What is Mucopolysaccharidosis Type II (Hunter Syndrome )?
Hunter syndrome is a condition passed down through genes, affecting the body’s ability to breakdown certain large sugar molecules, due to an enzyme deficiency. The enzyme called iduronate 2-sulfatase (IDS) is responsible for breaking down sugar molecules known as glycosaminoglycans. This enzyme is particularly scarce in those with Hunter syndrome, resulting in an unusual build-up of two types of sugars – heparan sulfate (HS) and dermatan sulfate (DS), in different organs throughout the body. This syndrome primarily affects males and is usually noticed in childhood.
What Causes Mucopolysaccharidosis Type II (Hunter Syndrome )?
Mucopolysaccharidosis 2 (MPS II) is a medical condition that occurs due to a lack of activity from an enzyme called IDS. This enzyme is produced by a gene, also called IDS, which is found on a specific part of the X chromosome. The IDS gene is made up of nine sections, or exons, and over 600 different mutations, or changes in the DNA, have been found to cause MPS II. These mutations can include different types, like slight changes in the DNA, shifts in the DNA sequence, insertions, mutations at the splice site (where different parts of a gene can be joined together), and minor to complete removals of the gene. These genetic differences can lead to different forms, or phenotypes, of the disease.
There are two main phenotypes of Mucopolysaccharidosis 2 which are:
1. Severe Phenotype – This form affects about 60% of individuals with MPS II. The first symptom usually is increased fluid in the brain, or hydrocephalus. This is then followed by changes in behavior and involvement of the central nervous system (our brain and spinal cord). Children with this form of the disease typically develop normally until around the age of 3 or 4. At this time, they may start to show changes in behavior, have difficulty paying attention, delayed speech, decreased cognitive abilities, and poor performance in school. These children may also experience hearing loss due to abnormalities in the ears and frequent ear infections. Some children may also have episodes of epileptic seizures.
2. Attenuated Phenotype: This form is less severe and doesn’t involve the central nervous system. Patients usually have normal cognitive and intellectual development. Some patients may experience some vision damage and neurological symptoms in the later stages of the disease.
Risk Factors and Frequency for Mucopolysaccharidosis Type II (Hunter Syndrome )
Hunter syndrome is a rare genetic disorder that usually affects males. It was first identified by a doctor named Charles Hunter in 1917, who found it in two brothers. The brothers had a variety of symptoms, such as being short, having difficulty hearing, an enlarged skull, and increased size of the tongue. They also had some signs that appear on the face, an expanded tummy with bigger liver and spleen, and peculiar skeletal formations. One of them even had symptoms related to the nervous system, while the other didn’t.
This syndrome is quite uncommon, found in about one of every 162,000 male newborns. It’s connected to the X-chromosome and typically only affects males. Despite this, some rare cases have been observed in females who carry the disease due to changes or inaction of the normal genes on the X-chromosome.
Signs and Symptoms of Mucopolysaccharidosis Type II (Hunter Syndrome )
Hunter syndrome is a complex condition that can affect many areas of the body.
Central Nervous System:
Initially, Hunter syndrome might show up as hydrocephalus, which leads to an enlarged head size. This is followed by issues like behavioral problems, difficulty paying attention, extreme activity, and seizures. Trouble with concentration can be linked to a smaller corpus callosum in the brain. Also, these individuals often struggle academically and have delayed language skills due to hearing loss and cognitive difficulties.
Oral Cavity:
These individuals may have a different number of teeth than normal, issues with their tooth enamel, abnormal tooth shapes, jaw defects, and improper tooth alignment. They may also experience cavities, cysts, and abscesses more frequently. Therefore, regular dentist check-ups are recommended.
Respiratory System:
There could be excessive buildup of a substance known as GAG in the respiratory tract, lymphoid organs, and tongue. This may lead to an enlarged tongue, swelling of the tonsils and vocal cords, and narrowing of the windpipe. They may produce an excessive amount of thick respiratory secretions and have an overactive immune response in the respiratory tract. This can lead to recurrent sinusitis, middle ear infections, loud and noisy breathing, and breathing difficulties during sleep due to narrowed airways.
