title: 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.
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, Connecticut 06520-8064, USA.
authors.forename: Tamar H
authors.initials: TH
authors.lastname: Taddei
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kacena
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Ruhua
authors.initials: R
authors.lastname: Yang
authors.forename: Advitya
authors.initials: A
authors.lastname: Malhotra
authors.forename: Michael
authors.initials: M
authors.lastname: Boxer
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Aleck
authors.forename: Gadi
authors.initials: G
authors.lastname: Rennert
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001851:Bone Diseases, Metabolic / Q000453:epidemiology / Q000235:genetics; D002648:Child; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D006942:Hypergammaglobulinemia / Q000453:epidemiology / Q000235:genetics; D015994:Incidence; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000453:epidemiology / Q000235:genetics; D020125:Mutation, Missense; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D017354:Point Mutation; D012306:Risk; D014781:Viscera / Q000473:pathology; D055815:Young Adult
chemical_list: D005962:Glucosylceramidase