Neurologists for the first time have reason to be optimistic about the potential usefulness of genetic testing for Parkinson's disease, following two reports that a specific mutation in the LRRK2 gene is relatively common in patients with Parkinson's disease, according to Dr. Zbigniew Wszolek, professor of neurology at the Mayo Clinic in Jacksonville, Fla.
Specifically, the LRRK2 G2019S mutation occurs in 13%–41% of cases in North African Arab and Ashkenazi Jewish patients, according to the two reports. Dr. Wszolek cautioned that uncertainties about the precise penetrance of the mutation mean that “the counseling [for asymptomatic patients] needs to be cautious.”
LRRK2 (leucine-rich repeat kinase 2) is the most recent gene to be implicated in Parkinson's disease, and the G2019S mutation is the first genetic mutation that appears to be relatively common. The mutation has been linked with autosomal dominant forms of Parkinson's disease.
Reports published in the past year or so on patients primarily of European ancestry—including three reports published last year (CLINICAL NEUROLOGY NEWS, March 2005, p. 24)—have shown that the G2019S mutation explained up to 2% of cases of sporadic Parkinson's and 5%–7% of familial cases. The latest reports, which were published as letters to the editor in the New England Journal of Medicine, described a much higher frequency of the G2019S mutation among North African Arabs and Ashkenazi Jews.
Researchers at the Beth Israel Medical Center, New York, detected the G2019S mutation in 22 of 120 (18%) Ashkenazi Jewish patients with Parkinson's disease and only 4 of 317 (1%) Ashkenazi Jewish patients without the disease.
When there was a familial pattern, 30% (11 of 37 patients) carried the mutation. In the absence of a family history, 13% (11 of 83) had the mutation, reported Laurie J. Ozelius, Ph.D., of Albert Einstein College of Medicine, New York, and associates (N. Engl. J. Med. 2006;354:424–5).
In the other letter, Suzanne Lesage, Ph.D., and colleagues from the French Parkinson's Disease Genetics Study Group described how they looked for the G2019S mutation in 104 North African Arabs with Parkinson's disease and 151 healthy Arab controls, and found the frequency to be 37% in familial cases and, “more unexpectedly,” 41% in sporadic cases (N. Engl. J. Med. 2006;354:422–3).
Matthew Farrer, Ph.D., of the Morris K. Udall Parkinson's Disease Research Center of Excellence at the Mayo Clinic in Jacksonville, cautioned against putting too much weight on such “convenience sample” reports because they are based on patients who present to the clinic and fall short in terms of epidemiologic rigor. That said, the reports are receiving growing appreciation among experts for showing an interesting pattern of frequency of the mutation in idiopathic or sporadic cases of Parkinson's disease, he said. Frequencies are low in Northern Europe and North America (1%–3%), are higher in Southern Europe (about 10% in southern Spain, for example), and explode in North Africa (as high as 41%).
Moreover, the mutation is associated with the same haplotype in different populations, which indicates the existence of a common ancestor.
More research needs to be done on the precise penetrance of the mutation for testing and counseling to be more meaningful. Penetrance in carriers at this point is known to be age dependent, increasing from approximately 20% at age 50 to 90% at age 80 and up, Dr. Wszolek said.
Overall, “we can educate as much as we can on the current status of the gene. But the management of the disease doesn't change,” Dr. Wszolek said. “We can tell patients that the disease related to this gene is generally well-managed, and the medications are well tolerated.” A test for the mutation is not yet commercially available.
The clinical phenotype of both homozygous and heterozygous carriers of the G2019S mutation (clusters of homozygotes have been identified) largely mirrors that of typical late-onset, levodopa-responsive, idiopathic Parkinson's disease, Dr. Farrer said. Still, the phenotype varies, even within families, he said.
The most striking variability, though, concerns the neuropathologic features of the disease, he said.
Most cases of LRRK2 Parkinsonism show the Lewy body disease that is consistent with a postmortem definitive diagnosis of Parkinson's disease. Some cases have tau-positive neurofibrillary tangles without Lewy bodies. Such multiple pathologic expressions have occurred within families as well.