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.

Rare Disease Day 2016

My daughter Ellen wrote this post last year for Rare Disease Day.  We repost it today.  It's frustrating that, in the age of genetics, when finding single genes for rare diseases is what the field does best, she is still seeking answers.   

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.

The story of a rare disease

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 28 is Rare Disease Day (well, Feb 29 technically; the last day of February which is, every four years, a rare day itself!); 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.

Elizabeth Barrett Browning had a rare disease

In the spring of 2011, Ken and I took a bit of a pilgrimage to England. We followed Darwin's footsteps in Malvern, but that was only opportunistic, though happily so (and described here).  Our primary goal was to find several of the places that were important to the Victorian poet Elizabeth Barrett Browning when she was young. We blogged about it then, and it seems fitting to re-publish that post today because it's Rare Disease Day 2014, a day established by a number of rare disease alliances and organizations around the world to raise awareness of the impact of rare diseases on patients' lives.  We think Elizabeth Barrett Browning had a rare disease, and it affected her life enormously. 

Elizabeth Barrett Browning

Born in 1806, Barrett Browning lived at Hope End in Malvern from age 3 to 25. Her father made his money by managing sugar plantations in Jamaica, and he had plenty of it. He built a very large house on a 200 or so acre estate near the Malvern Hills, and brought his growing family to live there in 1809. Eccentric this house was by all accounts, with Turkish minarets and other such out-of-place characteristics, but EBB loved it. As a child she rode her pony through the woods, and down the lanes that stretched to Ledbury and Great Malvern, and beyond. She and her beloved brother Edward spent many many happy hours running up and down the hills behind the house, until at age 12 or so her aunt scolded her for playing too rough. 

But, when Elizabeth reached puberty she experienced the first extended episode of an illness from which she suffered all her life, but that her doctors never were able to diagnose, to their and EBB's great frustration -- and her readers and EBB scholars have tried to puzzle it out ever since.

Apocryphally, it was said that she fell from her horse at age 15 and injured her spine, but she always insisted that that had nothing to do with her illness. Recent scholars have suggested that she had anorexia, or TB, neurasthenia, pertussis, an encephalomyelitis, non-paralytic poliomyelitis, paralytic scoliosis, or opium addiction or a mental illness including anxiety and agoraphobia. At least one biographer has suggested that ‘escape into illness’ was her way of dealing with the frustration of being an intelligent woman in Victorian England or a reaction to the exceptional sternness of her widowed, religiously strict father. She was also described simply as a malingerer. She was sent to a spa in Gloucester for a year during her teens, to recover, and she was better at some times than others, but she was never truly well for any length of time again.

While we will never know for certain, I think that she may have been suffering from a rare and elusive muscle disease called hypokalemic periodic paralysis (HKPP). It's an ion channel disorder, marked by a deficit of potassium, and involving episodes of weakness or frank paralysis with numerous triggers including heat, cold, exercise, rest after exercise, carbohydrates, salt, temperature change, and change of seasons. Causative mutations have been identified in three ion channel genes, but they explain only a minority of cases. And the disorder can run in families or it can be sporadic. And, age of onset at puberty is classic.

I've published an article suggesting this diagnosis, and because I've been thinking about this woman and her illness for so long we decided to go see the place of her childhood home, where she was so happy, as well as a place where she was exceedingly unhappy. (The home Barrett Browning's father built was torn down by the next owner of the estate, and replaced by a home that burned at the beginning of the 20th century. The picture here is the house that now stands on the site.) 

EBB's father lost much of his fortune when she was 25, and so he sold her beloved Hope End and moved the family to London. Elizabeth was particularly unwell during the move, suffering from weakness and palpitations of the heart, her usual symptoms, and as usual her doctors had no idea how to treat her. They had started her on opium in her teens, and she took it the rest of her life, and they now started her on Digitalis for her heart. Unfortunately this drug made her weak.

Her doctors recommended that she leave London not long after the move, which was not good for her health, so her father sent her to the seaside to recuperate. She spent three years in the Hotel Regina in Torquay, on the coast of Devon, where she suffered the most devastating heartbreak of her life when her brother, Edward, was drowned in a sailing accident.

