Overview

Hunter syndrome, also known as mucopolysaccharidosis type II, is a rare genetic disorder where the patient can’t properly digest a specific group of sugar molecules termed glycosaminoglycans (GAGs). 

The people affected by Hunter syndrome present a mutation (a change) in their IDS gene, encoding the enzyme iduronate 2-sulfatase (I2S), which breaks down GAGs in the body. 

Without enough or any of this enzyme in the body, such as in Hunter syndrome patients, no GAGs can be broken down, and instead, these sugar molecules build up in their cells in some small structures called lysosomes. This results in the significant build-up of GAGs in lysosomes all over the body, damaging various organ systems and negatively impacting the physical and mental development of the patient.¹  

Hunter syndrome predominantly occurs in people assigned male at birth (AMAB), and this is because this genetic disorder is known as an X-linked recessive disease, where the defected IDS gene is present on the X chromosome. 

People assigned female at birth (AFAB) have two X chromosomes (one inherited from each of their parents). If one of their chromosomes contains a mutated IDS gene, the other normal IDS gene on the other chromosome will still produce normal I2S enzyme, and the cells in their body will break down GAGs normally.  

However, people AMAB only have one X chromosome (inherited from the mother), and hence if their inherited chromosome contains a mutated IDS gene, then no I2S enzyme is made, and Hunter syndrome occurs.¹ 

This genetic disorder unfortunately often leads to severe symptoms in patients, resulting in a poor quality of life and death.¹ However, early diagnosis and active research into finding the best treatments can help people suffering from Hunter syndrome delay or prevent this. 

This article will detail the symptoms, the diagnosis methods and treatment options for Hunter syndrome. 

Symptoms of hunter syndrome 

The first signs of Hunter syndrome appear at around 4 years of age. Hunter syndrome is divided into two types: neuronopathic Hunter syndrome (severe type), and non-neuronopathic Hunter syndrome (milder type).

Neuronopathic hunter syndrome

60% of all Hunter syndrome cases develop into the severe, neuronopathic type.² The first sign of this type is hydrocephalus – the buildup of fluid in the brain. This typically leads to behavioural changes ( hyperactivity or difficulty paying attention), hearing loss and seizures.³

Other symptoms which patients typically develop in their childhood include:

• A decline in their cognitive and intellectual abilities - For example, patients tend to struggle at school and in developing their language skills. 
• Problems with their respiratory system - For example the narrowing of their windpipe (trachea), the enlargement of their vocal cords and macroglossia (the thickening of their tongue), all of which can lead to problems in breathing.
• Physical changes to the face - For example, patients typically have delayed teeth growth, an abnormal number of teeth, an atypical structure of their jaw, enlarged head, lips and nostrils, malocclusion (crowded teeth), short neck, the development of cysts and abscesses in the mouth, and an increased number of cavities 
• Problems with their cardiovascular system - For example, patients can develop valvular heart disease, left ventricle hypertrophy, and high blood pressure.
• Problems with their gastrointestinal system - For example liver enlargement, the development of hernias in the abdomen, and chronic diarrhoea. 
• Problems with their musculoskeletal system - For example patients can experience delays in their growth leading to a short stature, as well as bone and muscle abnormalities, which in turn results in stiffness in joints, limited movement of the limbs, and sometimes even scoliosis.¹ 

These symptoms of neuronopathic patients can significantly worsen their quality of life, reducing their life expectancy drastically to between 10-20 years old. Hence, diagnosing and treating these patients as early as possible will help improve their symptoms and lessen the life-threatening burden of the disease. 

Non-neuronopathic hunter syndrome

In the remaining 40% of Hunter syndrome cases, the disorder is known as non-neuronopathic. These patients experience milder versions of the symptoms detailed above, except for the hydrocephalus and neurological decline. These patients instead typically have normal intellectual and cognitive development and abilities.⁴ 

People who have this non-neuronopathic version of the disorder tend to live longer into their adulthood compared to neuronopathic patients.⁴ Regardless if diagnosed and treated early, their quality of life can improve.  

Diagnosis of hunter syndrome

It is imperative to visit a doctor as soon as a patient shows any potential symptoms of Hunter’s syndrome, such as delayed mental or physical development, or behavioural changes. These first signs are usually detected by the age of 4.³ 

Alongside the physical examination of the symptoms, doctors diagnose Hunter syndrome using various tests: 

• Blood tests and skin cell biopsies - Blood tests ( taking a small amount of blood from the patient) and skin cell biopsies (using a special instrument to punch a small hole into the skin of the patient to take a sample of their skin cells) are used to assess I2S enzyme levels. Affected patients will have significantly low to no levels of this enzyme in their blood and skin cells.⁵ 
• Urine tests and plasma tests - Urine tests and plasma tests (plasma is extracted and assessed from blood samples) assess GAG levels in the patient. Affected people will have high levels of these sugar molecules in their urine and plasma, as they have yet to be broken down and digested properly. 

