Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked recessive lysosomal storage disorder due to deficiency of iduronate-2-sulfatase (IDS, Xq28), causing accumulation of dermatan sulfate and heparan sulfate. Incidence is about 1 in 100,000 to 170,000 male births, and it is mostly seen in males, though females can be affected rarely by skewed X inactivation or Turner syndrome. The disease has a severe (neuronopathic, about two thirds) and attenuated spectrum. IDS gene deletions and rearrangements usually cause severe disease.

• Onset at 2 to 4 years (earlier in severe forms): coarse facies, macrocephaly, large tongue, thick lips, short neck and stature, hepatosplenomegaly, hernias, chronic otorrhoea, recurrent respiratory infections, chronic diarrhoea, and joint contractures
• Dysostosis multiplex and claw hands, carpal tunnel syndrome, and characteristic skin pebbling (ivory coloured papules on scapulae, a pathognomonic sign)
• Cardiac valve disease, upper airway obstruction and sleep apnoea, hearing loss, and communicating hydrocephalus
• Retinal degeneration with no corneal clouding (distinguishes from MPS I)
• Neuronopathic form: developmental delay by age 2 to 4 years, language regression, hyperactivity, aggression, seizures, and neurodegeneration, with death by the second decade
• Attenuated form: normal cognition, survival into adulthood with somatic disease

1. Urinary glycosaminoglycans (elevated heparan and dermatan sulfate).
2. Iduronate-2-sulfatase enzyme activity in plasma, leucocytes, dried blood spots or fibroblasts (deficient; diagnostic). Check a second sulfatase to exclude multiple sulfatase deficiency.
3. IDS molecular analysis (point variants, large deletions and rearrangements) to define genotype, carrier testing in female relatives, and prenatal diagnosis.
4. Baseline imaging and testing: skeletal survey, echocardiography, brain and cervical spine MRI, sleep study, audiology, ophthalmology, neurocognitive assessment, and abdominal ultrasound.

• Idursulfase (Elaprase), recombinant iduronate-2-sulfatase 0.5 mg/kg IV weekly infusion over 1 to 3 hours: reduces urinary glycosaminoglycans, liver and spleen size, improves walking (6-minute walk test) and respiratory function; does not penetrate the blood brain barrier, so does not treat neurological disease. Premedication with antihistamines and corticosteroids and monitoring for anaphylaxis are required. Intrathecal and brain penetrant enzyme therapies (pabinafusp alfa, tividenofusp alfa) are available in some regions or under study.
• Haematopoietic stem cell transplantation is used in selected neuronopathic patients in some centres (benefit is uncertain), and gene therapy trials are underway.
• Supportive care: tonsillectomy and adenoidectomy, tracheostomy, CPAP, ear tubes and hearing aids, hydrocephalus shunt, carpal tunnel release, cardiac valve surgery, physiotherapy, anaesthesia planning (difficult airway), and behavioural and educational support.
• Seizure treatment with antiepileptics; sleep disturbance with melatonin; and palliative care for advanced neurodegeneration.
• Genetic counselling: carrier mother has a 50% risk of affected sons and carrier daughters; carrier testing and prenatal diagnosis; two thirds of mothers of affected males are carriers.