Hunter’s Disease, also known as Mucopolysaccharidosis Type II (MPS II), is an inherited metabolic disorder affecting multiple body systems. It is classified as a lysosomal storage disease, where a specific enzyme deficiency prevents the breakdown of complex molecules within the cell’s recycling centers, the lysosomes. This failure leads to a progressive accumulation of undigested materials, causing damage to tissues and organs throughout the body. The condition is rare, affecting about 1 in 100,000 to 170,000 male live births, and its progressive nature means symptoms generally worsen over time.
The Enzyme Deficiency and Genetic Basis
Hunter’s Disease arises from a deficit in the lysosomal enzyme iduronate-2-sulfatase (I2S). This enzyme is responsible for breaking down complex sugar molecules known as glycosaminoglycans (GAGs). Specifically, I2S is needed to degrade dermatan sulfate and heparan sulfate. Without sufficient I2S activity, these GAGs are not properly broken down and accumulate inside the lysosomes of cells across the body, driving the progressive damage seen in MPS II.
This deficiency is caused by a mutation in the IDS gene, which provides the instructions for making the I2S enzyme. Hunter’s Disease follows an X-linked recessive inheritance pattern, meaning the IDS gene is located on the X chromosome. Because males have only one X chromosome, they are predominantly affected, while females are usually carriers.
Recognizing the Physical and Systemic Symptoms
The buildup of GAGs causes a wide range of signs that manifest as the condition progresses, often becoming noticeable before a child reaches two years of age. Physical signs include distinct changes in facial structure, often described as coarse features, and thickened skin. Skeletal abnormalities, collectively termed dysostosis multiplex, are common, leading to joint stiffness, limited mobility, and short stature.
The systemic impact of GAG storage affects multiple organ systems. Children often experience enlarged organs, specifically the liver and spleen (hepatosplenomegaly), which can lead to a distended abdomen and hernias. Cardiovascular complications are common, involving the thickening of heart valves and heart walls, which impairs cardiac function. Respiratory issues, such as upper airway obstruction and sleep apnea, also frequently occur due to GAG accumulation in the airways.
Hunter’s Disease is characterized by a spectrum of severity, categorized by the presence or absence of neurological involvement. The severe form involves the central nervous system, leading to cognitive decline, developmental delay, and progressive loss of learned skills. The attenuated, or non-neuropathic, form presents with milder physical symptoms and progression, with cognitive function remaining largely unaffected, often allowing patients to live into adulthood.
Diagnosis and Early Detection
Diagnosis typically begins with clinical suspicion based on physical symptoms and developmental history. The first step in laboratory testing is often a urine analysis to screen for elevated levels of GAGs. While increased GAG excretion indicates a mucopolysaccharidosis disorder, it is not definitive for MPS II, as other related conditions can also cause elevation.
A definitive diagnosis relies on measuring the activity of the I2S enzyme in specific cell types, such as white blood cells or cultured skin cells. A significantly low or absent level of I2S activity confirms the characteristic enzyme deficiency. Genetic testing then provides molecular confirmation by identifying the specific mutation in the IDS gene. Early diagnosis allows for prompt initiation of therapies and monitoring to mitigate the long-term effects of the progressive disease.
Management and Treatment Options
The current standard of care is Enzyme Replacement Therapy (ERT), which involves administering a manufactured version of the missing I2S enzyme, called idursulfase, intravenously. This weekly infusion replaces the deficient enzyme, helping to break down accumulating GAGs in various organs and tissues. ERT can effectively reduce GAG levels and improve outcomes related to organ size, walking ability, and respiratory function.
A primary limitation of conventional ERT is that the enzyme cannot effectively pass the blood-brain barrier, meaning it does not address the progressive neurological decline seen in the severe form of the disease. While ERT manages somatic symptoms for patients with the non-neuropathic form, it cannot prevent cognitive decline in those with neurological involvement. Supportive care is also a major component of management, including surgical interventions for skeletal issues, hernia repair, and therapies for hearing and respiratory problems.
Newer and emerging therapies aim to overcome the limitations regarding central nervous system involvement. Gene therapy, which modifies the patient’s cells to produce the correct enzyme, is under investigation and shows promise for a one-time treatment that could potentially reach the brain. Investigational treatments are also developing specialized molecular “Trojan horses” to transport the enzyme across the blood-brain barrier. Hematopoietic stem cell transplantation (HSCT) has been used, primarily in patients treated very early, showing effectiveness on visceral organs and some impact on brain involvement.