Rare Disease Day and the promises of personalized medicine

Our daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, February 29th, each year since. I wish I could include an update reporting that the cause of her rare disease has been identified. She would very much like to know, not only because it would explain this thing that has defined so much of her life, but also because, in this genetics age, being able to tell a new doctor the cause of her condition would mean they'd have no doubts. Sometimes a diagnosis isn't enough, and when you have a rare disease doubt can remain a frequent aspect of encounters with the medical system.

It's not there there has been no action. After a lengthy, ultimately failed attempt by a previous lab, which was unsuccessful for reasons unclear to us but probably technology-related, Ellen is currently included in another large sequencing project, and we're hopeful that we'll get some kind of an answer. They've done whole genome sequencing of her DNA as well as Ken's and mine, and are about to begin to look for her causal variant. To date, we know that she hasn't been found to have one of the known variants associated with her disease. There are occasional reports of new variants in other families with the same disease, and that could help identify hers, but what if she doesn't have one of these, either?

Finding a causal gene variant is easiest when a disease is rare and there are multiple cases in one family but Ellen is the only person in our family, for as far back as we can trace on both sides, with HKPP. When the disease is rare and only one family member has it, there's not really a peg to hang your hat on -- where do you start to look for the causal variant?

Ellen has classic hypokalemic periodic paralysis (HKPP), a disease for which causal DNA variants in a small number of ion channel genes have been identified in a number of families, where they essentially act as classical Mendelian variants. There are several possibilities here -- she could have a de novo mutation, a mutation new to her that she inherited from neither parent. If it's one that is shared by other people with HKPP, that would be easy to identify, but if not, even if it's on one of the three genes, to date, that have been found to be associated with the disease, how could it be shown that it is causal, rather than simply a mutation with no effect? And searches of 'her' genome are based on blood samples, and what if she carries a somatic mutation that arose after the embryonic separation of blood-related tissues from other tissues?

Some families with HKPP have members with the supposed causal variant who are symptom-free. This isn't unusual in genetics -- it's been called "incomplete penetrance" for a century, which basically means that one can have a causal mutation without the condition it apparently does cause in others. There can be various explanations for this. For example, when a disease responds to environmental triggers, as does HKPP, it's possible that gene by environment interaction at some critical age is required to set up the cascade of events that lead to paralytic episodes. Curiously, HKPP generally begins at puberty, for some unidentified reason -- perhaps some triggering event doesn't happen in disease-free family members with a causal variant, or perhaps the disease is polygenic rather than monogenic and those who are disease-free don't have the required critical mass of variants. This means that it's possible that Ken or I could have "the" causal variant but, because of incomplete penetrance -- whatever effect that would mean -- we don't have the disease. Or, we gave Ellen a mix of variants that together cause her disease but neither of us had the same mix that came together in her. But, at the very least, neither of us carries a known or plausibly relevant variant in the known HKPP-related genes that have been tested.

Ellen isn't the only person with HKPP whose cause is not known. Perhaps there are other ion channel genes associated with the disease, that are not yet identified. Or, perhaps in some people it's too genetically complex for causation to be parsed. Because of all these possible difficulties, identifying the cause of Ellen's disease is not likely to be straightforward. We are hopeful that the geneticists currently working on this will have something to tell her in the end, but whether it's something simple that she'll be able to tell her doctors we don't yet know.

This is one personal story for Rare Disease Day, but I think it's very relevant to all the promises of "personalized medicine" being made these days. Having your DNA sequenced isn't a magic answer. Sometimes the technology is limiting, sometimes the problem is actually impossible to solve.

By Ellen Weiss

Despite being the product of two of the authors of this blog – two people skeptical about just how many of the fruits of genetic testing that we've been promised will ever actually materialize  – I have been involved in several genetic studies over the years, hoping to identify the cause of my rare disease.

February 29 is Rare Disease Day; the day on which those who have, or who advocate for those who have, a rare disease publicly discuss what it is like to live with an unusual illness, raise awareness about our particular set of challenges, and talk about solutions for them.

I have hypokalemic periodic paralysis, which is a neuromuscular disease; a channelopathy that manifests itself as episodes of low blood potassium in response to known triggers (such as sodium, carbohydrates, heat, and illness) that force potassium from the blood into muscle cells, where it remains trapped due to faulty ion channels.  These hypokalemic episodes cause muscle weakness (ranging from mild to total muscular paralysis), heart arrhythmias, difficulty breathing or swallowing and nausea.  The symptoms may last only briefly or muscle weakness may last for weeks, or months, or, in some cases, become permanent.

