The Health Outcome

After Alzheimer's disease, Parkinson's disease is the most common neurodegenerative disorder, with an estimated prevalence of approximately 1 in 100. (2) Approximately two-thirds of Parkinson's disease cases are sporadic while the remainder are familial; although a small subset appears to follow autosomal dominant inheritance, the vast majority have no clear inheritance pattern. (3,4) A significant genetic role in disease causation has been inferred from familial aggregation in first- and/or second-degree relatives; results from more than 10 studies have suggested that risk of Parkinson's disease in first-degree relatives of affected individuals is 3-14 fold higher than in the general population. (5) Subsequent molecular genetic studies have identified at least 3 genes (parkin, alpha-synuclein, and synphilin-1), which, when mutated, can result in Parkinson's disease and linkage of the Parkinson's disease phenotype has been localized to several other chromosomal regions. (6) In addition to genetic susceptibility loci, there is evidence that environmental factors play a causative role in the development of Parkinson's disease. (7) Recent hypotheses have suggested several related etiologies for toxicity to dopaminergic neurons, resulting in the Parkinson's disease phenotype: misfolding and aggregation of proteins, leading to cell dysfunction by inhibition of the ubiquitin-proteasome system; and oxidative stress from mitochondrial dysfunction, resulting in an increased amount of misfolded proteins. (8,9) In essence, Parkinson's disease appears to have a multifactorial basis with a delicate interplay of genetic and environmental susceptibility factors. Teasing out the contributions of these factors to the cause of this very prevalent disease is the challenge.

Between 1996 and 2003, several studies reported an association of Parkinson's disease with Gaucher disease, type 1. (10-14) 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 typical antiparkinson therapy. (13) Gaucher disease is the most common recessively-inherited disorder of glycolipid storage; it is due to deficiency of the lysosomal enzyme glucocerebrosidase, which results in multiorgan disease (primarily involving 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. (15) These observations suggest that homozygotes and heterozygotes for Gaucher disease mutations may have an increased risk for developing Parkinson's disease, which could reflect a significant health risk for certain ethnic populations, particularly Ashkenazi Jews.

The Finding

The authors hypothesized that mutations in the glucocerebrosidase (GBA) gene may be involved in the development of idiopathic Parkinson's disease. To that end, they performed a case-control study, analyzing 99 patients with Parkinson's disease, 74 patients with Alzheimer's disease, and 1543 healthy control subjects for 6 mutations in the GBA gene. All patients and controls were of Ashkenazi Jewish ancestry by family history. Among the 1543 control subjects, 95 were heterozygous for a Gaucher disease-causing mutation (6.2%). None of the control subjects were homozygous or compound heterozygous for a mutation. Of the carriers, 92 were heterozygous for N370S and 3 were heterozygous for 84GG; these results were consistent with a carrier rate of 1 in 16.7 for the N370S mutation and 1 in 514 for the 84GG mutation (previous estimates of the carrier frequency for these mutations were 1 in 17.5 and 1 in 400, respectively).

The rates of “carriage of Gaucher disease” (heterozygotes plus homozygotes for any mutation) were calculated for patients with Parkinson's disease, Alzheimer's disease, and control subjects. The frequency of the mutant N370S GBA allele in the Parkinson's disease patients was 5 times that among the healthy Ashkenazi control subjects (p<0.001). The frequency of the mutant 84GG GBA allele in the Parkinson's disease patients was 21 times that among the healthy Ashkenazi control subjects (p<0.001). Three patients with Parkinson's disease were homozygous for the N370S mutation (nonpenetrant for Gaucher disease), while none of the 1543 control subjects were homozygous.

The authors also showed that patients with Parkinson's disease had significantly greater odds for being “carriers” of Gaucher disease than did patients with Alzheimer's disease (odds ratio, 10.8; 95% confidence interval, 3.0-46.6; p<0.001) or control subjects (odds ratio, 7.0; 95% confidence interval, 4.2-11.4; p<0.001). In addition, the rate of “carriage” of a GBA gene mutation among patients with Alzheimer's disease did not differ significantly from healthy controls (odds ratio, 0.6; 95% confidence interval, 0.2-2.2; p=0.62).

The authors' overall conclusions from the study were (1) the prevalence of GBA mutations in the population of Ashkenazi Jews with Parkinson's disease is much higher than the reported prevalence of mutations in other susceptibility genes, such as parkin and alpha-synuclein, and (2) mutations in the GBA gene emerge as a strong genetic determinant predisposing people to Parkinson's disease.