Hotel Regina, Torquay, Devon

She was desperate to leave Torquay after the accident, but too unwell. Her doctors cautioned the trip would surely kill her. She eventually decided that she would bear the consequences and traveled back to London, where she spent more years in her room at 50 Wimpole St, not leaving the house, and often not even well enough to leave her couch. 

But she continued to write and publish poetry, which came to the notice of the poet Robert Browning. He wrote to her, and eventually prevailed upon her to allow him to visit her. They quickly fell in love, as detailed in the beautiful and deeply emotional letters they sent to each other throughout 1845 and 6. But Elizabeth's father wouldn't allow any of his children to marry, and Elizabeth herself told Robert she didn't want to burden him with an invalid. But when EBB's father announced that he was moving the family to the country for a month, they realized they couldn't bear to be parted, so they married in secret and ran away to Italy where they lived until Elizabeth died, in 1861.

Elizabeth was much healthier and happier in Italy than she had been since she fell ill. She had spent years in her room, writing poetry, many many letters, and expecting to die. But she was never truly healthy, and she often wrote of her illness in her letters. It's in these letters, and the diary that she kept at age 25, that I found the clues to her disorder.

For example, Elizabeth wrote from Torquay to a friend:

…the last ten days have been dreary, uncomfortable ones to me, haunted throughout by weakness, an oppressive sense of weakness, and a lowness of spirits from which I am generally free. Such lowness of spirits, that I could have cried all day if there were no exertion in crying… This was the result of taking digitalis for three weeks instead of one… [She was aware that digitalis caused weakness, though it did calm her heart.]

And weeks later she wrote to the same friend:

I wanted to write to you very very soon in reply to your last welcome note. I wanted to say to you very soon some words which it suggested. But I have been exceedingly unwell—confined to my bed nearly a week by a sudden return of bad symptoms and so weak since as scarcely to bear without fainting even the passive fatigue of being carried from this bed to the sofa down stairs, by all the gentleness of my brother’s love for me. The prevalency of the east wind and sudden coldness of weather connected with it, are considered the causes of the attack.

And so on. But, many others have read these same documents and none has reached the same diagnosis as mine. The explanation for this is easy -- HKPP is rare, and the diagnosis is frequently missed even today, but we've got the disorder in our family, so I read EBB's words through a lens not shared by most readers, that of knowing the nature of the disease, and the profound and disabling weakness it can cause. I should add that two neurologists and two cell biologists agree with my diagnosis. It's pretty obvious when you know what you're looking for.

This has been a fascinating exercise, and not in small part because it is a stark reminder that we can only see what we are prepared to see. EBB scholars, who know much much more about the poet than I, haven't deciphered what has jumped out of the page at me because they don't know HKPP.

This is a sleuthing quest for me, but it's relevant to MT, because it is a combination of attempts to infer biological causation by combining circumstantial, informal evidence from the past with modern science. In the case of HKPP, several ion-channel genes are known, a couple of which appear to be causal for HKPP. But as with so many traits, most cases do not manifest changes in these genes, phenotypes are highly variable, so that even the name (HKPP) masks complexity.

In this case, retro-sleuthing is not about evolutionary fitness or long-term evolution, but even with direct first-person evidence, causal inference is a serious challenge. Any conclusions about specific past incidences, as in EBB's case, are conjectural -- and will remain so even if modern genetic methods identify the basis of most cases. But even then, inferring fitness effects, and hence the effects of evolution on the relevant genes, is problematic-squared: even the persistently ill EBB bore a child.

As with many attempts to delve into the biological past, however, the delving is what makes it interesting.

If I'm not healthy, should I have my genome sequenced?

We asked last week why healthy people should have their genome sequenced.  We appreciated the thoughtful comments people left on the post; people clearly have compelling reasons for wanting to know their sequence, including that it's just fun, or they want to contribute to growing knowledge, and more. Now we'd like to revisit this question from another angle, considering why people with unexplained disorders should have their genome sequenced.  We do this by reposting a piece we wrote last year. Rather than sequencing a genome for predictive reasons, which we believe will not often be all that useful as we wrote last week, sequencing in the hopes of explaining a disease is another matter entirely.

