HuGENet™ Case Study
Glucocerebrosidase Gene Mutations and Parkinson Disease Objectives
Stuart K. Shapira, M.D., Ph.D.
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
Aharon-Peretz, Judith et al. Mutations in the Glucocerebrosidase Gene and Parkinson Disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-7.
After reading this case study, you should be able to
- Identify inconsistencies between study and control populations which might bias the results of gene-disease association studies.
- Calculate gene-disease associations in terms of absolute, relative, and attributable risks.
- Assess the public health implications of the risk for developing Parkinson Disease for the Ashkenazi Jewish population, based on the findings.
After Alzheimer's disease, Parkinson Disease is the most common neurodegenerative disorder, with an estimated lifetime risk of approximately 1 in 100 persons. Approximately two-thirds of Parkinson Disease cases are sporadic while the remainder are familial; a small subset appears to follow autosomal dominant inheritance, whereas the vast majority have no clear inheritance pattern. Nevertheless, familial aggregation in first- and second-degree relatives suggests a significant genetic role in disease causation; results from more than 10 studies have suggested a 3-14 fold higher risk of Parkinson Disease in first-degree relatives of affected persons compared with general population risks. Subsequent molecular genetic studies have identified at least 3 genes (parkin, alpha-synuclein (SNCA), and synphilin-1 (SNCAIP)) with specific mutations associated with Parkinson Disease, and linkage of the Parkinson Disease phenotype has been localized to several other chromosomal regions. In one study (Scott et al., 1999), the SNCA gene was tested for the A53T mutation in 356 affected persons from 186 multiplex families with Parkinson Disease; one Greek-American family segregated this mutation as an autosomal dominant trait, giving a frequency for this mutation of less than 1 in 186, or 0.5%. In a study for mutations in the SNCAIP gene, Marx et al. (2003) performed mutation analysis in 328 German familial and sporadic Parkinson Disease patients; in 2 apparently sporadic patients the authors found a mutation (R621C), giving a frequency for this mutation of less than 1 in 164, or 0.6%. Therefore, these gene variants do not account for the majority of Parkinson Disease since they have been found only rarely in persons with either sporadic or familial disease. Additional evidence suggests that environmental factors play a causative role in the development of Parkinson Disease. Several related hypotheses suggest that the Parkinson Disease phenotype results from toxicity to dopaminergic neurons caused by (1) misfolding and aggregation of proteins leading to inhibition of the ubiquitin-proteasome system and cell dysfunction, and (2) oxidative stress from mitochondrial dysfunction resulting in an increased amount of misfolded proteins. In essence, Parkinson Disease appears to result from a delicate interplay of genetic and environmental susceptibility factors.
Between 1996 and 2003, several studies reported an association of Parkinson Disease with Gaucher disease, type 1. Persons with Gaucher disease may develop an atypical parkinsonism presenting in the 4th to 6th decades of life, which progresses relentlessly and is refractory to usual antiparkinson therapy. Gaucher disease is the most common recessively-inherited disorder of glycolipid storage; it is due to deficiency of the lysosomal enzyme, glucocerebrosidase, and involves multiple organs, primarily the spleen, liver, bones, and bone marrow. Type 1 Gaucher disease--the milder type of the disease--occurs in all ethnic groups, but is particularly prevalent among Ashkenazi Jews, with a carrier rate of 1 in 17 for the disease-associated variant of the glucocerebrosidase gene (GBA). These observations suggest that homozygotes and heterozygotes for Gaucher disease mutations may have an increased risk for developing Parkinson Disease, which could reflect a significant health risk for certain ethnic populations, particularly Ashkenazi Jews.
Bembi B et al. Gaucher's disease with Parkinson Disease: clinical and pathological aspects. Neurology. 2003;61:99-101.
Dauer W et al. Parkinson Disease: mechanisms and models. Neuron. 2003;39:889-909.
Hughes AJ et al. Accuracy of clinical diagnosis of idiopathic Parkinson Disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181-4.
Marx FP et al. Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson Disease. Hum Molec Genet. 2003;12:1223-31.
Pankratz N and Foroud T. Genetics of Parkinson Disease [PDF 57KB].
Scott WK. et al. The alpha-synuclein gene is not a major risk factor in familial Parkinson Disease. Neurogenetics. 1999;2:191-2.
Tayebi N et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab. 2001;73:313-21.