genes &PD: a heterogenous disorder, many diseases masquerading as one
 

http://finance.boston.com/boston/new...ChannelID=3191

“Parkinson’s Disease is a heterogeneous disorder, meaning that it is actually many diseases masquerading as one general set of symptoms,” said Jim Chinitz, Population Diagnostics’ Chief Executive. “Historically, Parkinson’s patients have been lumped together as a diagnosis based on clinical observations, but there may actually be dozens of subtypes of Parkinson’s that can be delineated as genetic subgroups. This grant will allow us to systematically reveal the genes that harbor disease-causing mutations for Parkinson’s Disease.”
Breakthroughs in the genetic and therapeutic research fields of Parkinson’s Disease have been stymied because the search for its genetic causes have mistakenly relied on the predication that this disease is mainly caused by “common” genetic variants (the “Common Disease / Common Variant” hypothesis). This theory meant that a common set of mutations would cause Parkinson’s and in aggregate explain why the Parkinson’s patient population may experience symptoms differently (for example, age of onset, severity, etc.). Genomic scientists are now beginning to acknowledge that...hypothesis and the related methodology behind discovering common variants is flawed.

... Population Diagnostics’ gene discovery platform stems from the company’s understanding that common complex diseases, such as Parkinson’s Disease, will ultimately be classified by a collection of rare variants within multiple genes. Each rare variant will be capable of independently causing the common set of symptoms that currently define a Parkinson’s diagnosis. Population Diagnostics has developed its patented gene discovery methods based on the Common Disease / Rare Variant hypothesis. Recent discoveries of rare causative variants that have a severe effect in other common diseases such as autism and schizophrenia, support Population Diagnostics’ strategy.

“A rational therapeutic approach to Parkinson’s Disease [“PD”] will remain elusive until more genetic subgroups of PD can be clearly delineated and validated,” said Dr. David Tegay, a Clinical Geneticist, and Parkinson’s Disease clinician who is a consultant to this project. “While known genes associated with PD such as SNCA and LRRK2 are medically relevant, they only permit genetic subtyping in fewer than 10 percent of PD patients. I am confident that Population Diagnostics’ novel biomarker discovery platform will be the key that rapidly unlocks the door to the missing heritability of this debilitating disease.”

Dr. Eli Hatchwell added, “Our approach to revealing causative, rare variants will result in the identification of multiple genes that affect different biological pathways. Thus, each mutation may cause the clinical symptoms of Parkinson’s Disease. It isn’t surprising that traditional therapeutics research has been disappointing, given that a particular drug molecule design is unlikely to be effective in more than one relevant pathway at a time. In the future, when a comprehensive set of causative rare variants collectively explain a far greater percentage of Parkinson’s patients, rational therapeutic development strategies targeted toward the correct pathways can be effectively applied. This exemplifies the promise of personalized medicine, the field in which Population Diagnostics is at the forefront.”...

And meanwhile....
 

....our best strategy would seem to be to promote homeostasis by minimizing stress and taking plant-based adaptogenics?

Eureka!
 

Madelyn,

Thank you so much for sharing this...in my mind this is huge to have someone within the "system" say that there really is no such thing as Idiopathic PD. I know Rick has thought this for quite some time and I jumped on board with the same idea last fall. It explains why people describe PD as "You see one person who has PD, then you have seen one person who has PD."

My hope is that this opens the door for a much needed redirection of focus in research; it may explain things like variable progression rates, variable treatment responses, plus differences in symptoms like some freeze, anxiety vs. depression. This also explains why lines are so fuzzy between PD and Dystonia or Essential Tremor. It also supports a researcher (now I cannot find the source) who said that the more genetic research they do the more the patient pool of those with Idiopathic PD will shrink. I think it was Ric who said this is junk diagnosis in the first place; this is affirmation.

My concern is will this ever translate into clinical benefit for us? I just read that it is now believed that 50% of young onset people are believed to be genetic PD...so why isn't anything happening to see that we are screened for this?

Laura

Just so that it isn't too easy, consider the possibility that there are at least two "stages" to PD, each having multiple paths crossing it to a variant of PD.

That's not the best presentation of an idea that I have ever generated, but let's take neuroinflammation as an example. We know a lot about that one. If the fetus is exposed to bacterial toxins at critical times of development, then it is changed in ways that increase the odds in favor of PD. There is already a ton of complexity in that one statement. Which bacteria? Several different ones. What development windows? Multiples. What changes? Fewer dopaminergic neurons in the SN. A hyperreactive immune response by the microglia that leads to neuronal death. All in that one sentence.

Once born we can still fall prey to the immune system's neuroinflammatory response by coming down with infections. Which ones? Influenza. Nocardia. Salmonella. More? And I suspect that the timing matters. The flu at a time when our stress system is overloaded is going to differ from when we are rested.

All that can lead to us having this loaded gun of neuroinflammation in our head. But once that first stage is in place, what pulls the trigger? A dozen different things. Pestcides. Herbicides. Mercury. Manganese. A bad tooth. A UTI. etc.

I suspect that the mitochondrial branch of the family is just as complicated, too.

I think that Modern Medicine has met its match here.

environmental triggers and genetic mutations
 

and if one has mutations in the HLA-DRA gene, the PON gene or the MTHFR gene, one's ability to deal with all the above environmental triggers is greatly compromised. then there are the mt function genes, LRRK2 and PINK. and the genes concerned with oxidative stress, such as DJ1. Makes my head hurt as I attempt to process all this information.