The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients

Abstract

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross-sectional study. In addition, the relative risk (RR) of cancer in patients compared with age-, sex-, and ethnic-group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17-54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49-6.79), and overall cancer risk (RR 1.80, 95% CI 1.32-2.40) was increased. Homozygous N370S GD leads to adult-onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma.

Figure 1

Kaplan-Meier curve showing age at onset of symptoms in n = 135 N370S/N370S homozygous GD (black line) and n = 126 N370S/other (gray broken line) Gaucher patients (log rank P-value < 0.0001).

Figure 2

Contrasting manifestations of N370S GD on the viscera versus skeleton by age of presentation. (HS: bone disease severity score, LXN: hepatomegaly expressed as multiples of normal, SXN: splenomegaly expressed as multiples of normal). Asplenic patients were excluded from this analysis. N370S homozygous compared with N370S heterozygous was statistically significant (P < 0.0001) in each of the three models. It should be noted that is almost universal presence of early bone disease manifesting as osteopenia (Herman score 1) even in young children. (Black = N370S homozygous, Gray N370S heterozygous) [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 3

Polyclonal gammopathy-, MGUS-, and multiple myeloma-free survival in 402 N370S Gaucher patients.