Cardiovascular System:
The heart valves are primarily made of dermatan and heparan sulfate. In people with Hunter syndrome, the accumulation of these substances can cause thicker heart valves leading to heart valve disease, left ventricular hypertrophy, and high blood pressure.
Gastrointestinal System:
The progressive buildup of GAG in the abdominal organs can cause hepatosplenomegaly (an enlarged liver and spleen). This can result in a protruding stomach and can increase the pressure inside the abdomen. This may also lead to chronic diarrhea with mucus-filled stools, and hernias (inguinal and umbilical).
Musculoskeletal System:
Affected individuals might exhibit features like rough facial features, short stature, joint stiffness, and muscle disease. They may also show skeletal abnormalities like shortened stature, kyphosis, scoliosis, and rib cage deformities. These spinal deformities can cause complications such as muscle weakness, paralysis, and incontinence. Joints may also become painful and stiff, and the range of motion may decrease. There can also be accumulation of dermatan and heparan sulfate in muscles and tendons, causing muscle disease, and death of muscle cells. These can lead to changes in the hip, knee, ankle, shoulder, and wrist joints, decreasing movement and muscle power.
Testing for Mucopolysaccharidosis Type II (Hunter Syndrome )
If your doctor suspects you have Hunter syndrome, they might start with a urine and blood test to check your GAG (glycosaminoglycans) levels. These are sugar molecules, and higher levels in your blood could suggest a group of conditions called lysosomal storage diseases, which include Hunter syndrome. Nevertheless, the urine test is not always accurate, especially in milder cases of the disease. So, the level of GAGs in your urine may not increase as the disease progresses or might vary depending on your kidney function.
The ‘gold standard’ or most reliable test for Hunter syndrome, however, is checking your IDS (Iduronate sulfatase) levels. These are enzymes, and they can be checked in the culture of various cells such as white blood cells, fibroblasts (a type of cells found in connective tissues), and dried blood cells. Doctors can also measure IDS levels in blood plasma or serum samples. In more advanced cases of the condition, IDS levels can be very low or even undetectable. Sometimes, doctors check levels of other enzymes to rule out other similar conditions.
If other tests are not conclusive or the patient’s symptoms are not typical of Hunter syndrome, then the doctor might carry out genetic testing. This can provide a definitive diagnosis and it’s also used for females who show signs of this condition, even though it’s very rarely seen in girls.
Your doctor might also order imaging tests, like X-rays, if your symptoms suggest you might have Hunter syndrome. These can show changes in your bones and joints, which are common in this condition. These changes, collectively called “dysostosis multiplex,” could include specific deformities in the skull, curved or bent bones in the spine (scoliosis and kyphosis, respectively), things like shortened long bones (like the bones in your arms and legs), and changes in the small bones of your hands, feet, and wrists.
Treatment Options for Mucopolysaccharidosis Type II (Hunter Syndrome )
Hunter syndrome, or MPS II, is a condition that currently does not have a permanent cure. However, a team of various healthcare professionals can manage the condition by making up for the enzyme deficiency in the body and managing associated symptoms. Hunter syndrome treatments are primarily enzyme replacement therapy and hematopoietic stem cell transplantation.
Enzyme replacement therapy:
Recombinant IDS is a form of treatment that involves introducing a lab-created enzyme into the body. This helps to increase the amount of IDS enzyme, which the bodies of those with Hunter syndrome lack. This therapy can cause significant improvements in symptoms like characteristic facial features, stiff joints, and high frequency of respiratory infections. However, this therapy is not effective in reducing symptoms that affect the central nervous system (CNS), as the enzyme can’t cross the blood-brain barrier when given through an IV. Scientists are exploring other ways to administer this treatment to increase its effectiveness on CNS symptoms. So far, early results showed improvement in neurocognitive symptoms, but there are risks of serious side effects.
