Hunter syndrome, also known as Mucopolysaccharidosis Type II (MPS II), is a rare genetic disorder where the body cannot properly break down certain complex sugar molecules. These molecules, called glycosaminoglycans (GAGs), accumulate in cells throughout the body, interfering with organ function. This progressive condition primarily affects males and is one of many diseases classified as lysosomal storage disorders.
Genetic Roots
Hunter syndrome stems from an inherited genetic variation in the IDS gene. This gene provides instructions for producing the enzyme iduronate-2-sulfatase (I2S). In individuals with Hunter syndrome, the I2S enzyme is either deficient or entirely absent.
The I2S enzyme normally breaks down specific GAGs within cellular compartments called lysosomes. Without sufficient functional I2S enzyme, these GAGs accumulate, causing cellular damage. The condition follows an X-linked recessive inheritance pattern, primarily affecting males because they have only one X chromosome. Females typically have two X chromosomes, so if one carries the altered gene, the other usually provides a functioning copy, making them carriers but generally unaffected.
Recognizing the Symptoms
Symptoms of Hunter syndrome are typically not apparent at birth but generally begin to emerge between 2 and 4 years of age. As a progressive condition, symptoms worsen over time. Distinctive facial features often develop, including a prominent forehead, a flattened nasal bridge, thick lips, and an enlarged tongue.
Skeletal issues are common, leading to joint stiffness and limited range of motion. Short stature and abnormalities in bone structure are also characteristic. Many individuals experience enlarged organs such as the liver and spleen, which can cause a distended abdomen and lead to umbilical or inguinal hernias.
Respiratory problems are frequent, including recurrent upper airway infections, thick nasal secretions, and sleep apnea due to thickened airway walls and enlarged tonsils and adenoids. Cardiovascular complications can arise from GAG accumulation in heart valves, potentially leading to heart valve thickening and dysfunction. Some individuals may also develop pebbly, ivory-colored skin lesions.
Neurological involvement varies; in severe forms, developmental delays and cognitive decline can occur. Behavioral issues like hyperactivity and aggression may also be present. Hearing loss is common, contributing to communication difficulties.
Diagnosis Process
Diagnosing Hunter syndrome typically begins with clinical suspicion based on the characteristic physical signs and symptoms. Initial screening tests often involve analyzing urine for elevated levels of GAGs. While increased GAGs in urine suggest a mucopolysaccharidosis, this test alone is not definitive for Hunter syndrome.
A confirmed diagnosis relies on specific laboratory tests. An enzyme assay, measuring I2S enzyme activity, is considered the gold standard. This test can be performed using blood samples (white blood cells or plasma) or skin fibroblasts from a biopsy. A low or absent level of I2S enzyme activity confirms the diagnosis.
Genetic testing can further confirm the diagnosis and is useful for family planning and genetic counseling. Newborn screening programs are also beginning to include tests for Hunter syndrome, measuring I2S activity in dried blood spots. Prenatal diagnosis is also available for at-risk pregnancies through enzyme assay or genetic analysis of amniotic fluid or chorionic villus tissue.
Treatment Approaches
While there is no cure for Hunter syndrome, available treatments focus on managing symptoms, slowing disease progression, and improving quality of life. Enzyme replacement therapy (ERT) is a primary treatment, providing the missing or deficient I2S enzyme. This therapy, typically administered intravenously once a week, helps reduce GAG accumulation in many organs and tissues.
Several FDA-approved ERT medications are available. ERT has shown benefits in improving walking capacity, reducing spleen and liver size, and lowering urinary GAG levels. However, traditional ERT has limitations, particularly in its ability to cross the blood-brain barrier, making it less effective for neurological symptoms.
Supportive treatments are also implemented to address specific complications. These can include surgical interventions for issues like hernias, carpal tunnel syndrome, and skeletal deformities. Therapies for respiratory problems, such as tonsillectomy and adenoidectomy for airway obstruction, are also common. A multidisciplinary team of specialists is often involved in managing the diverse symptoms of Hunter syndrome.
Emerging therapies like gene therapy and stem cell transplantation are under investigation, offering future treatment avenues. Gene therapy aims to introduce a healthy copy of the IDS gene, enabling the body to produce its own I2S enzyme. Hematopoietic stem cell transplantation (HSCT) has also been explored, with some success in improving somatic symptoms, though its effect on neurological outcomes can be limited if not initiated early.
Prognosis and Inheritance
The long-term outlook for individuals with Hunter syndrome varies significantly based on disease severity. Generally, two forms exist: a severe form with neurological involvement and an attenuated form with milder physical symptoms and typically no cognitive decline. Individuals with the severe form often experience a shorter lifespan, with death sometimes occurring in the second decade of life due to complications like cardiopulmonary failure.
Individuals with the attenuated form generally have a better life expectancy. Early diagnosis and initiation of treatment, especially ERT, can improve outcomes by addressing GAG accumulation before irreversible organ damage occurs. Genetic counseling is important for families with a history of Hunter syndrome to understand the inheritance pattern and assess the risk of passing the condition to future children.