Causes And Symptoms Of Hunter Syndrome

Introduction

The mucopolysaccharidoses (MPS) are a group of uncommon, inherited disorders. They belong to the bigger set of diseases known as lysosomal storage diseases (LSDs). Each MPS disease happens because there is not enough of a certain lysosomal enzyme. This enzyme is needed to break down complex sugar chains called glycosaminoglycans (GAGs). As a result, GAGs build up inside lysosomes, causing increased cellular damage and eventually resulting in organ failure and a shortened life span.¹

An X-linked disorder known as mucopolysaccharidosis II (MPS II or Hunter syndrome; OMIM 309900) has an incidence of 0.3 to 0.71 per 100,000 live births. It results from a missing or deficiency in the lysosomal enzyme iduronate-2-sulfatase (IDS), which leads to the build-up of the GAGs (dermatan sulphate (DS) and heparan sulphate (HS)). Hence, resulting in a multi-organ disease that progresses.¹ 

Genetic basis of Hunter syndrome

The Hunter Syndrome has a long arm of the X chromosome containing the gene for the enzyme iduronate sulfatase (IDS), which is defective. The gene consists of 9 exons spaced throughout 24 kb. There is a pseudogene with sequence homology to the IDS gene located close to it. It has been linked with more than 600 mutations including point mutations, insertions, duplications, deletions, and large gene rearrangements.⁴ 

Additionally, some of the mutations contain occurrences of the pseudogene. Despite being an X-linked recessive disorder, there have only been a few documented cases of affected females with Hunter syndrome. In females, the phenotypic expression can be explained by X-chromosome structural defects or skewed X-chromosome inactivation leading to IDS inactivation.²

Individuals with MPS II have reduced IDS activity causing heparan sulphate (HS) and dermatan sulphate (DS) to accumulate creating damage to the nervous system. The central nervous system in the brain is damaged by heparan sulphate. On the other hand, the connective tissue in the body is damaged by the dermatan sulphate. The process is known as multisystemic disease symptoms. The early stages of the disease are not as severe so it is hard to clinically diagnose MPS II.³

The pathophysiological understanding of mucopolysaccharides II

Mucopolysaccharides are long-chain sugar molecules made up of repetitive disaccharide units. These sugars contribute to the majority of the extracellular matrix of the connective tissue all across the body, which includes the skin, joints, heart valves, eyes and tendons. Lysosomes are where mucopolysaccharide hydrolysis begins.⁴

The initial enzyme that is responsible for breaking down heparan sulphate and dermatan sulphate is iduronate 2-sulfatase (IDS). It breaks the mucopolysaccharides' O-linked sulphate moiety in the body. The lack or absence of IDS enzymatic activity leads to the compilation of GAG, DS and HS in the lysosomes causing hypertrophy and excess production of lysosomes. Furthermore, the huge amounts of DS and HS build-up cause cell adhesion, endocytosis, intracellular trafficking of various molecules, and intracellular ionic equilibrium. Additionally, it encourages the production of nitric oxide and the inflammatory cascade, both of which are harmful.⁴

Signs and symptoms of Hunter syndrome on individuals

Children between the ages of two and four are usually the ones who first exhibit the signs and symptoms of Hunter syndrome. The symptoms of Hunter syndrome can range in severity and include:⁵

• Stiff joints
• Thickening of the lips, tongue, and nostrils on the face
• Teeth appear slowly or with large gaps between them
• Shorter neck
• Wide chest
• Larger than normal head
• Progressive loss of hearing over time
• Delayed growth, particularly after the age of five
• Enlarged liver and spleen
• Appearance of white growths on the skin

Complications associated with Hunter syndrome

Hunter syndrome has numerous complications that may arise depending on its severity. To treat these issues, doctors sometimes resort to surgery in addition to medicine.

Neurological and cognitive symptoms

The initial symptom of Hunter syndrome is hydrocephalus and that leads to a larger skull diameter presented clinically as macrocephaly. Moreover, it causes individuals to have seizures, attention issues, hyperactivity, and behavioural problems. 

The attention span of the individuals are shorter due to less amount of the corpus callosum available in the brain. Furthermore, individuals also have poor academic performance at school and thus resulting in cognitive impairment. both the cognitive decline and hearing impairment cause delays in language abilities.⁴

Respiratory system

GAG deposition piles up more in the lungs, tongue, and lymphatic system. It shows up as overgrown tonsils and adenoids, enlargement of voice strings, swollen tongue, and a tight windpipe.The respiratory system also presents thick secretions and an increased immune response. 

