Screening for a recently identified mutation shown to cause approximately 5%-6% of familial and 1%-2% of apparently sporadic cases of Parkinson's disease will likely become an important component of genetic testing and counseling for this disease, according to investigators involved in the research.
“No other single mutation identified so far … has occurred with such high frequency” in patients with Parkinson's disease, said William C. Nichols, Ph.D., of Cincinnati Children's Hospital Medical Center, and his associates. Their report was one of three on the mutation published online in the Lancet.
However, two issues need to be resolved before genetic testing for Parkinson's disease can fulfill its potential, Dr. Nichols told this newspaper.
“First, there is nothing which can be done for patients carrying the genetic mutation and thus might be predisposed to developing Parkinson's disease. And … [w]e can't yet predict what an individual's chances of developing the disease are, given they carry a predisposing mutation,” he said.
The new research reported in the Lancet builds on findings published last year showing that mutations in the gene termed LRRK2 (for leucine-rich repeat kinase 2) cause some forms of autosomal dominant Parkinson's disease (Neuron 2004;44:601-7).
The gene codes for the protein dardarin, which is the first kinase to be implicated in the disease.
In research completed since then, a specific mutation in the LRRK2 gene, Gly2019Ser, was identified in several families. The investigators of the just-published studies sought to investigate the frequency of this mutation and its role in susceptibility to Parkinson's disease.
Dr. Nichols and his colleagues analyzed 358 North American families with at least one pair of siblings with Parkinson's disease. They found that 35 of 767 affected members of these families (5%)–in 20 of the 358 families–had at least one copy of the mutated gene.
One of these 35 patients was homozygous for the mutation, they reported (Lancet 2005;365:410-2).
Alessio Di Fonzo, M.D., of the University of Milan, and his colleagues, also detected the mutation in 4 of 61 families (7%) with Parkinson's disease and apparent autosomal dominant inheritance. The families were from Italy, Portugal, and Brazil (Lancet 2005;365:412-5).
And William P. Gilks, of the Institute of Neurology and National Hospital for Neurology and Neurosurgery in London, and his associates, detected heterozygous Gly2019Ser mutations in 8 (2%) of 482 apparently sporadic cases, predominantly from the southeast of England.
Three of the patients turned out to have positive family histories (two involved first-degree relatives, and one involved a second-degree relative), Mr. Gilks and his colleagues reported (Lancet 2005;365:415-6).
Each of the studies included large control populations; the mutation was absent from all the control populations tested.
Alexis Brice, M.D., who commented on the studies in the same issue of the Lancet, called identification of the Gly2019Ser mutation “a major advance.” The mutation “accounts for a surprisingly high proportion of both familial and isolated cases (of the disease),” he said.
Still, there is much to learn, he said. Patients with the Gly2019Ser mutation have typical clinical features of Parkinson's disease, for instance, but the associated clinical spectrum “must be better established,” he said.
Pathologic markers also must be better understood; the neuropathology in patients with the mutations–for instance, the extent and type of Lewy bodies–appears to vary considerably, even within the same family, noted Dr. Brice of Université Pierre et Marie Curie in Paris (Lancet 2005;365:363-4).
He and the investigators also cited the need to know more about the precise penetrance of the mutation before the new results are translated into practice.
In addition to Dr. Gilks' finding of the mutation in patients without any family history of Parkinson's disease, Dr. Nichols found that “despite the apparent autosomal dominant effect (of the mutation),” only 13 (37%) of the siblings with a mutation reported having a parent with Parkinson's disease.
Dr. Di Fonzo and his colleagues also identified some asymptomatic carriers–a finding that suggests penetrance was reduced or was age dependent.
Dr. Nichols, moreover, pointed out that, in his study, carriers of the mutation also had less severe clinical symptoms despite having had the disease for a longer time, which suggests that “the mutation is associated with slowed disease progression,” he said.
Despite the unanswered questions, now that the Gly2019Ser mutation has been identified, “there will be requests for presymptomatic testing by offspring of carriers,” Dr. Brice said in his commentary.
This “raises ethical issues similar to those for Huntington's disease” since, without a preventive treatment, “testing offers no direct medical benefit,” he pointed out.
Dr. Nichols, in his remarks to this newspaper, noted: “I would not be surprised if there were not some company that will soon offer genetic testing for Parkinson's disease, maybe even at the prenatal level, because people are willing to pay for it.”