Pervaiz MA 1 , Matern D 1 , Rinaldo P 1 , Gavrilov D 1 , Tortorelli S 1 , Oglesbee D 1 , Raymond K 1 1 BGL, Mayo Clinic, Rochester, United States I-Cell disease is caused by defects in the targeting of lysosomal enzymes to lysosomes due to deficiency in the enzyme UDP-N-acetylglucosamine:Nacetylglucosaminyl-1-phosphotransferase. Multiple sulfatase deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 (SUMF1) which encodes formylglycine-generating enzyme (FGE). Patient 1 is a 7-year old female with extremetly elevated serum total hexosaminidase and α-N-Acetylglucosaminidase activity. Patient 2 is a 5year old girl with deteriorating clinical symptoms whose Arylsulfatase-B activity was only slightly below the normal range which triggered us to measure serum hydrolases. The activity of several serum hydrolases (Hexosaminidase, α-galactosidase, and α-N-acetylglucosaminidase) was high. A third patient had low enzyme activity for α-N-Acetylglucosamindase,α-L-Iduronidase, α-glucoronidase and Arylsulfatase B. Total serum hexosaminidase and α-Galactosidase activities were high which was consistent with a diagnosis of I-Cell disease. Patient 4 had reduced Arylsulfatase A and B, and α-NAcetylgalactosamine enzyme activities, findings suggestive of MSD. Conclusion: These cases demonstrate the difficulty of diagnosing as well as differentiating between I-Cell disease and MSD because of the overlap in abnormal enzyme activity levels in both conditions. It is very important to include I-Cell disease and MSD in the differential diagnosis of any abnormal lysosomal enzyme activity, especially if two or more enzymes are abnormal. Cases of I-cell disease diagnosed on the island of Ireland over 13 years (1/1/199-31/12/2010) were identified in collaboration with the clinical diagnostics laboratory. A database documenting details of diagnosis and clinical course where available was compiled and correlated with published birth rates including that of Irish Travellers (available only for the Republic). Twenty infants from 14 families were diagnosed with I-cell disease during the study period. 18 were born to Irish Traveller parents, one to non-Traveller Irish parents and one to parents from Southern Europe. Mutation analysis was available for 7 cases, of whom 6 (all Travellers) were homozygous for the c3503_3504delTC mutation. Median age of death in patients of the Traveller community was 232 days (range 3-936). Incidence estimated using population data for the Republic (ROI) and Northern Ireland was 1.56 per 100,000 live births. The incidence amongst Travellers (based on ROI cases and population data) was 114 per 100,000 live births, suggesting a carrier frequency of the common mutation of 1 in 15. The carrier rate amongst Irish non-Travellers remains rare at 1 in 512. This high incidence and carrier rate found in the Irish Traveller population is relevant for genetic counselling of this consanguineous community.