Individuals would often suffer from stuffy noses, loud breaths, and ear infection. The thickened windpipe wall and overgrown tonsils narrow the air path, causing lots of lung infection, blocked sleep breaths with sleep apnea, and difficulty breathing. In addition, the abnormal anatomy in the ribcage and spine contributes to the condition that breathing complicated.⁴

Cardiovascular system

HS and DS are two crucial and fundamental components of heart valves. An atypical build-up of these materials causes a thick valve which leads to hypertension, left ventricular hypertrophy, mitral and aortic regurgitation, valvular heart disease.⁴ 

Gastrointestinal system

Hepatosplenomegaly, which is the enlargement of the liver and the spleen, is the result of the accumulation of GAG in the abdominal organs. It is what causes one of the initial clinical signs in Hunter syndrome - abdominal distension or swelling. What hepatosplenomegaly does is increase the intra-abdominal pressure which then elevates the tension in the abdominal wall (can be called bloating). Other consequences can include inguinal and umbilical hernia, chronic diarrhoea with voluminous, and mucoid stools.⁴

Musculoskeletal system

Individuals with Hunter syndrome have myopathy, small height, joint contractures, stiff joints, and coarse facial features. A rare congenital disorder known as dysostosis multiplex is brought on by the skeletal appearance. The accumulation of GAG in the growth plate will prevent endochondral ossification from working, hence individuals are short. In addition, it causes scoliosis, kyphosis, and structural abnormalities in the rib cage.⁴

Muscle weakness, paralysis, urinary bladder incontinence, and bowel incontinence can all result from anatomical abnormalities in the vertebral column that compress the spinal cord and nerve roots. The accumulation of the DS and HS causes damage to articular and hyaline cartilage at the joint. A Reduced range of motion, contractures, stiffness, and joint pain are the results.⁴

Muscle spindle cell death and myopathy are also an outcome of GAG accumulation in tendons and muscles. The hip, knee, ankle, shoulder, and wrist joints become stiff and contractured as a result of these two conditions. It lessens the hand muscles' power, grip, and range of motion. Claw hand deformity is a result of these contractures. Carpal tunnel syndrome can result from the median nerve at the wrist joint being compressed by a buildup of GAGs surrounding tendons.⁴

Methods for diagnosing Hunter syndrome

The following tests can detect Hunter Syndrome:⁴

1. Urine and plasma GAG levels: Measuring the levels of GAG in the urine and plasma as the screening test for mucopolysaccharidosis II (MPS II). Newborns with lysosomal storage diseases including (MPS II) will have elevated levels of DM and HS in their plasma
2. Levels of iduronate sulfatase (IDS): Hunter syndrome is diagnosed using IDS levels, the most valuable standard test. IDS levels are determined through cell cultures, including leukocyte, fibroblast, and dried blood, as well as free plasma samples
3. Genetic testing: Hunter syndrome is confirmed by molecular genetic testing. It can provide a definitive diagnosis for patients who illustrate signs of Hunter syndrome but the lab results are not clear. Usually, some girls are documented to show symptoms of MPS II and are required to perform the genetics test
4. Imaging: Using a radiographic X-ray, a skeletal survey is conducted on patients who exhibit clinical signs of MPS II. They show specific abnormalities in the skull, joints, axial skeleton, and limbs that are identified as dysostosis multiplex

Summary

Mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage diseases caused by the lack of a specific enzyme needed to break down glycosaminoglycans (GAGs). Mucopolysaccharidosis II (MPS II or Hunter syndrome) is an X-linked disorder caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS), leading to multi-organ disease, failure, and reduced life span due to the buildup of GAGs (dermatan sulfate and heparan sulfate). 

Symptoms of Hunter syndrome typically appear between ages two and four and include stiff joints, facial changes, delayed growth, enlarged liver and spleen, and cognitive and respiratory issues. Complications include hydrocephalus, seizures, behavioural problems, hearing loss, cardiovascular issues, and gastrointestinal problems. The musculoskeletal system is also affected, causing joint contractures, skeletal abnormalities, muscle weakness, and decreased range of motion.

Diagnosis of Hunter syndrome involves measuring GAG levels in urine and plasma, assessing IDS levels in various cell cultures, and genetic testing to confirm the disorder, especially in ambiguous cases or affected females.