Public Health Implications

The authors concluded that GBA gene mutations may play a significant role in the pathogenesis of idiopathic Parkinson's disease. When one compares individuals in the Parkinson's disease group who had at least one mutant allele for the GBA gene (31 in a total of 99), with those in the normal controls that had at least one mutant allele (95 in a total of 1543), the estimated attributable fraction is 26%, indicating a significant effect from the GBA gene mutations evaluated in this study with regard to the development of idiopathic Parkinson's disease. However, these results are only relevant to this very circumscribed study population (Ashkenazi Jews within or near Haifa , Israel ) and may not be generalized to other groups, particularly populations in which these GBA gene mutations may be much less common.

The authors did not evaluate the effects of specific alleles, or the contribution of homozygosity for a mutant allele versus heterozygosity, on the risk for developing Parkinson's disease in this patient population. However, the data presented by the authors allowed for genotype-specific analysis to be performed, which revealed that (1) N370S homozygotes were approximately 47 times more likely than people without this mutation to have Parkinson's disease, but accounted for only 3 of 98 cases, (2) N370S heterozygotes were approximately 5 times more likely to have Parkinson's disease, and (3) 84GG heterozygotes were approximately 28 times more likely to have Parkinson's disease, but accounted for only 4 out of 98 cases. Although quite significant odds ratios (p<0.001) were found for all three genotypes in association with Parkinson's disease, these results are based upon small numbers and the confidence intervals are wide for N370S homozygotes and 84GG heterozygotes.

The data could also be analyzed to determine the absolute risk for developing Parkinson's disease among members of the Ashkenazi Jewish population, although the resulting risk estimates are somewhat speculative, given that there is no assurance that the study was population-based; furthermore, the odds ratios are imprecise for N370S homozygotes and 84GG heterozygotes because they are based upon small numbers. In spite of these limitations, this analysis suggests that there are indeed significant risks for developing Parkinson's disease, over the baseline population risk of 1%, for both N370S and 84GG carriers (4.0% and 21% risks, respectively), as well as for N370S homozygotes (35% risk); however, this analysis also suggests that 95% of individuals identified as homozygous or heterozygous for the N370S mutation are not expected to develop Parkinson's disease.

The authors' conclusion that “mutations in the GBA gene emerge as a strong genetic determinant predisposing people to Parkinson's disease,” reflects their finding that mutations in the GBA gene in this Ashkenazi Jewish population are much more common than mutations in other genes implicated in the genetic susceptibility to Parkinson's disease (parkin, alpha-synuclein, synphilin-1, etc.). However, the individual risk of developing Parkinson's disease for carriers of a mutation in the GBA gene (particularly the N370S mutation), is still very low (less than 5%). Since there is no means of determining which N370S heterozygotes or homozygotes will develop Parkinson's disease in relation to those who won't, and there are no clear lifestyle modifications or medical treatments to lower the risk, it would not be reasonable to test individuals to determine their carrier status for this mutation. N370S carrier identification would cause needless anxiety about the uncertain potential of a major future health problem and provide no direct health benefit.

References

1. Aharon-Peretz J et al. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004;351:1972-7.
2. Gelb DJ et al. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56:33-9.
3. Payami H and Zareparsi S. Genetic epidemiology of Parkinson's disease. J Geriatr Psychiatr Neurol. 1998; 11:98-106.
4. Lazzarini AM et al. A clinical genetic study of Parkinson's disease: evidence for dominant transmission. Neurology. 1994;44:499-506.
5. Pankratz N et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet. 2003;12:2599-2608.
6. Pankratz N and Foroud T. Genetics of Parkinson disease. NeuroRx. 2004;1:235-42.
7. Gorrell et al. The role of the environment in Parkinson's disease. Environ Health Perspect. 1996;104:652-4.
8. Bence NF et al . Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001;292:1552-5.
9. Dauer W et al. Parkinson's disease: mechanisms and models. Neuron. 2003;39:889-909
10. Neudorfer O et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. Q J Med. 1996;89:691-4.
11. Machaczka M et al. Parkinson's syndrome preceding clinical manifestation of Gaucher's disease. Am J Hematol. 1999;61:216-7.
12. Tayebi N et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab. 2001;73:313-21.
13. Varkonyi J et al. Gaucher disease associated with parkinsonism: four further case reports. Am J Med Genet. 2003;116A:348-51.
14. Bembi B et al. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003;61:99-101.
15. Horowitz M et al. Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population. Hum Mutat. 1998;12:240-4.