1067 Safety of Substrate Reduction Terapy in a Toddler with Niemann-Pick Typec Disease: A Case Report

Abstract

Background: Niemann-Pick type C (NPC) disease is a rare inborn error of metabolism caused by defective intracellular cholesterol traffic. Recently, substrate reduction therapy was introduced in the treatment of lysosomal storage disorders, especially of the glycosphingolipidoses with brain involvement. The iminosugar N-butyldeoxyjyrinomicin (miglustat) was reported to ameliorate neurologic phenotype of a murine NPC model. Initially used successfully in Gaucher and NPC diseases, concerns about its tolerance and safety arose related to peripheral neuropathy and diarrhea. The tolerance of very young children with NPC to miglustat is still largely unknown.Case report: Female patient, 3 years old, born from healthy and non-consanguineous parents was referred to us at the age of one month with cholestasis, hepatomegaly and splenomegaly. Two older twin sisters died at 6 months with severe cholestasis with no diagnosis. Bone marrow biopsy revealed the presence of “foamy cells” and Gaucher and Niemann-Pick type A diseases were ruled out. However, chitotriosidase level was 1300 nmol/ mL/h, prompting a fibroblast culture from skin tissue that revealed a positive filipin staining and abnormal cholesterol esterification studies, confirming the diagnosis of NPC. Sequence analysis of NPC1 gene revealed a compound heterozygote, harboring a missense mutation (c.3104C>T) and a deletion of one nucleotide (c.3662delT).Conclusions: Miglustat inhibits glucosylceramide synthase which catalyses the first step of glycosphingolipid synthesis. To the best of our knowledge, our patient is the youngest NPC patient treated during 36 months without any adverse event. This experience suggests that miglustat is well tolerated in small children and can ameliorate neurological phenotype.