Hunter Syndrome

Hunter syndrome is a rare lysosomal storage disorder (LSD) that leads to progressive tissue and organ damage throughout the body.1

Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, was first identified by the Canadian physician Charles Hunter.2 MPS II is one of more than 70 lysosomal storage diseases. These inherited metabolic diseases are characterized by the progressive accumulation of lysosomal waste products, ultimately causing the deterioration of cellular and tissue function.3,4 In the case of MPS II, loss of enzyme activity causes the accumulation of glycosaminoglycans (GAGs) in cells, which leads to progressive tissue and organ damage throughout the body.1,2,5

Hunter syndrome illustration

Epidemiology

MPS II is a rare disease with an estimated incidence of 1 in 60,000 to 1 in 150,000 live births, although rates are higher in certain ethnicities such as Ashkenazi Jews.2 The disease is X-linked and is diagnosed predominantly in males between 18 to 36 months of age.2,4,6 Females are typically asymptomatic heterozygous carriers, although there are rare cases of affected females through skewing of X-chromosome inactivation.2,5,6

Pathophysiology

MPS II is caused by a deficiency in the iduronate-2-sulfatase enzyme (IDS, EC 3.1.6.13), which catalyzes GAG breakdown by the removal of sulfate groups.1,2,4 In MPS II, GAGs accumulate in the tissues of multiple organ systems along with increased excretion of their breakdown products, heparan and dermatan, in the urine.2,4 Enzyme deficiency is most often due to protein misfolding, decreased production or decreased catalytic activity, rather than a complete lack of enzyme. Over 580 variants have been identified and are distributed over the entire IDS gene as small and large deletions, missense, nonsense and splicing variants, with about 25% of variants arising de novo.7 MPS II is also characterized by clinical heterogeneity, and due to its rarity, there is a poor understanding of the correlation between genotype and phenotype.7,8 However, the disease is often described as having two main phenotypes: severe, which is more common and caused by deletions or rearrangements that abolish iduronate-2-sulfatase (I2S) transcription; and attenuated, which lack cognitive impairment and developmental regression.2,8

Presentation

The presentation of MPS II can vary widely among patients depending on the organs involved.6,8,9 MPS II has some distinct physical characteristics, like short stature; a broad chest; coarse facial features; enlarged tongue, tonsils and adenoids; and thickening of the skin causing a “pebbly” appearance.4,9,10,11 Two thirds of patients have the severe form and experience progressive cognitive decline.2,5 Upper airway obstruction, cardiopulmonary disease and orthopedic sequelae are ultimately responsible for early death in patients with MPS II patients by 10 to 15 years of age.2,4,12

Diagnosis

Due to its clinical heterogeneity, the path to MPS II diagnosis is often long and indirect.1,8 Patients with severe MPS II are diagnosed earlier due to cognitive regression, typically between 18 to 36 months. For patients with attenuated MPS II, it can take much longer to make the diagnosis, until age 4 to 8, since these patients do not have neurodegeneration and may or may not have learning disabilities.4 Biochemical testing is essential to confirm clinical suspicion, and is part of 3 major categories of tests: 1) assessment of GAG levels in blood or urine, 2) assessment of I2S activity in dried blood spots, and 3) genotyping of iduronate-2-sulfatase gene.5,13,14 Total urinal GAG is often the first test, but as it is non-specific it necessitates further confirmation by enzymatic and genetic testing.5 Enzymatic testing is limited because it cannot determine carrier status or predict disease severity.4 Prenatal diagnosis via I2S enzyme assays or molecular testing in chorionic villi or amniotic fluid cells may be available at some centers.8

Navigating MPS II

There is no cure for MPS II.15 Currently, the goal of pharmacologic intervention is to replace the missing or deficient enzyme.2, 4 MPS II is a multi-systemic disease, and management requires involvement of specialized professionals in each of the affected organ systems (e.g. physical, occupational, and behavioral therapists, among others).4,5