Hematopoietic stem cell transplantation (HSCT):
This treatment involves replacing bone marrow (bone marrow produces blood cells) with healthy stem cells that can cross the blood-brain barrier. HCST is generally preferred over enzyme replacement therapy because it’s a one-time procedure that provides significant improvements in physical and cognitive symptoms related to Hunter syndrome. However, it’s important to remember that this procedure must be done before neurological symptoms emerge. Some of the observed improvements include reduction of enlarged liver and spleen, less thickening of the heart valves, improved speech, elasticity, and joint mobility.
NSAIDs:
Patients with Hunter syndrome often have inflammation and degenerative changes in their joints, causing pain and decreasing their range of joint movement. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are medications that reduce inflammation and can prevent the progression of these changes. They can also relieve pain, improving mobility and independence in daily tasks.
Gene therapy:
Researchers are actively exploring gene therapy, a one-time procedure that is anticipated to be superior to both enzyme replacement therapy and hematopoietic stem cell transplantation in terms of safety and efficacy. Since Hunter syndrome is caused by a faulty gene, gene therapy involves introducing a normal copy of the gene into the patient’s cells.
What else can Mucopolysaccharidosis Type II (Hunter Syndrome ) be?
- Mucopolysaccharidosis Type III (also known as Sanfilippo syndrome)
- Mucopolysaccharidosis Type IS
- Mucopolysaccharidosis Type IH
- Mucopolysaccharidosis Type I H/S
- Mucopolysaccharidosis Type VII (also known as Sly syndrome)
What to expect with Mucopolysaccharidosis Type II (Hunter Syndrome )
The outcome for individuals with Hunter syndrome largely depends on the specific characteristics of their disease. Those with a severe form of Hunter syndrome often face a high risk of dying young, commonly by their teen years, mainly due to lung problems, heart valve irregularities, or a combination of both.
Conversely, those with a milder (or “attenuated”) form of Hunter syndrome have a longer expected lifespan, often living until their fifties. Despite having a longer life expectancy than those with the severe form, the primary causes of death remain the same, being lung problems and heart valve issues.
Possible Complications When Diagnosed with Mucopolysaccharidosis Type II (Hunter Syndrome )
Complications from the progressive build-up of GAG in various tissues and organs can arise. Here are the main complications:
- Hydrocephalus, or excess fluid in the brain
- Short height
- Joints becoming stiff at the hip, resulting in the need for a wheelchair
- Breathing problems due to a thickened windpipe wall, enlarged tonsils, adenoids, and oversized tongue
- Heart muscle disease
- Narrowing or leakiness of the heart’s mitral and aortic valves
- Enlarged liver which could eventually lead to impaired liver functions
Preventing Mucopolysaccharidosis Type II (Hunter Syndrome )
Patients should be advised about the need for ongoing check-ups. Regular heart check-ups with a heart doctor (cardiologist) should be done every year to check on the heart valves and heart function. An echocardiogram, which is a type of ultrasound scan for the heart, should also be done regularly to identify any abnormal heart rhythms, blocked heart valves, leaky heart valves, or heart muscle disease.
An orthopedic surgeon, a specialist in conditions related to bones and joints, should also evaluate the patient’s joint function and the severity of any joint contractures (permanent shortening of muscles or joints). Potential treatments for joint pain or stiffness can include physical therapy, steroid injections into the joints, or even surgery.
Additionally, it’s crucial to closely watch the mental health and learning abilities of these patients. Patients with MPS II, a rare metabolism disorder, often face higher risks of depression and social withdrawal during their teenage years. Parents should be educated and counseled about these potential mental health and learning challenges. A variety of methods can be offered to handle hyperactivity, learning disabilities, and mood disorders, including counseling, medication management, special education classes, Individualized Education Programs (IEPs), classroom accommodations, and behavioral therapy. Psychologists can provide essential support to the patient and their families throughout this process.