Hunter Syndrome

Genetics

MPS II (or Hunter Syndrome) is a genetic disorder caused by a mutation to the I2S (iduronate-2-sulfatase) gene – this can be caused by inheriting the mutated gene, or by a mutation to the gene during egg and sperm formation. The latter case is rare, and the chance of the same mutation occurring in subsequent generations is low as neither the mother nor the father themselves carry the recessive gene.

MPS II most often affects males, as it is what is referred to as a sex-linked disease. This means that the I2S gene is located on the X chromosome, and not the Y. Since females have two X chromosomes, they are more likely to have a dominant X gene which supersedes the recessive (mutated) gene; males, having only one X chromosome, do not have this advantage and thus if they have the recessive gene, they will express the disease. Women are carriers, but very rarely develop MPS II, and generally MPS II only occurs in males.

There are approximately 2,000 people with Hunter Syndrome worldwide.

Effects

The mutation to the I2S gene means that the protein produced by the gene cannot function normally, and therefore the enzyme iduronate-2-sulfatase (I2S) is either absent or deficient. Enzymatic functions within the body are crucial to normal functioning as enzymes are the power-houses of the cell: they catalyze and facilitate reactions which allow the body to function normally. The I2S enzyme is one which breaks down and recycles specific mucopolysaccharides, also known as glycosaminoglycans (GAGs); Hunter Syndrome is one of several lysosomal storage diseases.

Due to the absence or inability of the I2S enzyme to function properly, GAGs builds up in cells throughout the body. This build-up interferes with the way the cells, and consequently organs, of the body function and leads to a variety of serious symptoms. Due to the fact that the symptoms are due to the buildup of GAGs, Hunter Syndrome is progressive: the symptoms get worse as the individual ages. The symptoms usually begin to appear in the first year of life, but many are also common in “healthy” children, and seem unrelated to physicians not familiar with MPS II. However, as the child ages, the severity of the symptoms increase, and the doctors begin to order testing. Some of these symptoms include: coarse facial features, enlarged abdomen (due to enlarged organs), abnormal skeleton and stunted growth, progressive joint stiffness, developmental delays, and loss of hearing.

There is no “date” for the onset of signs and symptoms, and not everyone with Hunter Syndrome is affected in exactly the same way; the rate of symptom progression varies widely. But one thing is clear: Hunter Syndrome is always severe, progressive, and shortens a child’s life span considerably. Due to the progressive nature of the disorder, there are chronic signs and symptoms of Hunter Syndrome which increase in severity with age and include: obstructive airway disease, frequent pneumonia, progressive skeletal dysplasia (limited movement), cardiac and valvular heart disease, progressive hearing loss, and central nervous system involvement. The central nervous system involvement is due to the storage of GAGs in the brain, which can cause delayed development.

Treatment

Due to the specific nature of the illness, treatment is difficult. For a long time, bone marrow grafts were used as a way to provide a source of the missing I2S for patients with MPS II, but the treatment is nearly totally inefficient against the neurological symptoms of Hunter Syndrome patients. Not to mention the fact that bone marrow grafts are a major surgical operation, and this treatment option has decreased.

In 2006, a drug company called Shire Human Genetic Therapies Ltd.developed a drug called Elaprase (Idursulfase), which is a synthetic version of the enzyme iduronate-2-sulfatase (I2S) and is produced by recombinant DNA technology. Elaprase provides most or all of the advantages of bone marrow grafts without some of the drawbacks. This kind of treatment is referred to as ERT – enzyme replacement therapy.

There is a broad range in the severity of symptoms of Hunter Syndrome, and although physicians distinguish between mild and more severe manifestations of MPS II, the effects of even the mild disease are quite serious. Two of the most significant areas of variability between the two concern the degree of developmental delays and expected lifespan. Without treatment, MPS II is a terminal illness that shortens the child’s lifespan considerably: in more severe forms, the life expectancy is usually 15 years or lower, with significant central nervous system involvement.

For more information, see: www.treypurcell.com and www.mpssociety.ca.