INTRODUCTION: The mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI. HYPOTHESIS: Somatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention]. MATERIALS AND METHODS: Forty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in "Longitudinal Studies of Brain Structure and Functions in MPS Disorders" across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA). RESULTS: PSS was positively associated with age in attenuated MPS I (P < 0.001), MPS II (P < 0.01) and MPS VI (P < 0.05). There was a negative association of PSS with FSIQ in attenuated MPS I (P < 0.001) and in MPS VI (P < 0.001) but not with MPS II. Although attention scores were below average in all groups, a significant negative association between PSS and one measures of sustained attention (TOVA d prime) was found only in MPS VI. CONCLUSIONS: Physical Symptom Score increased with age in attenuated MPS I, II and VI, reflecting progressive somatic burden of disease despite treatment with enzyme replacement therapy. Furthermore, the association of increased somatic disease burden with decreased neurocognitive ability suggests that both measures reflect disease severity and are not independent.