We often criticize the spending of taxpayer money on what we see as fruitless gene searches, but there are traits and diseases that truly are genetic, or, if associated genes aren't yet known, physiologically act as if they are. That means that the trait seems closely related to gene function in ways that could indicate that genetic variants are responsible for the variation of the trait from 'normal'.  We think these are where the genetics money should be spent.  Cancer is one example, as it is about cells behaving abnormally, and this was predicted and then confirmed by research, even decades ago.  Pediatric diseases and disorders are further examples, but there are certainly others.

Finding causal genes even for what look like 'single-gene disorders' isn't always easy, and even when it can be done, certainly doesn't always lead to therapy.  At the very least, when it is possible, it can be an important and valued piece in the puzzle of who one is.  And we think this is where heavy-duty research investment should be made.

Pink boulder, Shirehampton Road, Bristol
For no obvious reason, one of the boulders lining the north side of Shirehampton Road has been painted pink. By whom and why - unknown.
© Copyright Jaggery and licensed for reuse under this Creative Commons Licence.

Periodic paralysis -- a single gene disorder striking close to home (first posted 3/19/12, and modified for today)

One of the things Ken and I did while we were in New York last week was to have lunch with Dr Jacob Levitt, the head of the Periodic Paralysis Association (PPA).  The periodic paralyses are a rare set of ion channel disorders that are still not well-understood.  Partly of course it's because they are so rare (prevalence is 1 in 1 to 200,000), and partly because the normal functioning of ion channels isn't itself well-understood.  Channelopathies themselves are not rare -- epilepsy and cystic fibrosis are more well-known examples of ion channel dysfunction.

As the PPA website says,

Periodic Paralysis is a group of disorders whereby patients become weak due to triggers such as rest after exercise or certain foods.  These disorders are part of a broader class of disorders called ion channelopathies, in which a genetic defect in a muscle ion channel results in symptoms of episodic stiffness or weakness in response to certain triggers. 

Dr Levitt, a dermatologist, has HKPP himself and he runs the PPA.  We had a fine meeting, and, among other things, were inspired to learn more about ion channels, how they work normally, and how they can go awry.  Why?  Because our daughter has hypokalemic periodic paralysis (HKPP), and it is a life changer.  And not in a good way. 

There are various periodic paralyses (hypo and hyperkalemic pp, and Anderson Tawil syndrome), and they are often difficult to diagnose.  Indeed, many people go for years without a diagnosis.  Most physicians may have heard of them once, long ago (or slept through that part of med school, or forgot their physiology, or just have never seen a case of these rare disorders).  Indeed, even now and especially in the past, people with these disorders could live a lifetime with neither diagnosis nor therapy -- an extensive bit of sleuthing has led us to think the famous pioneering Victorian poet, Elizabeth Barrett Browning, who was notoriously debilitated with a mysterious disease about which she wrote prolifically in her love letters to the poet (and her future husband) Robert Browning, had HKPP, as we surmised in detail here.  The disorder wasn't recognized when she was alive, so it's no surprise that EBB's doctors were completely at a loss as to what was causing her perpetual weakness.  It's more of a surprise when the diagnosis is missed today, as it needn't be.  But it too often is.

As regular readers of MT know, we write a lot about complex diseases, and in particular about how the idea of genes 'for' disease can be a naive one.  For many traits, perhaps most traits, in organisms, multiple genes contribute and most of the genetic aspect of variation of the trait is due to multiple, small contributions from many different genes.  Each individual with a given trait value (like, say blood pressure, height, glucose or cholesterol levels) has a unique genotype that contributes to that value (not to mention environmental contributors).  The hunger to find simple causation that we often write about is manifest, and understandable, even if the reality is different.  That hunger is what feeds the GWASification of everything, that is currently at such a fevered pitch.