Specific GAGs tested are heparan sulphate (its accumulation in the lysosomes around the body typically results in neurological damage) and dermatan sulphate (its accumulation damages the connective tissues, leading to problems in movement).⁶

• Genetic testing - This genetic examination involves obtaining a blood or tissue sample from a Hunter syndrome patient and assessing whether they have any mutations in their IDS genes.⁵ 
• Imaging - Tests such as X-rays can visualise the musculoskeletal symptoms associated with Hunter syndrome.¹

Treatment options for hunter syndrome

Currently, no cure for Hunter syndrome has been found. Instead, available treatment for the genetic disorder aims to slow the progression of the condition and improve the quality of life of the patients.⁵ 

Enzyme replacement therapy (ERT)

ERT is a type of medical treatment which involves replacing any missing enzymes the patient may have. In the case of Hunter syndrome, the missing I2S enzyme is replaced with a man-made version known as idursulfase. 

This therapy effectively reduces GAG levels in the body, improving the function of various body systems and the patient's survival.⁷

This treatment is delivered to patients once a week through a needle inserted into a vein. Patients are advised to start ERT before they turn 6 for the treatment to work most effectively.⁸ 

Although considered generally safe, a limitation of ERT is that it is ineffective at treating the neurological symptoms of neuronopathic Hunter syndrome patients. This is because the man-made idursulfase is not able to cross the blood-brain barrier, which is a barrier that protects the brain from harmful substances in blood. Hence, ERT is not considered effective in treating cognitive impairments as it cannot get into the brain.⁹ 

Haematopoietic stem cell transplantation (HSCT)

HSCT is a one-time injection into the patient’s veins containing haematopoietic stem cells into their bloodstream. These stem cells are in charge of replenishing the patient’s blood cell production - replacing the patient’s blood cells, full of GAGs, with healthy blood cells. 

HSCT is a particularly effective treatment for neuronopathic Hunter syndrome patients, as the therapy can cross the blood-brain barrier and improve cognitive function in these patients, improving their quality of life.¹⁰ 

However, a limitation of HSCT is that the therapy leads to a high risk of infections in the patient. In addition, the patient may reject the new blood cells from the stem cells, in turn leading to side effects such as graft-versus-host disease (GVHD).¹¹ 

Supportive care

To manage the symptoms of Hunter syndrome, a variety of therapies can be used, including:

• Medication - A prime example includes nonsteroidal anti-inflammatory drugs (NSAIDs) to help reduce the degeneration of joints in Hunter syndrome patients, improving their mobility.¹ 
• Physiotherapy - This type of therapy helps improve movement in Hunter syndrome patients.¹ 
• Occupational therapy - This type of therapy helps improve both physical and cognitive problems of Hunter syndrome patients, aiding them in becoming more independent.¹
• Developmental therapy - This type of therapy supports Hunter syndrome toddlers and children with developmental delays and disabilities.¹ 
• Surgery - Certain surgeries can be performed to relieve symptoms. For instance, hernias and joint problems can be corrected through surgery, tonsils can be removed to improve breathing, and cardiac valve replacement surgery can be performed to improve cardiovascular problems.¹² 

Emerging research on the diagnosis and treatment of hunter syndrome

Active effort is being made in research to find better treatments and possible cures for Hunter syndrome. Examples of current research include:

• Neonatal genetic screening - A patient can be diagnosed early in life, before developing symptoms. Newborns can be genetically tested and identified if carrying a faulty mutation of the IDS gene.  This would allow doctors to manage the condition before its symptoms develop, improving the patient’s prognosis and preventing severe symptoms.¹³
• Gene therapy - This type of therapy implies removing some haematopoietic stem cells from the patient, inserting a working copy of the IDS gene, and then returning these cells to the patient, via a one-time injection. This edits the patient’s cells and enables them to produce the I2S enzyme and break down GAGs, without needing a donor. 

This therapy is being researched as a potential curative therapy. For this therapy to be effective, patients must be very young (up to 1 year old), so no severe symptoms have been developed yet.  

• Substrate reduction therapy - This type of therapy uses small molecule inhibitors to limit the amount of GAGs produced throughout the body. With less production of these sugar molecules, there will be less accumulation in lysosomes, reducing the symptoms.¹⁴

Summary

Hunter syndrome is a genetic lysosomal storage disorder affecting the AMAB. It is an X-linked recessive condition and is characterised by a deficiency in the enzyme iduronate-2-sulfatase (I2S) which leads to the accumulation of the sugar molecules called glycosaminoglycans (GAGs), in the body. The accumulation of GAGs disrupts the normal function of various organ systems, resulting in a low life expectancy. 

Diagnosis of the syndrome involves the clinical examination of symptoms, blood and urine tests, genetic testing, and imaging studies. Treatment options include enzyme replacement therapy with the missing I2S enzyme, haematopoietic stem cell transplantation to provide functional I2S-producing cells, and supportive care to manage symptoms. 

Emerging therapies that aim to cure the disease include gene therapy and substrate reduction therapy. Early diagnosis and intervention are critical for optimising treatment outcomes and improving the quality of life for individuals with Hunter syndrome.