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Mucopolysaccharidosis II (MPS II) also known as “Hunter syndrome” is a rare X-linked disease that primarily affects males, with pathologic manifestations in multiple organ systems and tissues. The disease is caused by a defect in the gene coding for the lysosomal enzyme Iduronate-2-sulphatase (I2S); as a result, the cells of affected individuals either are unable to produce the enzyme or produce it in low amounts. This results in an inability of the lysosome to effect the stepwise degradation of certain glycosaminoglycans (GAGs) - namely dermatan sulfate and heparan sulfate - a process essential for normal growth and homeostasis of tissues. These glycosaminoglycans, which are important constituents of the extracellular matrix, joint fluid, and connective tissue throughout the body, progressively accumulate in the lysosome, ultimately causing cell, tissue, and organ dysfunction by largely unknown pathophysiological mechanisms. This buildup of GAGs over time makes signs and symptoms of Hunter syndrome become more obvious. Although the signs and symptoms may vary from person to person, some of the common features 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. 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 may be life-limiting.

The Diagnosis of Hunter Syndrome(MPS II)

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. Making the diagnosis of Hunter syndrome involves 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. The physician may also order a set of Xrays (typically of the hands, long bones, and spine) to look for a specific pattern of bone development that can be suggestive of a diagnosis of Hunter syndrome. 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.

The Genetics of Hunter Syndrome (MPS II)

Hunter syndrome (MPS II) affects at least 1 in 162,000 people. 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 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. However, Hunter syndrome has been reported to occur in females.