Reliable Assay of Acid Sphingomyelinase Deficiency with the Mutation Q292K by Tandem Mass Spectrometry.

Abstract

To the Editor: Niemann-Pick-A/B disease is a lysosomal storage disease caused by deficiency of acid sphingomyelinase (1). Efforts are underway to develop novel therapies for this disease, and some newborn screening centers have started to test for acid sphingomyelinase enzymatic activity in dried blood spots on newborn screening cards. Available assays for newborn screening include tandem mass spectrometry (MS/MS)1 (2) and fluorometry (3). Diagnostic laboratories have typically used a radiometric assay with radiolabeled sphingomyelin or the fluorometric assay (4). However, in a detailed study of 24 patients confirmed as having Niemann-Pick-A/B disease, 4 had the Q292K missense allele. Fibroblasts from these 4 patients showed a normal to increased acid sphingomyelinase activity when assayed with the fluorometric substrate but displayed activity in the radiometric assay with natural sphingomyelin substrate in the low end of the range of the affected samples (4). The age of onset of symptoms in these 4 patients was <1, 1, <2, and <3 years, suggesting that the disease can be quite severe in patients harboring this allele (4). This led to the conclusion of a “diagnostic pitfall” in the use …