So, it is a bit ironic that we have a daughter with what HKPP has generally been considered to be a monogenic condition -- a condition caused by a single mutation. To date, causal mutations have been identified in three ion channel genes, that disrupt the structure of the channel so that it malfunctions in response to specific environmental triggers.  One is a sodium channel genes, and one is a calcium channel gene, which is interesting because calcium channels don't seem to even be used by skeletal muscles, as sodium channels are, so it's difficult to understand why disrupted calcium channels can shut down these muscles.  Insulin is also related to the process, but it doesn't seem to be related to diabetes.  So is the trait due to a channel mutation, or mutations of more general sorts that affect the ion concentrations that normal channels respond to?  It seems to be a mix.

The problem exemplifies the importance of partial sequestration and modularity, and others of the basic principles of life that we often write about.  An ion channel is used by a cell to sense and relate to its environment: to shove excess negative or positive molecules out or import them in, to keep the ionic or pH (chemical) balance suitable for the reactions that must occur inside the cell, and an appropriate difference from the outside world of, say, the blood stream.  In simplified terms, if the cell is too salty relative to the blood stream, or too unsalty, the cell can burst, or be drained of water, or be unable to import needed ingredients or export waste, etc.  It's a fundamental way that cells relate to their environment.  And many different genes are involved in the ion channels, or chemical pores, through which these molecules shuffle in and out.

But, as we've blogged about before (here, e.g.), even these 'simple' processes are complex.  Many genes are involved, but it is not always the case that multiple minor contributions from different genes add up to trouble.  In some cases, and HKPP may be one, there is what is called multiple unilocus causation:  In a given case, only one variant gene may be responsible, but in different cases different genes--but only one gene per case.

Some people can trace a specific form of periodic paralysis through generations in their family, and others are the only known family member to be affected.  And, the same mutation in a single family can have very different symptoms, from very infrequent, or even no attacks of weakness, to waking daily with paralysis.  And, essentially the same phenotype, or at least spectrum, is due in different individuals to mutations in different genes.  Or different people with the same variant can have different symptoms. Other examples of similar multiple unilocus causation include retinitis pigmentosa, an inherited disease that leads to blindness in middle age, and another is congenital deafness.

Some individuals, including our daughter, have none of the known mutations.  This is known because a physician in Germany, Dr Frank Lehmann-Horns, generously donates genotyping and sequencing services to anyone who has been diagnosed with one of these disorders.  Affected individuals naturally would very much like to know the cause of their disorder, however, and when the cost of whole genome sequencing really is $1000 per genome, they will likely have their genomes sequenced so that a systematic hunt for causation may be undertaken.

Of course, finding the causative mutation in such situations, with hundreds of ion-channel genes, and their regulation, to search through, won't be easy when, as in our daughter's case, there aren't other affected family members to compare.  We all differ from each other at millions of loci in our genomes, and determining which one causes a given case, even focusing in on ion channel genes alone.

Affected individuals don't need to know what causes their disorder in order to treat it, certainly, because it is the ion concentration that's the trait, regardless of its origin--at least up to a point as is understood today.  Indeed knowing the gene that causes a monogenic disease is rarely useful in treatment: hundreds of such 'Mendelian' traits are known but few really treatable based on the gene in question. But, patients often worry that in the future some doctor won't believe their diagnosis unless they have an identified mutation, so the identification can be comforting in that sense.  And, identifying as completely as possible the suite of mutations that cause this disorder could be useful in understanding how things go awry, and could in principle lead to better treatment.

Of course, we study and write about aspects of genetic causation and generally see complexity when others yearn for simplicity, so there is the danger that when the story strikes close to home, we like others might naturally drift towards a search for simple causation -- making the very 'gene for' mistake we note when others do it.  We are interested in understanding more about these cellular disorders, but have to be wary lest we fall into that trap.  Indeed, that is a major reason for writing about this issue here.

So, while we do think that complex traits should not be treated as though they were simple, traits that really are relatively simple are a different matter.  The search to understand the genetic basis of complex multilocus disease is challenging.  The search to understand multiple unilocus traits, and to know whether they are only the clearest subset of multilocus versions in the population is somewhat different -- single gene changes might be easier to track and confirm when they are inherited.  The unexplained cases, like unexplained heritability that we've written about, may be those due to multiple, individually minor, genetic variants.  As we have often said, the truly genetic disorders are where the money should go, at least to show that understanding causation at the gene level is an important way to approach life.

