The clinical expression of Gaucher disease correlates with genotype: Data from 570 patients

Abstract

Gaucher disease is the most common lysosomal storage disease and is caused by a deficiency of glucocerebrosidase. It is typically considered an adult disorder, manifest with hematologic changes and bone fractures. The five most common genotypes, consisting of 570 patients, were selected from the ICGG Registry (2000+ patients) and stratified according to clinical symptoms. Surprisingly, 50% of all patients in the registry were less than 10 years when diagnosed. The most common genotype was N370S/N370S (38%), followed by N370S/L444P (27%), N370S/84GG (20%), L444P/L444P (11%), and N370S/IVS2+1 (4%).

The age at diagnosis was 27.8 years for N370S/N370S, 17.9 years for N370S/L444P, 9.4 years for N370S/84GG, 8.9 years for N370S/IVS2+1, and 2.5 years for L444P/L444P.

All patients with the N370S allele were classified as type I and were free of neurologic symptoms. 78% of children with the L444P/L444P genotype had eventual neurologic symptoms and were classified as type III. Radiologic evidence of bone disease was present in 92% of N370S/N370S, but was rare in L444P/L444P patients at diagnosis. The largest spleen volumes were in L444P/L444P (40 × norm), followed by N370S/IVS2+1 (19.1 x), N370S/84GG (18.7 x), N370S/L444P (15.4 x), and N370S/N370S (12.1 x).

Some rare alleles present with unique clinical signatures. Patients homozygous for D409H are severe with aortic valve calcification. Infants homozygous for a rare recombinant allele, RecNcil, are born with “collodian” skin and severe neurologic symptoms.