In short
Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare genetic disorder that occurs almost exclusively in boys. This progressive condition affects many parts of the body, from physical appearance to organ function, and its severity varies greatly among affected individuals.
Identification codes and alternative names
Hunter Syndrome, Iduronate-2-Sulfatase Deficiency, I2S Deficiency, Mucopolysaccharidosis Type II (MPS II)
309900
What is Mucopolysaccharidosis Type II?
Mucopolysaccharidosis type II is a rare disease in which the body is missing or does not have enough of an enzyme (a specialized protein that helps break down substances in the body) needed to break down long chains of sugar molecules called glycosaminoglycans (GAGs). These GAGs were originally called mucopolysaccharides, which is where this condition gets its name.
The specific enzyme that is missing or not working properly is called iduronate 2-sulfatase, often shortened to I2S. This enzyme is responsible for the breakdown of two types of GAGs: heparan sulfate and dermatan sulfate. These substances are found throughout the body and help build bone, tendons, cartilage, corneas, skin, and connective tissue. They are also found in the fluid that lubricates the joints.
When the I2S enzyme is absent or present at low levels, the body cannot break down these sugar molecules properly. As a result, GAGs build up inside special compartments within cells called lysosomes. Lysosomes are parts of cells that break down and recycle molecules. This buildup causes damage to many organs and tissues throughout the body, leading to the various health problems seen in people with MPS II.
At birth, individuals with MPS II do not display any features of the condition. Between ages 2 and 4, they begin to develop signs of the disease. MPS II is classified as a lysosomal storage disorder, which is a group of conditions that cause sugar molecules to accumulate inside lysosomes.
Causes and inheritance
MPS II is caused by changes (called variants or mutations) in the IDS gene. This gene is located on the X chromosome and provides instructions for producing the I2S enzyme. The IDS gene consists of 9 sections called exons, and over 600 different types of mutations have been reported to cause MPS II.
The condition is inherited in an X-linked recessive pattern. This means the gene that causes the condition is located on the X chromosome, one of two sex chromosomes found in every cell. Because boys have only one X chromosome (inherited from their mother), a single altered copy of the IDS gene is enough to cause disease. Girls have two X chromosomes, so an altered copy of the IDS gene must be present in both chromosomes to cause disease, which is extremely rare.
Women who carry one normal X chromosome and one X chromosome with the genetic variation for disease are known as "carriers." These mothers do not have symptoms of the disease, but they can pass the condition to their sons. A few sporadic cases have been reported in carrier females, mainly due to nonrandom inactivation of one of their X chromosomes.
How common is this condition?
MPS II occurs in approximately 1 in 100,000 to 1 in 170,000 males. It is estimated that fewer than 40 babies are born with this rare condition each year in the United States. The condition occurs almost exclusively in boys, although it has been reported in a few girls.
The incidence varies by region and ethnicity. In some East Asian countries like Japan and South Korea, MPS II is the most common type of mucopolysaccharidosis, with higher incidence rates of 0.84/100,000 and 0.74/100,000 live births respectively.
Types of MPS II
There are two main types of MPS II: the neuropathic (severe) form and the non-neuropathic (attenuated or mild) form. The severity of the condition depends on how much I2S enzyme activity is present in the body.
The severe phenotype occurs in about 60% of affected individuals. In this form, the child develops normally until 3 or 4 years of age when behavioral changes, attention difficulties, speech delay, cognitive decline, and poor performance in school appear. This type presents initially with changes in the brain, including a buildup of fluid in the brain called hydrocephalus, followed by behavioral changes and involvement of the central nervous system. Children with this form also experience a decline in intellectual function and more rapid disease progression. They may develop episodes of epileptic seizures and hearing loss.
The attenuated phenotype is less severe. Patients have milder clinical symptoms without central nervous system involvement. They have normal cognitive and intellectual development. However, a few patients may report problems with the light-sensitive tissue in the back of the eye (retina) and neurological symptoms at an advanced stage.
While both types affect many different organs and tissues, people with neuropathic MPS II also experience a decline in intellectual function and a more rapid disease progression. Individuals begin to lose basic functional skills between the ages of 6 and 8.
Signs and symptoms
Newborn screening helps babies lead healthier lives by identifying the condition early. If a baby has an out-of-range result, it is important to follow healthcare provider instructions quickly. In some cases, treatment may need to start right away, even if signs or symptoms are not yet showing.
At birth, individuals with MPS II do not display any features of the condition. The signs and symptoms typically begin to appear in children between the ages of 2 and 4. Between these ages, affected children develop full lips, large rounded cheeks, a broad nose, and an enlarged tongue called macroglossia. The vocal cords also enlarge, which results in a deep, hoarse voice.
The timing that MPS II develops and the type of problems it causes vary between different people. Common symptoms include stiff joints, thickening of facial features including nostrils, lips and tongue, delayed appearance of teeth or wide spaces between teeth, and a larger than normal head (called macrocephaly) with a wide chest and short neck.
Narrowing of the airway causes frequent upper respiratory infections and short pauses in breathing during sleep called sleep apnea. As the disorder progresses, individuals need medical assistance to keep their airway open. Many affected individuals develop hearing loss that gets worse over time. Hearing loss occurs due to deformities in the middle ear, inner ear, and frequent ear infections.
