Near-term genetic PSP-ology

Remember the Human Genome Project?  It cost about $3 billion and took 13 years (1990 to 2003) – and that was with 20 labs around the world working in parallel.  A commercial lab can now sequence your whole genome in a few days for about $600.  Now the problem is how to recognize a “abnormal” result and what to do with that information.  We all have mutations that our parents don’t, and most of those have no health implications.  The problem is knowing which ones do.  This makes it medically and ethically tricky to interpret the results of a whole-genome sequence. 

Until that knowledge base improves, whole-genome sequencing will probably be useful mainly in assaying for known mutations in well-studied genes.  It is also possible to roughly predict the health implications of a never-before-seen mutation in a well-studied gene by working out the amino acid substitution that would result in the protein being encoded.  Then, using the physical and chemical principles of protein structure and function, one could roughly predict how that amino acid substitution might affect the function of the protein.  But that’s still an inexact science.  Besides, a lot of the genome doesn’t encode proteins at all – it has regulatory functions, which sometimes involves encoding small stretches of RNA that in turn regulate protein production.

So, with those challenges in mind, here’s a bit of speculation as to what might be in store, near-term, for genetic testing in the routine clinical care of PSP.  Thanks go to my friend and colleague Alex Pantelyat, MD of Johns Hopkins for his input.

  • Once effective treatments for PSP arrive, we may find that people with different variants in the gene encoding tau (or other gene) respond differently to specific medications.  This might be especially true for treatments targeting the process where the information in the DNA is encoded into proteins (called “transcription”).  Right now, short stretches of DNA or RNA called “antisense oligonucleotides” (ASOs) that interfere with the encoding of the normal form of tau are in clinical trials.  As you’d imagine, this risks side effects caused by a lack of normal tau protein.  But if we knew what gene mutation was causing PSP in an individual, an ASO could be specifically tailored for it. 
  • It will become standard practice for clinical trials of any sort of treatment to be designed for people with, or without, specific gene variants.  Or if a trial doesn’t try to restrict enrollment in that way, it will at least do the sequencing at the time of enrollment and apply the genetic information retrospectively to check if the treatment works in people with specific gene variants. 
  • As discussed in my last post, variants in the LRRK2 gene help determine the duration of survival of people with PSP, though they don’t affect the risk of developing the disease to begin with. There are bound to be other genes with similar effects.  Sequence data from such genes could be useful to people with PSP and their families in preparing for the future financially and emotionally.
  • The last point, about prognostic genetic markers, is about single-gene variants.  But the same point could apply to combinations of variants in multiple genes where no single variant has a measurable effect. 
  • Using a battery of gene variants as a high-accuracy diagnostic test for PSP (as opposed to prognosticating a rate of progression or what symptoms might develop next) seems unlikely to come to pass, as the list of genes already linked to PSP probably are the most informative ones, and they are insufficient as a diagnostic test.  But if that list is coupled with other non-genetic tests such as MRI, PET and blood tests for tau or neurofilament light chain, a highly accurate test battery could result. 

Beyond the $600 lab fee are the bills for the necessary interpretation and counseling, which add about $2,000.  While the lab fee has been declining because of technological improvements, the other services are provided by human beings and are only likely to rise.  Insurance companies, Medicare and Medicaid don’t presently cover any of this unless it’s for someone with cancer or a very ill newborn.  I assume this is because we don’t yet have enough use for the data in terms of alterations in management.  But what are the financial implications if my above predictions come true and actionable uses do become available?  PSP is a rare disease, but what if similar uses of whole-genome sequencing are developed for Alzheimer’s, atherosclerosis, depression and the many other diseases where genetic variants, or combinations thereof, affect disease risk or prognosis?   Even if we manage to reform the medical payment in the US and improve access to that system for those presently under-served, who will provide all that counseling? And who will respond to patients’ demands for preventive treatment? And who will pay for that treatment? Scary.

Some prognostic help

Sooner or later, most patients with PSP or someone they rely on will ask the doctor, “What’s going to happen next, and when?”  Until now, that question has only been answerable by saying, “Well, the symptoms you have now will slowly get worse and you may develop some additional ones.” or “I don’t know; everyone’s different.”  If the question is, “How long will I survive?” the only available answer has been to quote the published averages for PSP, which have a wide variance. All too often, the answer is, “Don’t worry about that — just take it one day at a time.”

A long-gestating project of mine has finally seen the light of day.  It uses scores on my patients’ PSP Rating Scale (PSPRS) scores gathered from 1995 to 2016 to allow clinicians to predict how much longer it will take for a given patient to reach certain disability milestones and death.  It also proposes a new five-point clinical staging system that we used as some of the disease milestones.  It appears in the August 2020 issue of Movement Disorders Clinical Practice and is available here.

Assisting in the effort was my trusty statistician, Pam Ohman-Strickland, of the Rutgers School of Public Health.  She was also my co-author in the original validation of the PSPRS in 2007.  BTW, if you want to read that paper, here’s your chance. Since then I’ve refined the rules and instructions for administering the PSPRS and that’s available here.

Two undergrads helped out in the new project: Emily Beisser did most of the analysis for the new staging system and Francesca Elghoul helped with data wrangling.

The outcome milestones number 13 in total.  The first seven are severe difficulty with swallowing solids, swallowing liquids, speech, eye movement, general movement, balance and thinking. For each, “severe” is defined as exceeding a specific score on the relevant PSP Rating Scale item(s).  The next five are the stages on the proposed “PSP Staging System” and the last milestone is death.  

We created the five PSP stages by totaling four of the 28 items on the PSPRS: swallowing solids, swallowing liquids, gait, and the ability to return to one’s seat safely from a few steps away without using the hands.  They’re items 3, 13, 26 and 28 on the PSPRS.  The point total for those four items, each rated 0 to 4, are divided into five groups: 0 points, 1-4, 5-8, 9-12, 13-15 and the full 16.  Although this staging rubric uses only two of the many possible deficit areas in PSP, we found that the total of these those four items correlates very closely with the total PSP Rating score.  We chose swallowing and gait/balance as candidates because so many of the serious complications and disabilities of PSP lie in those areas. I’ll devote a future post to the issue of “stages” in PSP.

Tables 3 and 4 in the new paper show the meat of the matter.  You’ll see that the input data are gender, the total PSP Rating Scale score at the time of the visit, and the rate of progression to date.  The last one has to be calculated by dividing the current PSPRS score by the number of months since the onset of the first PSP symptom.

Just a quick caveat: Please don’t try this at home. Many of the exam items on the PSPRS require training and experience to administer correctly; the scale and its instructions are in technical language; and the dating of the onset of PSP symptoms may not be interpreted by the patient or family as an experienced neurologist would.

I hope that these new results, to quote myself from the paper’s introduction, “may influence decisions to retire from work, hire caregivers, alter the home environment, move to a seniors-oriented or institutional living arrangement, decide on a feeding gastrostomy and not least, prepare psychologically for advanced disability and death.”  Until we have a way to prevent or halt the progression of PSP, this will be an important part of how clinicians can help their patients.