|Structure of heparan sulfate, one of the GAGs that builds up in the tissues of people with Hunter syndrome|
|Symptoms||Skeletal abnormalities, hearing loss, retinal degeneration, enlarged liver and spleen|
|Complications||Upper airway disease; cardiovascular failure|
|Causes||Defiency of the enzyme iduronate-2-sulfatase|
|Differential diagnosis||Mucopolysaccharidosis type I; other mucopolysaccharidoses|
|Prognosis||In severe cases, death usually occurs by age 15. In attenuated cases, patients may survive into their 50s|
|Frequency||1 in 100,000 to 150,000 male births|
Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a lysosomal storage disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. These chemicals are types of glycosaminoglycans (GAGs), also known as mucopolysaccharides. Hunter syndrome is the only MPS syndrome to exhibit X-linked recessive inheritance.
The symptoms of Hunter syndrome are comparable to those of MPS I. Hunter syndrome causes abnormalities in many organs, including the skeleton, heart, and respiratory system. In severe cases, this leads to death during the teenage years. Unlike MPS I, corneal clouding is not associated with this disease.
Signs and symptoms
Hunter syndrome may present with a wide variety of phenotypes. Hunter syndrome has traditionally been categorized as either "mild" or "severe" depending on the presence of central nervous system symptoms. However, this is an oversimplification. Patients with "attenuated" or "mild" forms of the disease may still suffer from significant health issues. For severely affected patients, the clinical course is relatively predictable; patients will normally die at an early age. For those with milder forms of the disease, there is a wider variety of outcomes. Many live into their 20s and 30s, but some may have near-normal life expectancies and may even have children. Cardiac and respiratory abnormalities are the usual cause of death for patients with milder forms of the disease.
The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth. Often, the first symptoms may include abdominal hernias, ear infections, runny noses, and colds. As the buildup of GAGs 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. They may also have a large head, as well as an enlarged abdomen. For severe cases of MPS II, a diagnosis is often made between the ages of 18 and 36 months. In milder cases, patients present similarly to children with Hurler–Scheie syndrome, and a diagnosis is usually made between the ages of 4 and 8 years.
The continued storage of GAGs leads to abnormalities in multiple organ systems. After 18 months, children with severe MPS II may suffer from developmental decline and progressive loss of skills. The thickening of the heart valves and walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened, as well, leading to obstructive airway disease. As the liver and spleen grow larger with time, the abdomen may become distended, making hernias more noticeable. All major joints 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 walking normally increasingly difficult. If carpal tunnel syndrome develops, 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, legs, and upper back of some people with Hunter syndrome. These skin lesions are considered pathognomic for the disease. Finally, the storage of GAGs in the brain can lead to delayed development with subsequent mental retardation and progressive loss of function.
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 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. By the time of death, most children with severe MPS II have severe mental disabilities and are completely dependent on their caretakers.
MPS II primarily affects males due to its X-linked recessive inheritance. It interferes with the body's ability to break down and recycle specific mucopolysaccharides (GAGs). Hunter syndrome is one of several related lysosomal storage diseases called the MPS diseases. The inability to break down certain GAGs leads to their inappropriate buildup in the lysosomes of all body tissues.
Since Hunter syndrome is an X-linked recessive disorder, it preferentially affects male patients. The IDS gene is located on the X chromosome. Females generally have two X chromosomes, whereas males generally have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.
If a female inherits one copy of the mutant allele for MPS II, she will usually have a normal copy of the IDS gene which can compensate for the mutant allele. This is known as being a genetic carrier. However, a male who inherits a defective X chromosome does not have another X chromosome to compensate for the mutant gene. Thus, a female would need to inherit two mutant genes in order to develop Hunter Syndrome, while a male patient only needs to inherit one mutant gene. However, it is possible for a female carrier to be affected due to X-inactivation, which is a random process.
The human body depends on a vast array of biochemical reactions to support critical functions. One of these functions is the breakdown of large biomolecules, which is the underlying problem in Hunter syndrome and related storage disorders.
The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue known as the extracellular matrix. This matrix is made up of a variety of sugars and proteins. It 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 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 (GAGs).
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, GAGs build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. The rate of GAGs buildup is not the same for all people with Hunter syndrome, resulting in a wide spectrum of medical problems.
The first laboratory screening test for an MPS disorder is a urine test for GAGs. Abnormal values indicate that an MPS disorder is likely. The urine test can occasionally be normal even if the child actually has 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. If a specific mutation is known to run in the family, prenatal molecular genetic testing can be performed. DNA sequencing can reveal if someone is a carrier for the disease.
Because of the wide variety of phenotypes, the treatment for this disorder is specifically determined for each patient. Until recently, there was no effective therapy for MPS II. Because of this, palliative care was used. However, recent advances have led to medications which can improve survival and well-being in people with MPS II.
Enzyme replacement therapy
Idursulfase, a purified form of the missing lysosomal enzyme, underwent clinical trial in 2006 and was subsequently approved by the United States Food and Drug Administration as an enzyme replacement treatment for Hunter syndrome. Idursulfase beta, another enzyme replacement treatment, was approved in Korea by the Ministry of Food and Drug Safety.
Recent advances in enzyme replacement therapy (ERT) with idursulfase have been proven to improve many signs and symptoms of MPS II, especially if started early in the disease. After administration, it can be transported into cells in order to break down GAGs. However, as the medication cannot cross the blood–brain barrier, it is not expected to lead to cognitive improvement in patients with severe central nervous system symptoms. Even with ERT, treatment of various organ problems from a wide variety of medical specialists is necessary.
Bone marrow and stem cell transplantation
Bone marrow transplantation and hematopoietic stem cell transplantation (HSCT) have been used as treatments in some studies. While transplantation has provided benefits for many organ systems, it has not been shown to improve the neurological symptoms of the disease. Although HSCT has shown promise in the treatment of other MPS disorders, its results have been unsatisfactory so far in the treatment of MPS II. ERT has been shown to lead to better outcomes in MPS II patients.
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. 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, called 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. 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.
Beginning in 2010, a phase I/II clinical trial evaluated intrathecal injections of a more concentrated dose of idursulfase than the intravenous formulation used in enzyme replacement therapy infusions, 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.
In 2017, a 44-year-old patient with Hunter syndrome was treated with gene therapy in an attempt to prevent further damage by the disease. This is the first case of gene therapy being used in vivo in humans. The study was extended to six patients in 2018.
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