Fatal Familial Insomnia (FFI) is a rare genetic neurodegenerative disease.  It belongs to a family of diseases called prion diseases which are caused by infectious proteins.  This is somewhat unique in the world of biology: until 20 years ago everyone thought that you needed a a virus or bacterium or some other parasite — something with DNA or RNA — in order to have an infectious agent.  It was Stanley Prusiner at UCSF who championed the idea that proteins were the infectious agent in some diseases, an idea that is now widely accepted and for which Prusiner won a Nobel Prize in 1997.

The specific protein Prusiner was talking about is now known as prion protein (PrP) and we now know it’s encoded by the gene PRNP.  Every human– in fact every mammal– has this gene and produces prion protein, but we don’t all have prion diseases.  So a bit of terminology is in order:

  • PRNP is a particular gene in the human genome, located on the short arm of Chromosome 20.
  • PrP is the protein encoded by that gene.  It’s 208 amino acids long.
  • A prion is any infectious particle composed primarily or solely of protein.  This originally referred only to infectious forms of PrP, but over the last decade people have discovered other proteins that behave in a similar way and so nowadays you’ll hear people refer to prions in yeast (no relation to PrP or to human prion diseases), and you’ll also hear people argue (though it’s not yet universally accepted) that Aβ proteins implicated in Alzheimer’s disease behave as prions.

So if we all have PrP, what determines who gets a prion disease?  Most of the time, PrP is folded into a normal healthy form we call PrPC – C for cellular – and it does whatever its job is (we still don’t really know) in the cell.  But PrP has a nasty tendency to, very rarely, misfold into a toxic and infectious form we call PrPSc – Sc for scrapie, the name of a sheep and goat prion disease.

Once it’s misfolded into PrPSc, it converts other PrPC molecules into PrPSc (if you’ve read Cat’s Cradle by Kurt Vonnegut, think of PrPSc as ice-nine).  So once this starts to happen, the infection can spread throughout the brain and potentially from organism to organism.  Because the infectious material is almost exclusively in brain tissue, the infection is very difficult to spread between organisms unless one organism is eating the other one’s brain.

Which is exactly how the mad cow epidemic happened.  Feed lots in Britain were feeding “meat and bone meal” to cows (who are normally herbivores) and the feed got contaminated with brain and spinal cord matter from a cow that had PrPSc, and so the cows that ate it got the disease too, and then the people that ate those cows got the disease.

Mad cow is just the most famous prion disease.  In animals, you also have chronic wasting disease in deer, scrapie in sheep and goats, and others. In humans, prion diseases can come about in a few different ways.  Cases acquired by infection — such as eating contaminated meat — are called acquired, or iatrogenic for surgical contamination, and the human form of mad cow is called variant Creutzfeldt-Jakob Disease.   Other cases arise through a genetic mutation in PRNP which changes the amino acid sequence of PrP, making it more prone to misfold into PrPSc. These cases are called familial.  Most cases happen randomly and for no known reason– these are called sporadic.

Although prion diseases are infectious, they’re not very easily transmitted.  Remember your sex ed class in the 90′s when the teacher told you not to be afraid of shaking hands with people because of AIDS because AIDS isn’t transmitted through handshakes, only sexual contact or blood transfusions?  Prion diseases are even harder to get than AIDS – you really need contact with a diseased brain.  There have been a few reports of transmission through blood transfusions (which is why the American Red Cross still asks you not to donate blood if you were in the U.K. for at least three months between 1980 and 1996) and no confirmed cases of transmission through sexual contact — or handshakes.

You can also categorize the human prion diseases by the type of symptoms that characterize the disease.  The most common is Creutzfeldt-Jakob Disease (CJD), there are also Gerstmann–Sträussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI).  All of these diseases involve infectious prions spreading throughout the brain, killing neurons.  Each of these has a different pattern of which areas of the brain it affects and how rapidly it progresses.

FFI especially affects the thalamus, which is the part of the brain that controls the sleep-wake cycle among other things.  That’s why FFI causes insomnia as a major feature of the disease.  Other symptoms are weight loss, lack of appetite, hyper- or hypothermia, and rapidly progressive dementia – forgetfulness and confusion at first, leading eventually to inability to walk, talk, or do much of anything.  From the time first symptoms appear to death is usually around a year.  Average age of onset is around 50.

It’s dominant, meaning you only need one copy of the bad genetic mutation in order to get the disease.  FFI is caused by having the D178N mutation, meaning that the 178th amino acid in PrP is asparagine (N) instead of aspartate (D).  This mutation is bad no matter what, but to cause FFI, it has to be on the same chromosome that has 129M, i.e. methionine (M) as the 129th amino acid; if you have valine (V) at position 129 instead, then you get a form of familial CJD instead of FFI.

As far as we know, everyone who has the mutation eventually gets FFI and dies of it.  There’s a lot of variance, with cases having been reported at ages ranging from 20 to 72.  We hear (though it’s not published) that there’s also been one or two people who managed to live into their eighties and then die naturally of something else, even while carrying the FFI mutation their whole life.  So you could say the penetrance (percent of people with the mutation who get the disease) is like 99%.

Right now all prion diseases, including FFI, are incurable and untreatable.  If a patient comes into a hospital with a prion disease, there is nothing that doctors can do for them.  That where we — CureFFI.org and Prion Alliance — come in.  Our goal is to develop a treatment or cure for prion disease.

And we’re not alone in that mission.  There are several major prion research centers worldwide – at UCSFMRC, Alberta, Tohoku, Case Western, and Rocky Mountain Labs – and dozens of small and medium-sized research labs.  Prion diseases are fairly rare, but attract, and deserve, extra attention for a few reasons.  Protein folding holds a lot of important secrets in science, and figuring out how exactly PrP spreads in its diseased form would be a huge step forward.  Although agricultural practices have improved, mad cow disease continues to be a threat. And most importantly, prion diseases, though still mysterious in many ways, are simpler and better understood than many other neurodegenerative protein-folding diseases such as Alzheimer’s and Parkinson’s.  Unlike those diseases, which involve risk factors in multiple genes and pathways through multiple proteins, genetic prion diseases are caused only by PrP, so they’re somewhat easier to model in a test tube or an animal.  For this reason, prion diseases could be the platform for better understanding neurodegenerative disease more generally.

Right now is a good time to be a scientist.  While we still don’t have a treatment for prion diseases, we know a lot more about them than we did 10 years ago and the science is moving fast.  Our goal at Prion Alliance is to catalyze that science through fundraising to support specific research goals, and our goal at CureFFI.org is to collect the scientific knowledge and promote discussion and discovery.  If this sounds awesome to you, get involved.