Enzyme Replacement Therapy For Hunter Syndrome

Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare inherited disorder. People with this condition lack an enzyme, causing abnormal buildup of complex sugars in their cells, affecting many organs and systems in their bodies and damaging physical and mental development. Although there is no cure for this disease, enzyme replacement therapy (ERT) aims to replace the deficient or missing enzyme in the body and improve the symptoms and quality of life in those affected. This article will provide an overview of Hunter syndrome and the use of ERT.

Overview of hunter syndrome 

Introduction to hunter syndrome (Mucopolysaccharidosis II)

Hunter syndrome is an inherited condition caused by a genetic mutation. The condition presents in childhood, mostly affecting children assigned male at birth (AMAB), although those assigned female at birth (AFAB) may be carriers of a mutation that causes the condition. It is very rare, occurring in approximately 1 in every 100,000 to 170,000 children AMAB.¹

Hunter syndrome belongs to a group of disorders called lysosomal storage diseases, characterised by genetic mutations that disrupt the normal activity of structures in cells known as lysosomes. Lysosomes are responsible for breaking down and recycling a wide range of substances with enzymes that break down specific molecules such as complex sugars and fats. A genetic mutation can cause one of these enzymes to be in low quantities or absent altogether, resulting in the body not being able to break down the large molecules. This in turn causes a build-up of these molecules in the organs and tissues of the body over time. ²

Causes and symptoms of hunter syndrome

Hunter syndrome is caused by a genetic mutation in the IDS gene and over 600 different identified mutations can cause the condition.³ This gene is found on the X chromosome, and as the majority of children AMAB have only one X chromosome, a mutation that alters this single copy of the gene is enough to cause the condition. AFAB individuals have two X chromosomes, so even if there was a mutation in one copy of the IDS gene, the other copy would most likely be functional.

The IDS gene is responsible for producing a specific enzyme called iduronate 2-sulphatase (I2S), which breaks down large sugar molecules called glycosaminoglycans (GAGs). People with Hunter syndrome are either missing or are low in this enzyme, which is needed to break down two specific GAGs - dermatan sulphate and heparan sulphate. When these are not degraded, they can accumulate in tissues of the body and cause a wide range of symptoms.^{4, 5}

Newborns with Hunter syndrome may not yet show signs of the condition, but as more and more cells accumulate GAGs, the signs and symptoms become more apparent between the ages of 2 and 4.¹ People with Hunter syndrome may experience a wide spectrum of signs and symptoms due to multiple organ systems being affected, and these signs can range from mild to severe. symptoms include:

• Abnormally large  head, wide chest and short neck
• Clouding in the front of the eye (corneal clouding)
• More frequent Upper respiratory infections 
• Enlargement of the tonsils and/or adenoids
• Distinct thickening of facial features

Over time, other symptoms may arise in children, such as:

• Delayed growth and short stature
• White skin growths
• Deep, hoarse voice
• Enlargement of the heart chambers
• Enlarged liver and spleen
• Build up of fluid around the brain
• Compression and damage to the spinal cord
• Decline in intellectual or developmental measures

Hunter syndrome can cause several long-term complications:

• Breathing problems due to thickened tissue and blocked airways
• Heart disease
• Joint and bone abnormalities
• Declining brain function
• Hernias
• Seizures
• Behavioural problems

It is important to note the variation of effects caused by Hunter syndrome, even across generations and between siblings, due to the variety of organ systems affected.^1,2

Diagnosis and identification

In addition to doctors taking a detailed history and performing a physical examination, there are several ways to diagnose Hunter syndrome:

• Urine test: a urine test for GAG levels can be performed to  show if there is an unusually high level of these molecules¹
• Blood tests: Iduronate 2-sulphatase (I2S) blood tests are the gold standard for diagnosis. The levels of I2S are assessed in several different blood cells and people with Hunter syndrome will show a low or absent level of activity of this enzyme³
• Genetic testing: genetic testing can identify mutations in the IDS gene and can confirm a diagnosis of Hunter syndrome^3,6

Overview of enzyme replacement therapy (ERT)

Whilst no cure has been produced for Hunter syndrome, current treatments aim to restore the level of deficient enzymes, reduce the level of GAGs in body tissues, improve the severity of the symptoms, and improve the quality of life for those with Hunter syndrome.

Enzyme replacement therapy (ERT) is a long-term treatment for people with inherited enzyme deficiencies that involves using purified human, animal-derived or recombinant enzymes. Usually, these enzyme treatments are given by intravenous infusion (through a needle inserted into a vein) and have typically been modified to have improved activity, to last longer in the body, or be targeted to a particular organ or tissue in the body. These treatments are generally well tolerated with minimal adverse effects. Some people undergoing this treatment may experience a local reaction to the infusion, where the needle has entered the skin, this has been reported in roughly 30% of people undergoing treatment with idursulphase. The majority of these reactions are mild and can be treated easily by administering treatment to reduce this reaction, enabling successful future infusions.⁷ Treatments involving ERT have now been developed for several lysosomal storage diseases.⁸

ERT has been used in treating people with Hunter syndrome and involves replacing the missing or deficient I2S enzyme with a purified, human-made version of the enzyme called idursulphase (branded as Elaprase®), given once a week. The treatment ideally aims to reduce GAG build-up and reduce organ enlargement. Idursulphase has been shown to potentially slow the progression of the disease, and improve many of the signs and symptoms by reducing many of the non-brain related symptoms, such as reducing joint stiffness, improving growth and reducing bone abnormalities, improving lung function, and overall improving the quality of life for people with Hunter syndrome.^1,4 The earlier that treatment can be started, the better the benefit is likely to be, with the best outcome resulting from treatment being started before 6 years of age. It should be noted that this treatment cannot cross the blood-brain barrier, and therefore cannot reach the brain, resulting in little to no effect on brain-related symptoms.³

Despite the promising potential, there remain challenges and limitations to ERT. A fundamental drawback is that this treatment does not affect the cause of the condition, the genetic mutation that results in Hunter syndrome, and aims to address the symptoms of the condition. Benefits in signs and symptoms and improvements in quality of life have mostly been demonstrated in small case series, which highlights a potential need for larger controlled trials.

Other questions remain, surrounding the nature of management, including when to start treatment, what benefits can be expected, and how to tell if the treatments are working, using objective measures. These considerations are likely to vary person-to-person, which reflects the highly individualistic nature of Hunter syndrome.⁹
The future presents alternative prospects as other drugs are currently being developed: different types of more powerful ERT, that specifically target tissues such as bones where the disease can be prominent. The advent of gene therapy is another promising treatment avenue, which could potentially lead to faster treatment outcomes and improvement in quality of life.^{7, 10}

Summary

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a rare inherited condition that is characterised by the absence or deficiency of the iduronate 2-sulphatase (I2S) enzyme, leading to an abnormal buildup of complex sugars (GAGs) in cells. This is caused by a genetic mutation in the IDS gene, found on the X chromosome, and results in a variety of symptoms affecting physical and mental development. In recent years, enzyme replacement therapy (ERT) has emerged as a promising long-term treatment to improve symptoms and enhance the quality of life of people with Hunter syndrome. 

While Hunter syndrome remains without a cure, ERT, involving the use of idursulphase, presents a significant advancement in managing the symptoms and enhancing the lives of people with this rare genetic disorder. As with most treatments, a personalised approach to treating Hunter syndrome is important to ensure the best quality of life possible for those affected. Despite challenges and the need for further research and larger clinical trials, ERT stands as a promising treatment option for those living with Hunter syndrome, offering a path towards improved well-being and management of the condition.