Objectives: We quantified medical signs and symptoms to construct the Physical Symptom Score (PSS) for use in research to assess somatic disease burden in mucopolysaccharidoses (MPS) to track disease and monitor treatments. We examined scoring reliability, its concurrent validity with other measures, and relationship to age in MPS type I. Methods: Fifty-four patients with MPS I (36 with Hurler syndrome treated with hematopoietic cell transplant and 18 with attenuated MPS I treated with enzyme replacement therapy), ages 5 to 18 years, were seen longitudinally over 5 years. The summation of frequency and severity of signs of specific organ involvement, surgeries, and hydrocephalus drawn from medical histories comprise the PSS. We examined relationship to age and to daily living skills (DLS) from the Vineland Adaptive Behavior Scale and physical quality of life from the Child Health Questionnaire (CHQ) for each group. Results: The PSS was associated with age in both groups, indicating increase in disease burden over time. The PSS was significantly negatively associated with DLS (r = −0.48) and CHQ (r = −0.55) in the attenuated MPS I but not in the Hurler group. Conclusions: The association of somatic disease burden with physical quality of life and ability to carry out daily living skills suggests that the PSS will be useful in the measurement of disease and treatment effects in the attenuated MPS I group. Earlier treatment with transplant and differing parental expectations are possible explanations for its lack of association with other outcomes necessitating an adaptation for Hurler syndrome in the future.