Response to Torralba and Pérez‐Calbo

Abstract

We thank Drs Torralba and Perez-Calbo for their interest in our work, for their understanding of the importance of the identification of a relatively severe N370S homozygosity subgroup, and for their comments and suggestions (Torralba & Perez-Calvo 2009). The key message of our paper is that Gaucher disease patients with N370S homozygosity have substantial phenotypic heterogeneity, and that some are at risk for early disease onset and severe clinical manifestations. We discussed a number of possible mechanisms that could lead to such phenotypic variability. As noted by Drs Torralba and Perez-Calbo, we indeed stipulated that some patients with compound heterozygosity for N370S/55 bp deletion may have been misclassified as true N370S homozygotes in the Gaucher Registry database. Such individuals frequently, but not invariably, have phenotypically more severe disease. We apologize for omitting the report of Torralba et al (2002), in which 40% of putative unrelated Spanish N370S homozygous patients were found to have the N370S/55 bp deletion genotype. We support the recommendation of Drs Torralba and Perez-Calvo that, where feasible and medically available, genotyping should include screening for this mutation. However, we note that––based on unpublished studies from Israel (A. Zimran, personal communication)––the prevalence of the N370S/55 bp deletion in the worldwide population represented in the Gaucher Registry database is likely to be much lower than that reported in the Spanish cohort. More to the point, even in the Spanish population reported by Torralba et al (2002), true N370S homozygotes had high severity score indices, substantial hepatosplenomegaly, moderate-to-severe thrombocytopenia, and, most significantly, bone pain and osteonecrosis. In general, there was substantial heterogeneity in their Ftrue_ N370S homozygotes, and, in some parameters, this patient group showed more severe manifestations than the N370S/55 bp deletion compound heterozygotes. These finding are very much in keeping with our conclusion that Gaucher disease with N370S homozygosity is not invariably a clinically benign disorder, and that there exists a subgroup of such patients with severe clinical manifestations. J Inherit Metab Dis (2009) 32:455–456 DOI 10.1007/s10545-009-9963-z