OBJECTIVES: To validate a new instrument, the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS), a new instrument for assessing functional status in children and adolescents with Mucopolysaccharidosis II (MPS II; Hunter syndrome [HS]), one of a group of rare genetic, lysosomal storage diseases. METHODS: Following IRB approval, participants were recruited from the 2003 Annual MPS Family Conference and an ongoing MPS II Phase I/II clinical trial. Eligible participants were individuals with MPS II at least 12 years old or a parent of a child of any age with MPS II. The instrument was administered twice over a three-week period. Face validity, internal reliability, domain intercorrelation, parent-child correlations, and test-retest reliability were assessed for each of six domains (standing/walking, grip/reach, sleeping, schooling/work, activities, and breathing) and for the overall disability score. RESULTS: Eleven patients with MPS II and 27 parent caregivers of patients with MPS II completed the HS-FOCUS. Face validity was confirmed through interviews with expert clinicians, patients with MPS II, and their families. The instrument showed very good overall internal reliability (Cronbach's alpha = 0.93 [parents] and 0.83 [patients]). The HS-FOCUS showed good reproducibility (rs = 0.85, p <0.0001 [parents] and 0.71, p = 0.031 [patients)] for overall function in test-retest analyses, although sleeping and breathing domains had weaker correlations. Intercorrelation coefficients for each domain with the overall functional disability score were strong (range rs = 0.69 to 0.89). Weak correlations were reported between the nine parent-child pairs, which is commonly accepted as a challenge in survey research of children and adolescents. CONCLUSIONS: Findings of this validation study suggest that the HS-FOCUS may effectively capture disability and functional status in individuals with MPS II. Additional assessment of sensitivity and construct validity are warranted, and could be conducted as part of ongoing clinical trials.