Some science behind the scenes

Hunter syndrome

Hunter syndrome, or mucopolysaccharidosis II (MPS II), is a lysosomal storage disease caused by a deficient (or absent) enzyme, iduronate-2-sulfatase (I2S). The accumulated substrates in Hunter syndrome are heparan sulfate and dermatan sulfate. The syndrome has X-linked recessive inheritance.

There are estimated to be approximately 2,000 people afflicted with Hunter syndrome worldwide, 500 of whom live in the United States. There are 2 Hunter syndrome patients in New Zealand. There are 6 Hunter syndrome patients in Ireland, at least 1 case in Iran, 1 case in Saudi Arabia, 1 case in Chile, 1 case in Pakistan, 20 cases in the Philippines, 1 case in the West Bank (Palestine) and 70 Hunter syndrome patients reported in Korea. There is one case in the city of Kolkata, a boy in the city of Siliguri, West Bengal, India. In Gangtok, the 8-year-old son of the editor of 'Voice of Sikkim' also suffers from the disease.

A study in the United Kingdom indicated an incidence among males of approximately 1 in 130,000 male live births.

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 glycosaminoglycans (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) and noisy breathing generally.

 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 common symptom even in young children with Hunter syndrome, 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 and progressive loss of function. The rate and degree of progression may be different for each person with Hunter syndrome.

Although Hunter syndrome is associated with a broad spectrum of clinical severity, two main forms can be recognized - severe and mild/attenuated. The differences between the severe and attenuated forms are mainly due to the progressive development of neurodegeneration in the severe form. It is important to note, however, that though the terms "attenuated" or "mild" are used by physicians in comparing people with Hunter syndrome, the effects of even mild disease are quite serious. Between the two main forms of disease, and even within them, two of the most significant areas of variability concern the degree of mental retardation and expected lifespan.

Some people who have Hunter syndrome experience no mental handicaps and live into their 20s or 30s; there are occasional reports of people who have lived into their 50s or 60s.

In contrast, others with Hunter syndrome develop severe mental impairment and have life expectancies of 15 years or fewer often due to neurodegeneration or physical complications from the disease. The age at onset of symptoms and the presence/absence of behavioral disturbances are predictive factors of ultimate disease severity in very young patients. Behavioral disturbances can often mimic combinations of symptoms of attention deficit hyperactivity disorder, autism, obsessive compulsive disorder, and/or sensory processing disorder, although the existence and level of symptoms may differ in each affected child. They often also include a lack of an appropriate sense of danger, and aggression. The behavioral symptoms of Hunter syndrome generally precede neurodegeneration and often increase in severity until the mental handicaps become more pronounced.

Cause

The cause is a mutation to the I2S gene.

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 glycosaminoglycans (GAGs). 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 GAGs: 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.

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inherited diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.

References

  • Schwartz et al, A clinical study of 77 patients with mucopolysaccharidosis type II, Acta Paediatr (April 1996) vol 455 pp 63-70.
  • Annibali et al, Hunter syndrome (Mucopolysaccharidosis type II), severe phenotype: long term follow-up on patients undergone to hematopoietic stem cell transplantation, Minerva Pediatr. 2013 Oct;65(5):487-96.
  • Young ID, Harper PS (1982). "Incidence of Hunter's syndrome". Hum. Genet. 60 (4): 391–2. doi:10.1007/BF00569230. PMID 6809596.
  • Hunter, C. A. (1917). "A Rare Disease in Two Brothers". Proceedings of the Royal Society of Medicine (London) 10 (Sect Study Dis Child): 104–116. PMC 2018097. PMID 19979883.