Many other organs and tissues are affected in people with MPS II. Individuals with this disorder often have an enlarged liver and spleen (called hepatosplenomegaly), a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia), and thick skin that is not very stretchy. Some affected individuals also have distinctive white skin growths that look like pebbles.
Carpal tunnel syndrome commonly occurs in children with this disorder and is characterized by numbness, tingling, and weakness in the hand and fingers. Narrowing of the spinal canal (called spinal stenosis) in the neck can compress and damage the spinal cord.
The heart is also significantly affected by MPS II, and many individuals develop heart valve problems. Heart valve abnormalities can cause the heart to become enlarged and can eventually lead to abnormalities in the heart's rhythm and heart failure.
Children with MPS II grow steadily until about age 5, and then their growth slows and they develop short stature. Individuals with this condition have joint deformities (contractures) that significantly affect mobility. Most people with MPS II also have dysostosis multiplex, which refers to multiple skeletal abnormalities that can be seen on x-rays. This includes a generalized thickening of certain bones, particularly the ribs.
Diagnosis and testing
Newborn screening for MPS II requires collecting a small amount of blood from the baby's heel. Screening measures the activity of the enzyme I2S in the baby's blood. Screening may also measure GAG levels. Babies with low activity levels of I2S and high levels of GAGs might have MPS II.
An out-of-range screening result does not mean that a baby definitely has the condition. It does mean that the baby needs more follow-up testing. Healthcare providers will contact families to discuss next steps and follow-up plans. Any recommended follow-up testing should be completed as soon as possible, as babies with this condition can have serious health problems if they are not diagnosed and treated quickly.
The baby may need the following tests after an out-of-range screening result: blood and/or urine tests, and genetic testing using a blood sample. False-positive newborn screening results for this condition may happen. Some babies with positive newborn screening results for MPS II have a "pseudodeficiency," which means that the baby's enzyme levels are low on the screening but are normal in their body. These babies do not have and will never develop MPS II.
Healthcare providers use several tests to diagnose Hunter syndrome. A urine test checks for unusually high levels of sugar molecules (GAGs). Blood tests can check enzyme activity levels to determine if there is a deficiency of the I2S enzyme. The diagnosis is established by identification of absent or reduced I2S enzyme activity in leukocytes (white blood cells), fibroblasts (skin cells), or plasma in the presence of normal activity of at least one other similar enzyme.
Genetic testing can confirm the diagnosis by identifying changes in the IDS gene. Additional tests may include imaging studies such as x-rays to look for bone abnormalities, and examinations of the heart, eyes, and hearing.
Treatment and management
Currently, symptomatic treatment is the main therapeutic approach. There is no cure for MPS II, but there are treatments available to help manage the symptoms and slow down disease progression.
The medicine called idursulfase (brand name Elaprase) replaces the enzyme iduronate sulfatase and may be recommended. It is given through a vein (intravenously or IV) as a weekly infusion. This is the current standard of care and is approved to treat somatic (body) manifestations and prolong survival. Pretreatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions.
In patients aged 16 months to 5 years, no data are available to demonstrate improvement in disease-related symptoms or long-term clinical outcomes; however, treatment with idursulfase has reduced spleen volume in patients with MPS II. The medicine has also shown to improve walking capacity in patients aged 5 years and older. The safety and effectiveness of Elaprase have not been established in children younger than 16 months.
Hematopoietic stem cell transplantation (HSCT), also called bone marrow transplant, could provide sufficient enzyme activity to slow or stop the progression of the disease. However, no controlled clinical studies have been conducted in individuals with MPS II. Studies have shown that most children who underwent bone marrow transplant continued to show marked deterioration in their intellectual abilities, though some showed improvement in their physical symptoms.
Each health problem caused by this disease should be treated separately. Supportive care is essential and includes treatment of eye problems by an ophthalmologist with experience in MPS, early and aggressive treatment of ear infections (sometimes requiring pressure-equalizing tubes), hearing aids as needed, physical therapy for joint problems, and management of breathing problems with positive pressure ventilation (CPAP) as needed.
Many children with MPS II require surgical intervention for clinical complications. These include surgery for chronic hydrocephalus, tracheostomy (breathing tube), nerve entrapment (carpal tunnel syndrome), abdominal wall hernias, and joint contractures. Tonsillectomy and adenoidectomy may be needed, and hip replacement may be necessary as children grow older.
Gene therapy is a promising but inadequately developed treatment option. Difficulties with vector selection and efficiency of delivery persist, so this therapy is still in the early stages of development.
Life expectancy and prognosis
The life expectancy for people with MPS II varies greatly depending on the type and severity of the condition. People with the early-onset (severe) form usually live for 10 to 20 years. Their life expectancy is typically in the first or second decade of life due to progressive involvement of the central nervous system, progressive airway disease, and cardiac disease.
People with the late-onset (mild) form usually live 20 to 60 years. Survival into the early adult years with normal intelligence is common in the non-neuropathic phenotype. Individuals with non-neuropathic MPS II also have a shortened lifespan, but they typically live into adulthood, and their intelligence is not affected.
Heart disease and airway obstruction are major causes of death in people with both types of MPS II. The rate of progression varies among affected individuals, making it a progressively debilitating disorder.
Early diagnosis and treatment are important to help prevent or delay some of the severe health outcomes associated with the condition. When MPS-II is detected early and treatment is started, many individuals with the condition are able to live longer lives with improved growth and development.
