Human study identifies genetic variation for type and rate of physical decline Parkinson’s disease.

With Parkinson’s disease clinicians have long noted that the presence of tremors, rather than balance and walking problems is the initial or dominant symptom and hypothesize this may even suggest slower progression of the disease.  On top of this, it is also unclear why some patients present with more tremor as opposed to walking/balance difficulties. Now, researchers led by the University of Pennsylvania have uncovered a site of genetic variation, known as single nucleotide polymorphisms (SNPs), that identify which patients with Parkinson’s disease are more likely to have tremors versus difficulty with balance and walking. The team state that they also observed patients with this genetic variation had a slower rate of Parkinson’s disease progression, and that their brains contained lower amounts of alpha-synuclein, a protein which plays a role in the development of Parkinson’s disease.  Their findings were presented at the 68th Annual Meeting of American Academy of Neurology.

Previous studies show that SNPs are the most widespread kind of genetic variation among people. There are about 10 million of them in the human genome and most have no effect on health or development.  However, it has been shown that when SNPs occur within a gene or in a regulatory region near a gene, they may play a more active role in disease by affecting the gene’s function.  The human alpha-synuclein protein is made of 140 amino acids and is encoded by the SNCA gene. Alpha-synuclein is the primary structural component of Lewy bodies, which are clumps of protein that develop inside nerve cells in Parkinson’s disease and some other disorders.  The current study shows that in Parkinson’s patients with the genetic variation GG genotype, a relatively common SNP near the alpha-synuclein (SNCA) gene, tremors rather than walking/balance problems, slower physical progression of the disease, and lower levels of alpha-synuclein in the brain were all exhibited.

The current study ranked 251 Parkinson’s disease patients at the University of Pennsylvania Health System on tremor and balance/walking scores. They then looked at the patients’ genotypes to see if there were correlations between ten genetic variations previously associated with Parkinson’s disease and the primary symptoms that the patients displayed; patients were followed up to seven years in some cases.

Results show that 39 of the 251 patients who had the genetic variation known as GG genotype at the rs356182 SNP 3′ to the SNCA gene were more likely to have tremors rather than walking/balance problems, slower physical progression of the disease, and lower levels of alpha-synuclein in the brain.  The lab carried out the same type of analysis with an additional group of 559 patients at three other clinical sites in the United States and found similar results for the association between the genotype and the type of Parkinson’s disease symptoms.  They go on to conclude that to their knowledge this study is one of the first to link this difference to a specific genetic variation.

The team surmise that their findings provide information that has implications for diagnosis, prognosis, treatment, and prevention efforts.  They go on to add that this precision medicine can both serve as a biomarker for and influence the disease course of Parkinson’s patients. For the future, the researchers state that this opens up the possibility of achieving a hallmark of precision medicine, namely, targeted therapies for different ‘versions’ of what was once thought to be a single disease.

Source: Perelman School of Medicine at the University of Pennsylvania