Mucopolysaccharidosis type 2, severe form

Mucopolysaccharidosis type 2, severe form (also known as severe Hunter syndrome) is a rare, life-threatening X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS). This enzyme is essential for the breakdown of glycosaminoglycans (GAGs), specifically dermatan sulfate and heparan sulfate. When these complex sugars cannot be properly degraded, they accumulate progressively in cells and tissues throughout the body, leading to widespread organ damage. The severe form is distinguished from the attenuated form by the presence of significant and progressive central nervous system (CNS) involvement, including cognitive decline and neurodevelopmental regression. The severe form typically presents between ages 18 months and 4 years with coarse facial features, hepatosplenomegaly (enlarged liver and spleen), skeletal abnormalities (dysostosis multiplex), joint stiffness, short stature, recurrent ear and respiratory infections, hearing loss, cardiac valve disease, and hernias. Distinctive features include a broad nose, thick lips, and macroglossia. Crucially, children with the severe form develop progressive intellectual disability, behavioral disturbances (including hyperactivity and aggression), and eventual loss of previously acquired developmental milestones. Airway obstruction, cardiac disease, and respiratory complications are common. Life expectancy is significantly reduced, with most patients dying in the second decade of life. Intravenous enzyme replacement therapy (ERT) with idursulfase (Elaprase) is approved and can address some somatic symptoms such as organomegaly and walking capacity, but it does not cross the blood-brain barrier effectively and therefore has limited impact on the neurological progression of the severe form. Intrathecal ERT and hematopoietic stem cell transplantation (HSCT) are being investigated as potential approaches to address CNS disease, though evidence for their efficacy in the severe form remains limited. Supportive and multidisciplinary care, including management of airway, cardiac, orthopedic, and developmental needs, remains a cornerstone of treatment.

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