Similar issues apply to evolution.  A multiple unilocus trait favored by natural selection could arise in different individuals in a population because of mutations in different genes with similar effect.  Over time, the population could come to be made of individuals who had the favored trait.  But this doesn't mean that they share the same genotype or that there would be detectable evidence for natural selection in any specific part of the genome -- because many different genes could each have experienced only weak selection in the population as a whole.  If there are many roads to Toledo, none of them need to be superhighways.
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Update: Our daughter outed us last year here on MT, noting in a comment to a post of Holly's that we'd all been enrolled in a sequencing study of rare Mendelian diseases.  The study is ongoing, but our exomes have been completely sequenced now and are currently being analyzed in an attempt to find the genetic basis of her disease.  We certainly hope they find it, though it's probably a long shot.  But it would mean a lot to her to know the cause of the disease that too often rules her life.

The HKPP Hall of Fame

We posted last week about hypokalemic periodic paralysis (HKPP), a disorder that causes weakness and sometimes even temporary paralysis, due to a drop in blood potassium levels.  As it happens, one of our favorite BBC radio programs, In Our Time, discussed the 18th century philosopher, Moses Mendelssohn last week as well.  He is considered to have been one of the foremost architects of the Jewish Enlightenment, who helped to bring Judaism into mainstream European culture. He was a strong proponent of religious tolerance.

Because neither of us knew much about Mendelssohn (grandfather of the composer, Felix Mendelssohn), Ken googled him. Among other facts about his life, the Wikipedia article about him had an arresting paragraph about an affliction he was known to suffer from.

In March 1771 Mendelssohn's health deteriorated so badly that Marcus Elieser Bloch, his doctor, decided his patient had to give up philosophy, at least temporarily. After a short and restless sleep one evening, Mendelssohn found himself incapable of moving and had the feeling of something lashing his neck with fiery rods, his heart was palpitating and he was in an extreme anxiety, yet fully conscious. This spell was then broken suddenly by some external stimulation. Attacks of this kind recurred. The cause of his disease was ascribed to the mental stress due to his theological controversy with Lavater. However, this sort of attack, in milder form, had presumably occurred many years earlier.  

Could this be another addition to the HKPP Hall of Fame (we've previously written about Elizabeth Barrett Browning and the possibility that she had this disorder)?  We're on the trail.

Chance and the prepared mind: Elizabeth Barrett Browning's lifelong illness

Elizabeth Barrett Browning

As we wrote last week, we were in England, on a bit of a pilgrimage.  We followed Darwin's footsteps in Malvern, but that was a rather opportunistic pilgrimage, though happily so, (and described here).  But our primary goal was to find several of the places that were important to the Victorian poet Elizabeth Barrett Browning when she was young.

One was Hope End, the estate where she lived from age 3 to 25.  Her father made his money by managing sugar plantations in Jamaica, and he had plenty of it.  He built a very large house on a 200 or so acre estate near the Malvern Hills, and brought his growing family to live there in 1809.  Eccentric this house was by all accounts, with Turkish minarets and other such out-of-place characteristics, but EBB loved it.  As a child she rode her pony through the woods, and down the lanes that stretched to Ledbury and Great Malvern, and beyond.  She and her beloved brother Edward spent many many happy hours running up and down the hills behind the house, until at age 12 or so her aunt scolded her for playing too rough.  

Hills behind Hope End where EBB
would have ridden her horse and
roamed with her brother.

But, when Elizabeth reached puberty she experienced the first extended episode of an illness from which she suffered all her life, but that her doctors never were able to diagnose, to their and EBB's great frustration -- and her readers and EBB scholars have tried to puzzle it out ever since.

Apocryphally, it was said that she fell from her horse at age 15 and injured her spine, but she always insisted that that had nothing to do with her illness.  Recent scholars have suggested that she had anorexia, or TB, neurasthenia, pertussis, an encephalomyelitis, non-paralytic poliomyelitis, paralytic scoliosis, or opium addiction or a mental illness including anxiety and agoraphobia.  At least one biographer has suggested that ‘escape into illness’ was her way of dealing with the frustration of being an intelligent woman in Victorian England or a reaction to the exceptional sternness of her widowed, religiously strict father.  She was also described simply as a malingerer.  She was sent to a spa in Gloucester for a year during her teens, to recover, and she was better at some times than others, but she was never truly well for any length of time again.

