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.

Amazing - a measured story on the benefits of DNA sequencing

Here's a welcome, and all too rare example of a measured story about DNA sequencing and what it can offer.  Gina Kolata writes in the New York Times about sequencing increasingly being used in attempts to explain rare, particularly pediatric disorders.  Rather than overselling the promise of treatment and cure, she writes that it isn't always a panacea, and is proving to sometimes be successful and sometimes not.

The piece is about sequencing being done for clinical purposes, primarily at Baylor College of Medicine in Houston.  The sequencing center there is increasingly busy these days with exome and whole genome sequencing, a service that is only just beginning to be affordable -- and often covered by insurance.

Demand has soared — at Baylor, for example, scientists analyzed 5 to 10 DNA sequences a month when the program started in November 2011. Now they are doing more than 130 analyses a month. At the National Institutes of Health, which handles about 300 cases a year as part of its research program, demand is so great that the program is expected to ultimately take on 800 to 900 a year. 

But, here's the dilemma.  Most people who are looking to whole genome sequencing for diagnosis are doing so because they've got condition or disease that is so rare, or so poorly understood, that it has perplexed their physicians.  Often many physicians.  They may already have been genotyped for known conditions that their symptoms suggest, but with no success. These traits are often called 'orphan' diseases for these types of reasons.

The rarity of the condition means there's unlikely to be a cure, or even treatment for the disorder, even if sequencing does find the cause.  That is because developing enough knowledge, and then some drug or other approach, takes lots of time and many cases to study in a well-controlled way.  Indeed, Kolata writes that the success rate for finding a genetic "aberration" is only about 25 - 30%, and finding a causal mutation results in improved management for only 3% of patients, and treatment and a "major benefit" for only 1%.  So, what's the point?

As an example, some diseases have clearly familial occurrences -- that is, among several close relatives, and in some of those a gene has been guessed at and a likely causative variant found in the gene.  These are rather clear-cut cases, to the point that the trait can come to be defined in terms of the gene or process in which the gene participates -- even if most patients have neither variants in the named gene, nor affected relatives.  That's a stumbling block to understanding, if the studies of the disease are restricted to these clearly-caused cases, as often occurs.  So, for many people with such diseases, genotyping won't show anything that seems relevant.  Very discouraging.

Still, there's more to human life than what's in the flesh.  For many people, it's important just to know why they or their child has this rare disorder.  And there are practical reasons as well.  As one parent told Kolata after her child's mutation was identified, “It really became definitive for my husband and me. We would need to do lifelong planning for dependent care for the rest of his life.”  And, with a definitive diagnosis, insurers are more likely to cover medical costs without question and the  patient is treated with more understanding.

Even without a diagnosis of that clear kind, there may be satisfaction of a sort in knowing that one has at least looked, and also to have become part of a data base that may, someday, be large enough and well-studied enough to lead to other discoveries (such as genetic variants found in other genes that come under suspicion).

Unlike the fly-by-dusk outfits that sell genetic risk assessments to pay for their yachts, the studies we are referring to occur in professional, clinical settings and are done by geneticists and genetic counselors, not businessmen.  These are the well-established, fully licensed and professional, legitimate clinical contexts in which this type of work should be done.  And these investigators are not just collecting data, but typically committed as their main job, to figuring out what to do about the diseases.

Why is it so hard to find causal mutations?
There are several very simple reasons why even common diseases are hard to characterize at the gene level.  First, many different genetic disruptions or modifications can give similar effects.  By analogy, there are many ways to fiddle with a car so that it goes slower than it did when it was new.  Just because it doesn't perform up to specs, doesn't mean we know what the cause is (and cars are actually a whole lot simpler in this kind of respect than people are). 

Second, most of the effects are individually very small, so that a disease is the result of multiple contributions of sub-par genes or environmental experiences.  And these first two reasons -- many different contributing factors, and each of them individually minor -- imply that each affected person may be affected for a different reason.

Third, many factors, including major ones, are rare enough in the population that we simply can't get enough instances of their mutated state in the kinds of data that are usually being collected (for example, case-control studies) to generate statistically detected evidence.  Even a major effect can be buried among a mountain of minor ones if the major isn't common enough.

Different kinds of data can certainly reveal different kinds of causes, and studies of various types are being designed.  Often, this is rather superficially rationalized to obtain funding for very large, expensive, studies.   Our science establishment, like our culture generally, believes that SuperSize must be better.

Another reason for frustration is that very rare traits simply defy many types of statistical approaches.  Often, diagnosis is not consistent, cases go unreported or mis-diagnosed, different studies can't be compared.  Family studies, which are statistically very powerful in some situations, are often hampered by such factors, or by the fact that relatives who may be deceased were not diagnosed (maybe that was simply not possible during their lives).

So there are issues of all sorts surrounding the challenge. BUT, when enough is known, and the approach is a responsible, professional one, genetic counseling can be extremely effective.

Conventional wisdom about orphan drugs turned on its head

Conventional wisdom has it that pharmaceutical companies won't invest in drugs for rare, or 'orphan' diseases because it's just not profitable.  Many diseases are rare and the cause unknown, but there are some rare diseases for which enough is known that, in principle at least, one can envision developing a targeted medicinal approach.  Many of these are also known to be, or seem to be genetic, and that at least leads to the idea of a targetable problem for Pharma.  The costs of the research can be so high that pharmaceutical companies just don't want to wade in, or this has been the usual view. But, in an unusual twist on the story, it turns out there's some reason for optimism for those with one of the 8000 or so such diseases, with 250 more discovered every year.

Rare diseases are defined by the National Institutes of Health Office of Rare Disease Research as those that affect fewer than 200,000 people in the US.  Some, far fewer than 200,000.  A new study, reported in Medical Marketing and Media, and published in the July Drug Discovery Today, suggests that in fact there is money to be made in rare disease pharmaceuticals.  And that's potentially good news for a lot of people.  

The government offers an "Orphan Drug Designation" program, which allows tax credits for what can be prohibitively expensive RandD for drugs for rare diseases.  In addition it offers grants to cover costs, waived FDA fees, which can be high, and the promise of seven years of exclusivity.  Granted, there's a lot that's unsavory about the workings of the pharmaceutical industry, but patents, of course, are the prime protection that pharmaceuticals have for recouping RandD costs and eventually profiting from a drug.   And, given that most orphan drugs are novel, "biosimilars" are not as much of a threat when the patent expires as they are for more popular compounds such as Viagra or Lipitor, say.

And, the MMM piece points out that marketing to a small target population is much cheaper than the population at large, clinical trials can be less expensive, and in fact the orphan drug market grew at a higher rate than the drug market in general.  

There's a lot to be said against the pharmaceutical industry, but that's not our point today.  Of course bottom line is the primary consideration when it comes to developing new drugs, but if it really does become financially attractive to develop new drugs for rare diseases, this is good news for a lot of people.  The scientific challenges are still real, but at least there's motivation to take them on.  

Now to hope that it becomes profitable to invest in research into drugs for another and much larger group of forgotten people, those with "neglected tropical diseases."