OBJECTIVES: Mucopolysaccharidosis II (MPSII, Hunter syndrome) is an ultra-rare genetic disease (incidence rate: 0.38 to 1.09/100,000 live male births) with manifestations caused by mutations in the iduronate-2-sulfatase gene, leading to impaired enzymatic function and accumulation of glycosaminoglycans in multiple systems and organs. The non-neuronopathic phenotype (nnMPSII) is characterized by delayed recognition and absent or milder CNS manifestations. Although enzyme replacement therapy (ERT) for MPSII was approved in 2006, ERT is unable to access the CNS, and characterization of unmet need has predominantly focused on the severe population. A systematic literature review was conducted to assess clinical, humanistic and economic burden, mortality, and efficacy/safety of nnMPSII patients on current SOC treatment.

METHODS: Medline, Embase, Cochrane Central/Reviews were searched from 2003 to February 2023, for peer-reviewed articles and conference abstracts (in English), supplemented by a search on conference websites (last 3 years), and study registries. While a broad search was conducted for any phenotype, only data for nnMPSII was included during the selection.

RESULTS: Of 2590 records identified, following full-text review, 57 publications were included. Clinical burden was derived from 36 studies (10 investigating joint-related comorbidities, 10 cardiac, 10 hearing, 9 respiratory, 17 CNS) with heterogenous symptoms and varying study quality. Humanistic burden was assessed in a variety of domains using different instruments (patient-reported in 16, caregiver-reported in 4). No economic analysis and only limited resource utilization data (5 studies) could be identified. 25 studies investigated efficacy/safety, with urinary glycosaminoglycan, 6-Minute-Walking-Test, and pulmonary function being most frequently assessed endpoints.

CONCLUSIONS: Review suggests that despite the lack of severe CNS involvement, attenuated patients are still profoundly affected. Disease burden appears to be underestimated as many studies have not separated results for nnMPSII and hence could not be included in our review. There are substantial data gaps and further research into the impact of this phenotype is warranted.