Genetics of Gaucher Disease

Gaucher disease is an autosomal recessive disorder defined by the presence of two mutant alleles for the glucocerebrosidase gene. To date, more than 200 mutant alleles have been identified,^[1] which have been found to code for enzymes with either decreased stability or decreased binding affinity.^[2] The clinical features and course of the disease can vary among patients with the same genotype.^[1]

Although Gaucher disease is panethnic, the incidence rate is relatively high (as many as 1 in 450 people) among individuals of Eastern European (Ashkenazi) Jewish descent, with a carrier frequency of 1 in 12 to 15 Ashkenazi Jews.[1, 3, 4] The four most commonly identified allele mutations account for 89% to 96% of those in the Ashkenazi population.[5] Facts About Genetic Disease: Ashkenazi Jewish Descent (PDF) To view PDFs, you must have Adobe Acrobat® Reader®. To download this software for free, click here.

With each pregnancy, each carrier has a 50% chance of passing along a mutated gene. Carriers are normal, asymptomatic persons, and being a carrier per se is no medical problem. However, when both parents are carriers, there is a 25% chance with each pregnancy that the child will be affected, i.e. will develop Gaucher disease.^[6]

The diagrams below show how the Gaucher gene can be passed from one generation to the next.

Genetic counseling and testing
People at risk of being carriers may want to consider genetic counseling and family DNA testing. Individuals at risk include: relatives of Gaucher disease patients, persons of Ashkenazi Jewish descent, and symptomatic individuals.

Knowledge of carrier status may be important for reproductive choices and should warrant a consultant with a geneticist, for genetic counseling. ^{[7, 8]}

Here are the addresses of the 8 Centres for Human Genetics in Belgium:

Université de Liège - ULg
http://www.genetique-hum-ulg.be/

Universiteit Gent - UG
http://allserv.rug.ac.be/~sdebie/index.html

Université Libre de Bruxelles - ULB
http://www.ulb.ac.be/

Vrije Universiteit Brussel - VUB
http://www.az.vub.ac.be/AZlabogids/gbl/genetica.htm

Université Catholique de Louvain - UCL
http://www.ucl.ac.be/

Centrum Menselijke Erfelijkheid - KULeuven
http://organigram.kuleuven.be/5/50000622e.htm

Centrum Medische Genetica - Universiteit Antwerpen
http://www.uia.ac.be/cmg

Institut de Pathologie et de Génétique - Loverval
ipg@ipg.be

References

1. Grabowski GA. Lysosomal storage diseases. In: Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2276-2281.

2. Beutler E, Grabowski G. Gaucher disease. In: Scriber CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995;2:2641-2661.

3. National Center for Biotechnology Information. Genes and disease. Available at: http://www.ncbi.nlm.nih.gov/disease/Gaucher.html. Accessed May 2, 2002.

4. Zimran A, Gelbart T, Westwood B, et al. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991;49:855-859.

5. Grabowski G. Gaucher disease: enzymology, genetics, and treatment. In:Harris H, Hirshchorn K, eds. Advances in Human Genetics. New York, NY: Plenum Press; 1993:377-441.

6. Jameson JL, Kopp P. Principles of human genetics. In: Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:375-396.

7. Morales LE. Gaucher's disease: a review. Ann Pharmacother. 1996;30:381-388.

8. National Library of Medicine. Medical encyclopedia: Gaucher disease. Available at: www.nlm.nih.gov/medlineplus/ency/article/000564.htm. Accessed August 5, 2002.