I first became ill, as is typical of HKPP, at puberty.  It was around Christmas of my seventh grade year, and I remember thinking to myself that it would be the last Christmas that I would ever see.  That thought, and the physical feelings that induced it, were unbelievably terrifying for a child.  I had no idea what was happening; only that it was hard to breathe, hard to eat, hard to walk far, and that my heart skipped and flopped all throughout the day.  All I knew was that it felt like something terrible was wrong.

Throughout my high school years I continued to suffer. I had numerous episodes of heart arrhythmia that lasted for many hours, that I now know should've been treated in the emergency department, and that made me feel as if I was going to die soon; it is unsettling for the usually steady, reliable metronome of the heart to suddenly beat chaotically. But bound within the privacy teenagers are known for, my parents struggled to make sense of my new phobic avoidance of exercise and other activities as I was reluctant to talk about what was happening in my body.

HKPP is a genetic disease and causal variants have been found in three different ion channel genes.  Although my DNA has been tested, the cause of my particular variant of the disease has not yet been found.  I want my mutation to be identified.  Knowing it would likely not improve my treatment or daily life in any applicable way.  I'm not sure it would even quell any real curiosity on my part, since, despite having the parents I have, it probably wouldn't mean all that much to this non-scientist.  

But I want to know, because genetics has become the gold standard of diagnostics.  Whether it should be or not, a genetic diagnosis is considered to be the hard-wired, undeniable truth.  I want that proof in my hand to give to physicians for the rest of my life.  And of course, I would also like to contribute to the body of knowledge about HKPP in the hopes that future generations of us will not have to struggle with the unknown for so many years.

For many people, having a rare disease means having lived through years of confusion, terrible illness, misdiagnoses, and the pressure to try to convince skeptical or detached physicians to engage in investigating their suffering.

I was sick for all of my adolescent and young adult years; so sick that I neared the edge of what was bearable.  The years of undiagnosed, untreated chaos in my body created irrevocable changes in how I viewed myself and my life.  It changed my psychology, induced serious anxiety and phobias, and was the backdrop to every single detail of every day of my life.  And yet, it wasn't until I was 24 years old that I got my first clinical clues of what was wrong.  An emergency room for arrhythmia visit revealed very low blood potassium.  Still, for 4 more years I remained undiagnosed, and there was horrible suffering during which my loved ones had to take care of me like a near-infant, accompanying me to the hospital, watching me vomit, struggle to eat or walk to the bathroom, and waking up at 3am to take care of me.  For 4 more years I begged my primary physician and countless ER doctors during desperate visits to investigate what was going wrong, asked them to believe that anxiety was a symptom not a cause, and scoured medical information myself, until I was diagnosed.  It wasn't until I was 28 that I found a doctor who listened to me when I told him what I thought I had, made sense of my symptoms, recognized the beast within me, and began to treat me.

My existence, while still stained to a degree every day by my illness, has improved so immeasurably since being treated properly that the idea of returning to the uncontrolled, nearly unbearable sickness I once lived with frightens me very much.  I fear having to convince physicians of what I know of my body again.

What I went through isn't all that uncommon among the millions of us with a rare disease.  Lengthy periods of misdiagnoses, lack of diagnoses, begging well-meaning but stumped, disbelieving, or truly apathetic physicians to listen to us are common themes.  These lost years lay waste to plans, make decisions for us about parenthood, careers, and even whether we can brush our own teeth.  They induce mistrust, anxiety, exhaustion.

Each rare disease is, of course, by definition rare.  But having a rare disease isn't. Something like 10% of us has one.  It shouldn't be a frightening, frustrating, lengthy ordeal to find a physician willing to consider that what a patient is suffering from may be outside of the ordinary since it isn't all that unlikely at all.  Mathematically, it only makes sense for doctors to keep their eye out for the unusual.

I hope that one day the messages we spread on Rare Disease Day will have swept through our public consciousness enough that they will penetrate the medical establishment.  Until then, I will continue to crave the irrefutable proof of my disorder.  I will continue to worry about someday lying in a hospital bed, weak and verging on intolerably sick, trying to convince a doctor that I know what my body needs, a fear I am certain many of my fellow medically-extraordinary peers share.

And that is why I, this child of skeptics, seek answers, hope and proof through genetics.