Summary
Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid β-glucosidase. The most prevalent mutant genotype in type I Gaucher disease, N370S/N370S, is commonly thought to confer a mild phenotype presenting in adulthood. To characterize a subset of more severely affected N370S homozygotes, we assessed the phenotypes at or near the time of diagnosis of all N370S homozygotes with available data enrolled in the International Collaborative Gaucher Group Gaucher Registry. N370S compound heterozygotes were analyzed for comparison, as they are expected to present with a more severe phenotype. Of 798 N370S homozygotes and 1,278 N370S compound heterozygotes identified, 32% (251/788) and 65% (820/1269), respectively, were diagnosed before age 20 years. At diagnosis, N370S homozygotes as compared to N370S compound heterozygotes had the following clinical characteristics: irreversible skeletal lesions 17% (34/198) for N370S homozygotes versus 26% (76/290) for N370S compound heterozygotes; anaemia 18% (59/327) versus 29% (145/494); thrombocytopenia 52% (170/327) versus 62% (281/453); hepatomegaly 44% (83/190) versus 72% (141/195); splenomegaly 73% (142/194) versus 91% (178/195); and osteopenia or osteoporosis 48.6% (34/70) versus 51% (25/49). Some N370S homozygotes exhibited more severe clinical manifestations: 9% (29/327) had severe thrombocytopenia; 3% (5/190) had severe hepatomegaly; 11% (22/194) had severe splenomegaly; 7% (18/255) reported bone crises; 11% (8/70) had osteoporosis. In conclusion, N370S homozygosity does not consistently confer a mild, adult-onset phenotype. Gaucher disease patients with the N370S/N370S genotype exhibit a high degree of phenotypic heterogeneity and some may be at risk for early disease onset and severe clinical manifestations.
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Communicating editor: Gerard Berry
Competing interests: A. Z. receives grant and honoraria from Genzyme Corporation with relation to ICGG activities; is a paid consultant to Shire Human Genetic Therapies and to Protalix Biotherapeutics; and has received speaker fees and honoraria from Actelion Corporation. S. P. receives support from Genzyme Corporation for education, outreach, and programmatic activities, and receives support for research related to Gaucher disease from Amicus Therapeutics and the Actelion Corporation. N. W. is the recipient of an educational and research grant from Genzyme Corporation, Cambridge, MA, has received speaker’s fees and honoraria from Genzyme, honoraria from Actelion Corporation and Shire Human Genetic Therapies, and receives support for research related to Gaucher disease from Amicus Therapeutics and Shire Therapeutics. M. C., C. F. and J. Y. are currently employed by Genzyme Corporation; C. F. was not employed by Genzyme Corporation while the study was conducted.
References to electronic databases: Gaucher disease: type I, OMIM 230800; type II, OMIM 230900; type III, OMIM 231000). Acid β-glucosidase (glucosylceramidase): EC 3.2.1.45.
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Fairley, C., Zimran, A., Phillips, M. et al. Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: An analysis of 798 patients from the ICGG Gaucher Registry. J Inherit Metab Dis 31, 738–744 (2008). https://doi.org/10.1007/s10545-008-0868-z
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DOI: https://doi.org/10.1007/s10545-008-0868-z