While we will never know for certain, I think that she may have been suffering from a rare and elusive muscle disease called hypokalemic periodic paralysis (HKPP).  It's an ion channel disorder, marked by a deficit of potassium, and involving episodes of weakness or frank paralysis with numerous triggers including heat, cold, exercise, rest after exercise, carbohydrates, salt, temperature change, and change of seasons.  Causative mutations have been identified in three ion channel genes, but they explain only a minority of cases.  And the disorder can run in families or it can be sporadic.  And, age of onset at puberty is classic.

I've written an article suggesting this diagnosis, and because I've been thinking about this woman and her illness for so long we decided to come see the place of her childhood home, where she was so happy, as well as a place where she was exceedingly unhappy.  (The home Barrett Browning's father built was torn down by the next owner of the estate, and replaced by a home that burned at the beginning of the 20th century.  The picture here is the house that now stands on the site.) 

Hotel Regina, Torquay, Devon

EBB's father lost much of his fortune when she was 25, and so he sold her beloved Hope End and moved the family to London.  Elizabeth was particularly unwell during the move, suffering from weakness and palpitations of the heart, her usual symptoms, and as usual her doctors had no idea how to treat her.  They had started her on opium in her teens, and she took it the rest of her life, and they now started her on Digitalis for her heart.  Unfortunately this drug made her weak.

Her doctors recommended that she leave London not long after the move, which was not good for her health, so her father sent her to the seaside to recuperate.  She spent three years in the Hotel Regina in Torquay, on the coast of Devon, where she suffered the most devastating heartbreak of her life when her brother, Edward, was drowned in a sailing accident. 

She was desperate to leave Torquay after the accident, but too unwell.  Her doctors cautioned the trip would surely kill her.  She eventually decided that she would bear the consequences and traveled back to London, where she spent more years in her room at 50 Wimpole St, not leaving the house, and often not even well enough to leave her couch.

But she continued to write and publish poetry, which came to the notice of the poet Robert Browning.  He wrote to her, and eventually prevailed upon her to allow him to visit her.  They quickly fell in love, as detailed in the beautiful and deeply emotional letters they sent to each other throughout 1845 and 6.  But Elizabeth's father wouldn't allow any of his children to marry, and Elizabeth herself told Robert she didn't want to burden him with an invalid.  But when EBB's father announced that he was moving the family to the country for a month, they realized they couldn't bear to be parted, so they married in secret and ran away to Italy where they lived until Elizabeth died, in 1861.

Elizabeth was much healthier and happier in Italy than she had been since she fell ill.  She had spent years in her room, writing poetry, many many letters, and expecting to die.  But she was never truly healthy, and she often wrote of her illness in her letters.  It's in these letters, and the diary that she kept at age 25, that I found the clues to her disorder.

For example, Elizabeth wrote from Torquay to a friend:

…the last ten days have been dreary, uncomfortable ones to me, haunted throughout by weakness, an oppressive sense of weakness, and a lowness of spirits from which I am generally free.  Such lowness of spirits, that I could have cried all day if there were no exertion in crying…  This was the result of taking digitalis for three weeks instead of one… [She was aware that digitalis caused weakness, though it did calm her heart.]  

And weeks later she wrote to the same friend:

I wanted to write to you very very soon in reply to your last welcome note.  I wanted to say to you very soon some words which it suggested.  But I have been exceedingly unwell—confined to my bed nearly a week by a sudden return of bad symptoms and so weak since as scarcely to bear without fainting even the passive fatigue of being carried from this bed to the sofa down stairs, by all the gentleness of my brother’s love for me.  The prevalency of the east wind and sudden coldness of weather connected with it, are considered the causes of the attack.

