|Classification and external resources|
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.
- 1 Etymology
- 2 Pathophysiology
- 3 Signs and symptoms
- 4 Diagnosis
- 5 Treatment
- 6 Epidemiology
- 7 Notable cases
- 8 See also
- 9 References
- 10 External links
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, 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.
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 IDS 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 IDS gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal IDS gene, and she passes along the abnormal gene to him. Alternatively, during egg and sperm formation, a mutation can develop in the IDS 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 IDS gene and are usually not affected.
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 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) 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. Since the implementation of enzyme replacement therapy for Hunter syndrome, lifespans for those without mental handicaps are expected to lengthen since their physical disease appears to improve or stabilize with such treatment. 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 often due to neurodegeneration or physical complications from the disease. The age at onset of symptoms and the presence/absence of behavioural 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.
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.
Because of the very specific nature of the illness, treatment has been proven very difficult. The treatment for this disorder can usually be diagnosed specifically for specific patients because all cases are different.
Because of the nature of the illness, and absent a 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. In light of the diversity of symptoms, it is quite common to use a wide spectrum of palliative strategies where surgery and therapies are often pivotal.
Bone marrow graft and hematopoietic stem cell transplantation
For a long time, the most efficient approach had been to use bone marrow graft, emerging into hematopoietic stem cell transplantation. Based upon the same theory, they each have the advantage of procuring a new source of the missing I2S. However, the results have been considered imperfect at best.
While this treatment alternative is able to improve or stop the progression of some of the physical symptoms, it does not prevent the eventual cognitive regression that occurs in Hunter syndrome patients who are cognitively affected, although it may slow such regression early on. Therefore, for attenuated patients, this may still serve as a viable treatment option because of its more permanent nature, possibly even equivalent to weekly enzyme replacement therapy, resulting in much improved life expectancy.
However, even for attenuated patients, it is a major intervention with not insignificant mortality risks and potential for life-threatening or altering complications such as graft-versus-host disease. For cognitively affected patients, without solving the challenge of cognitive regression, it is limited at best as a permanent treatment alternative. Because of all these reasons, grafts have seen a decrease in their application as Hunter syndrome treatment.
Idursulfase, a purified form of the lysosomal enzyme iduronate-2-sulfatase produced by recombinant DNA technology in a human cell line which underwent clinical trial in 2006 was approved by the United States Food and Drug Administration as an enzyme replacement treatment for Hunter syndrome.
Beginning in 2010, a Phase I/II clinical trial evaluated intrathecal injections of a more concentrated dose of Idursulfase than the intravenous formulation in hopes of preventing the cognitive decline associated with the severe form of the condition. Results were reported in October 2013. A Phase II/III clinical trial began in 2014.
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 (Israel) and 70 Hunter syndrome patients reported in Korea. There is one case in the city of Kolkata, West Bengal, India as broadcast by a regional television channel. In addition, reports include approximately 20 cases in Poland.
A study in the United Kingdom indicated an incidence among males of approximately 1 in 130.000 male live births.
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, who was diagnosed with Hunter syndrome. 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.
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- Hunter's syndrome (Charles A. Hunter) at Who Named It?
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- 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.
- Muenzer, J; Wraith, JE; Beck, M; Giugliani, R; Harmatz, P; Eng, CM; Vellodi, A; Martin, R; Ramaswami, U; Gucsavas-Calikoglu, M; Vijayaraghavan, S; Wendt, S; Puga, AC; Ulbrich, B; Shinawi, M; Cleary, M; Piper, D; Conway, AM; Kimura, A (August 2006). "A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome).". Genetics in medicine : official journal of the American College of Medical Genetics 8 (8): 465–73. doi:10.1097/01.gim.0000232477.37660.fb. PMID 16912578.
- "A Phase I/II, Randomized, Safety and Ascending Dose Ranging Study of Intrathecal Idursulfase-IT Administered in Conjunction With Intravenous Elaprase in Pediatric Patients With Hunter Syndrome and Cognitive Impairment". Clinicaltrials.gov. U.S. National Institutes of Health. 6/12/2009. Retrieved 7/20/14.
- "A Safety and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous System Involvement and Are Receiving Treatment With Elaprase® - Results". Clinicaltrials.gov. U.S. National Institutes of Health. 10/31/13. Retrieved 7/20/14.
- "Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment (AIM-IT)". Clinicaltrials.gov. U.S. National Institutes of Health. July 2014. Retrieved 7/20/14.
- LaTercera.com (in Spanish)
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- NEWS.BBC.co.uk, "Father cleared of murdering son", BBC News
- Guardian.co.uk, "Former SAS soldier who smothered terminally ill son walks free" The Guardian
- NEWS.BBC.co.uk, "Review 'will clarify murder laws'" BBC News
- MPSsociety.org, National MPS Society
- About.com, "Hunter Syndrome", About.com
- CCHS-DL.SLIS.ua.edu, Hunter Syndrome Patient/Family Resources CCHS Resources
- GeneReview/NIH/UW entry on Mucopolysaccharidosis Type II
- HideandSeek.org, Foundation For Lysosomal Disease Research
- Elaprase.com, (idursulfase) website
- LysosomalStorageResearch.ca, The Hunter Disease eClinic and eBook — virtual education (English), (Japanese)
- SavingCase.com, Saving Case & Friends
- HunterSyndromeResearch.org, Hunter Syndrome Research Coalition