate and heparan sulfate. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme I2S. In people with Hunter syndrome, this enzyme is either partially or completely inactive. As a result, GAG build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this buildup continues, it interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. The rate of GAG buildup is not the same for all people with Hunter syndrome, resulting in a wide spectrum of medical problems.

Signs and Symptoms
The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth, but usually start to become noticeable after the first year of life. Often, the first symptoms of Hunter syndrome may include abdominal hernias, ear infections, runny noses, and colds. Since these symptoms are quite common among all infants, they are not likely to lead a doctor to make a diagnosis of Hunter syndrome right away. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical appearances of many children with Hunter syndrome include a distinctive coarseness in their facial features, including a prominent forehead, a nose with a flattened bridge, and an enlarged tongue. For this reason, unrelated children with Hunter syndrome often look alike. They may also have a large head as well as an enlarged abdomen. Many continue to have frequent infections of the ears and respiratory tract.

The continued storage of GAG in cells can lead to organs being affected in important ways. The thickening of the heart valves along with the walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened as well, leading to breathing problems while sleeping (obstructive airway disease). People with Hunter syndrome may also have limited lung capacity due to pulmonary involvement. As the liver and spleen grow larger with time, the belly may become distended, making hernias more noticeable. All major joints (including the wrists, elbows, shoulders, hips, and knees) may be affected by Hunter syndrome, leading to joint stiffness and limited motion. Progressive involvement of the finger and thumb joints results in decreased ability to pick up small objects. The effects on other joints, such as hips and knees, can make it increasingly difficult to walk normally. If carpal tunnel syndrome develops, a further decrease in hand function can occur. The bones themselves may be affected, resulting in short stature. In addition, pebbly, ivory-colored skin lesions may be found on the upper arms and legs and upper back of some people with Hunter syndrome. The presence or absence of the skin lesions is not helpful, however, in predicting clinical severity in Hunter syndrome. Finally, the storage of GAG in the brain can lead to delayed development with subsequent mental retardation. The rate and degree of progression may be different for each person with Hunter syndrome. There is a broad range of severity in the symptoms of Hunter syndrome. It is important to note that though the term "mild" is used by physicians in comparing people with Hunter syndrome, the effects of even mild disease are quite serious. Two of the most significant areas of variability concern the degree of mental retardation and expected lifespan. Some people who have Hunter syndrome are not mentally retarded and live into their 20s or 30s; there are occasional reports of people who have lived into their 50s or 60s. The quality of life remains high in a large number of people, and many adults are actively employed. In contrast, others with Hunter syndrome develop severe mental impairment and have life expectancies of 15 years or fewer.

Prevalence and incidence
There are estimated to be approximately 2,000 people afflicted with Hunter Syndrome worldwide, 500 of whom live in the United States. There are about 30 Hunter Syndrome patients in Canada. There is 1 Hunter Syndrome patient in New Zealand. There are 6 Hunter Syndrome patients in Ireland, 1 case in Saudi Arabia and 1 case in Chile.

A study in the United Kingdom indicated an incidence among males of approximately 1 in 130.000 male live births.

Treatment
Because of the very specific nature of the illness, treatment has been proven very difficult.

For information on clinical trials visit Clinicaltrials.gov

Palliative treatment
Because of the nature of the illness, and in front of the lack of really efficient treatment, it is important to emphasize the need for extensive palliative treatment against the diverse symptoms. Their objective is to reduce the effects of the deterioration of many bodily functions. Surgery and psychiatry are often pivotal here.

Bone marrow graft
For a long time, the most efficient approach has been to use bone marrow graft. It has the advantage of procuring a new source of the missing I2S. However, the results have been considered imperfect at best.

While the treatment is able to stop most of the symptoms, it is nearly totally inefficient against the brain symptoms of the Hunter syndrome patients. Mostly, this translates in much improved life expectancy, much improved life conditions but it does not solve the mental deficiencies of the patients.

However, bone marrow graft is a major surgical operation with several adverse effects of such surgery, including life threatening risks for the patient.

Because of these reasons, grafts have seen a decrease in their application as Hunter syndrome treatment.

Elaprase
Originally developed and introduced by 'Shire Human Genetic Therapies Ltd' (previously named 'Transkaryotic Therapies, Inc.'), on July 24, 2006, a synthetic version of I2S, called Elaprase (Idursulfase), was approved by the United States Food and Drug Administration as an enzyme replacement treatment for Hunter syndrome. Elaprase is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA technology in a human cell line. Elaprase may be one of the most expensive drugs ever produced, with an estimated cost of USD300,000 per patient, per year.

From the beginning, Elaprase has been considered as an opportunity to find most or all of the advantages of bone marrow grafts without some of its drawbacks.

A 53-week, randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that Elaprase provides clinically important benefits to Hunter syndrome patients. The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a 6-minute walk test and percent predicted forced vital capacity. Shire is pleased to report that this endpoint achieved statistical significance compared to placebo. After one year of treatment, patients receiving weekly infusions of Elaprase experienced a mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo. Treatment with ELAPRASE was generally well-tolerated by patients in the Phase II/III trial. Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate. The Elaprase label includes a boxed warning with information on the potential for hypersensitivity reactions. The boxed warning states that “Anaphylactoid reactions, which may be life threatening, have been observed in some patients during Elaprase infusions. Therefore, appropriate medical support should be readily available when Elaprase is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.”

In all phases of clinical study for Elaprase, eleven patients experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of a hypersensitivity reaction. The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache and arthralgia.

Fifty-one percent (32 of 63) of patients in the weekly Elaprase treatment arm in the pivotal clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies.

Parents of Hunter syndrome patients should be aware that the therapy implies a strict regimen of long duration IV transfusion. For hyperactive boys like most young Hunter syndrome patient, this is still a considerable constraint. Similarly, the permanent nature and the heaviness of this treatment is to be kept in mind.

Notable Cases
On July 24, 2004, Andrew Wragg, 38, of Worthing, West Sussex, England, suffocated his 10 year old son Jacob with a pillow, because of the boy's disabilities related to Hunter syndrome. On December 13, 2005 Andrew Wragg walked out of Lewes Crown Court a free man after a jury determined that he did not murder his 10-year-old son. A military security specialist, Wragg also claimed that he was under stress after returning from the war in Iraq. He denied murdering Jacob, but pleaded guilty to manslaughter by reason of diminished capacity. Mrs. Justice Anne Rafferty, calling the case "exceptional", gave Wragg a two-year prison sentence for manslaughter, then suspended his sentence for two years. Rafferty said there was "nothing to be gained" from sending Wragg to prison for the crime.