Hunter syndrome

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Hunter syndrome 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.

Hunter syndrome is a serious genetic disorder that primarily affects males. 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.

There are estimated to be approximately 2,000 people afflicted with Hunter Syndrome worldwide, 500 of which live in the United States.

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.

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.

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 inguinal 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 manifestations for some people with Hunter syndrome include distinct facial features, a large head, and an enlarged abdomen. People with Hunter syndrome may also experience hearing loss, thickening of the heart valves leading to a decline in cardiac function, obstructive airway disease, sleep apnea, and enlargement of the liver and spleen. Range of motion and mobility may also be affected. In some cases of Hunter syndrome, central nervous system involvement leads to developmental delays and nervous system problems.

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.

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. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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.

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. ^[1][2][3]

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Hunter syndrome is a serious genetic disorder that primarily affects males. 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 build 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.

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. However, 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. Hunter syndrome has been reported to occur in females.

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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There are estimated to be approximately 2,000 people afflicted with Hunter Syndrome worldwide, 500 of which live in the United States.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief:

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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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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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.

• Airway obstruction
• Carpal tunnel syndrome
• Hearing loss
• Joint stiffness
• Contractures
• Deterioration of mental function over time

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 less.

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