And so on.  But, many others have read these same documents and none has reached the same diagnosis as mine.  The explanation for this is easy -- HKPP is rare, and the diagnosis is frequently missed even today, but we've got the disorder in our family, so I read EBB's words through a lens not shared by most readers, that of knowing the nature of the disease, and the profound and disabling weakness it can cause.  I should add that my diagnosis has been confirmed by two neurologists and two cell biologists.  It's pretty obvious when you know what you're looking for.

This has been a fascinating exercise, and not in small part because it is a stark reminder that we can only see what we are prepared to see.  EBB scholars, who know much much more about the poet than I, haven't deciphered what has jumped out of the page at me because they don't know HKPP.

This is a sleuthing quest for me, but it's relevant to MT, because it is a combination of attempts to infer biological causation by combining circumstantial, informal evidence from the past with modern science.  In the case of HKPP, several ion-channel genes are known, a couple of which appear to be causal for HKPP.  But as with so many traits, most cases do not manifest changes in these genes, phenotypes are highly variable, so that even the name (HKPP) masks complexity.

In this case, retro-sleuthing is not about evolutionary fitness or long-term evolution, but even with direct first-person evidence, causal inference is a serious challenge.  Any conclusions about specific past incidences, as in EBB's case, are conjectural -- and will remain so even if modern genetic methods identify the basis of most cases.  But even then, inferring fitness effects, and hence the effects of evolution on the relevant genes, is problematic-squared:  even the persistently ill EBB bore a child.

As with many attempts to delve into the biological past, however, the delving is what makes it interesting.

Even single-gene disorders are complex

We've written a lot about complex disease in this blog, but we thought it was now time to give the complexity of single-gene disorders its due. Genes for what are often called 'simple' Mendelian traits (traits that are inherited in families in predictable patterns) are much easier to find than genes for complex traits like heart disease or asthma, but that doesn't make them simple.

In part, it's easier to define a 'simple' trait--for example, some forms of oligodontia, or missing teeth, run in families and most forms are due to mutations in Msx1 or Pax9. But it turns out that even a trait that should be easy to define isn't so straightforward--when multiple family members are affected they aren't always missing the same teeth, or the same number of teeth. So, there's something about the timing of the initiation of teeth during development that varies, and probably not by much, but enough to make the phenotype unpredictable, and the variation may well be random.

And, of course more complex phenotypes are even more unpredictable, even if due to single genes. A rare genetic disorder called hypokalemic periodic paralysis (hkpp) is one such trait. This is a channelopathy, an ion channel disorder, usually of sodium ion channels, which regulate the flow of ions into and out of the cell, but in individuals with hkpp, they let potassium into muscle cells but don't let it out in a timely way, thus weakening or paralyzing the muscle.

Hkpp involves anything from fleeting weakness to full paralysis, and in rare cases can be fatal if breathing is involved. The attacks generally resolve within hours, or sooner if the individual consumes potassium, but sometimes can linger for weeks. There are known 'triggers', including heat, hunger, sugar, carbohydrates, alcohol, exercise, and rest after exercise, but attacks can happen even without a trigger, and not everyone shares all the same triggers. So, in a sense this would seem to be a classic case of gene by environment interaction--sometimes. Why is there no apparent trigger for some attacks? And, it's interesting that age of onset is typically during adolescence--so why were these channels seemingly doing their job properly during the active childhood years?

Causative mutations have been found in at least three genes, and have been traced in families, but 30% of the families with this disorder don't have mutations in these genes (and often don't share the classic food triggers), and individuals with the same mutation within an affected family can have very different forms of the disorder, from no symptoms at all to just one in their lives to daily episodes of full paralysis.

A similar description could be written for most 'simple' single-gene disorders. The more common the trait, or the more intensely it has been studied, the more this has been shown. Usually, the story is different in different populations, and this is what would be expected on grounds of evolution (population history): in each region of the world, different mutations have arisen or risen in frequency, there are different environmental exposures, and the genomic background (variation at genes other than the 'causal' gene) differs, even with similar phenotypes.

The classic examples are diseases like PKU, cystic fibrosis, and even genes related to resistance to malaria (like sickle-cell hemoglobin). Even the once-simple ABO blood group system is like this. So, if simple diseases are so complex, it's no wonder that complex diseases are so hard to understand.