Hunting for Huntington's
The year is 1872. A young American doctor - George Huntington - has just started his career, following in the footsteps of his father and grandfather, who were general practitioners in the prosperous Hamptons area of New York. Graduating from Columbia University the year before, at the tender age of 21, George is keen to make an impression on the medical world.
Building on a series of intriguing cases first gathered by Pa and Grandpa Huntington – all ancestors of one Jeffrey Francis who emigrated from England in 1634 – George realises that a number of his patients all have the same terrible and progressive disease, and that it runs in families.
He refers to this condition as ‘chorea’, from an Ancient Greek word referring to quick dance-like movements of the hands and feet. The reason becomes obvious in this excerpt from his essay published in the Philadelphia Medical and Surgical Reporter, describing the disease in detail:
“The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation. Its most marked and characteristic feature is a clonic spasm affecting the voluntary muscles...
“The disease commonly begins by slight twitchings in the muscles of the face, which gradually increase in violence and variety. The eyelids are kept winking, the brows are corrugated, and then elevated, the nose is screwed first to the one side and then to the other, and the mouth is drawn in various directions, giving the patient the most ludicrous appearance imaginable.
“The upper extremities may be the first affected, or both simultaneously… As the disease progresses the mind becomes more or less impaired, in many amounting to insanity, while in others mind and body gradually fail until death relieves them of their suffering. When either or both the parents have shown manifestations of the disease, one or more of the offsprings invariably suffers from the condition... It never skips a generation to again manifest itself in another...”
What quickly became known as Huntington’s chorea and later Huntington’s disease was actually well known for centuries, referred to as ‘magrums’ by New Englanders since the 1600s and familiar since the middle ages.
The first definitive medical description actually comes in 1842, thirty years before George Huntington’s paper, in a letter from a doctor Charles Oscar Waters, which notes the key symptoms of the disease and its hereditary nature. In 1846 Charles Gorman had noticed that cases tended to cluster in isolated populations, and by 1860, Norwegian physician Johan Christian Lund had also noted an unusually high prevalence of the condition in people living in the remote area of Setesdalen. But, as is so often the case, it’s the guy with the best PR who gets the glory…
By the early 20th century, geneticist William Bateson – who rediscovered Mendel’s laws on inheritance – had used genealogies from affected families to figure out that Huntington’s follows a pattern of autosomal dominant inheritance. This means that getting just one faulty copy of the gene from either parent is enough to cause the condition, although it would take another 80 years for researchers to track down the actual gene responsible.
But while scientists got on with figuring out the molecular nuts and bolts underpinning Huntington’s disease, society got on with being absolutely terrible to families affected by it. Back in colonial New England, people with Huntington’s were treated as witches and publicly burned to death. Jumping on the hot new trend for eugenics at the turn of the 20th century, US researchers began tracing detailed family records from affected families and calling for them to be forcibly sterilised so as to avoid passing the condition onwards.
In 1916, American geneticist Charles B Davenport, director of the Biological Laboratory at Cold Spring Harbor in New York and founder of the Eugenics Record Office, published a paper based on family trees in New York and New England drawn up by physician, Elizabeth B Muncey. In it he argued that a vast number of cases had stemmed from just a handful of initial progenitors who had come as colonists to the US, and therefore this was justification for immigration restrictions, surveillance of families, and compulsory sterilisation.
Another terrible person in this tale is Connecticut psychiatrist Percy Vessie, who in 1932 traced one of his own Huntington’s patients back to her 17th-century colonial forebears - three married couples from the English village of Bures in Suffolk, who he saw as the likely seeds of all the US cases of Huntington’s disease. As evidence, he cited witchcraft accusations against one woman and her relatives, along with ‘misconduct’ by the men, and argued for “rigid sterilization” of afflicted families.
We can’t be smug about our record here in the UK either. In 1933, The Lancet printed an extract from Vessie's paper, boasting that “we [Britons] may congratulate ourselves on their loss, for…there can be no doubt that [these men] and their progeny were undesirable characters, and would nowadays be classified as belonging to the social problem group”.
And in 1934, British neurologist MacDonald Critchley shamefully added to the stigma by claiming that all members of affected families were “liable to bear the marks of a grossly psychopathic taint, and the story of feeblemindedness, insanity, suicide, criminality, alcoholism and drug addiction becomes unfolded over and over again.”
In fact, Vessie’s tale of enchanted ancestors turned out to be misleading. In a fascinating feature published in the Lancet, writer Alice Wexler, whose own family is affected by Huntington’s disease, points out that Vessie had confused Elinor Knapp, the immigrant ancestor of Huntington's families in Connecticut who was never accused as a witch, with Goodwife Knapp, an unrelated woman who was executed as a witch.
We’ve come a long way since the #problematic attitudes of the 1930s (at least one might hope…), but the scientific story of Huntington’s disease has made similar leaps in understanding. In 1983, researchers tracked down the location of the responsible gene fault to human chromosome 4, and by 1993 the actual gene – known as Huntingtin – had been identified and sequenced.
It quickly became obvious that in people with the disease-causing version of the gene, a short section of DNA just three ‘letters’ long was repeated over and over, far more times than in the healthy version. When the gene is decoded within brain cells to make Huntingtin protein, this so-called triplet repeat – the DNA letters C, A and G – encodes an extra-long run of glutamine amino acids, one of the building blocks of proteins.
We also now know how the triplet repetition happens. It turns out that the molecular machines responsible for copying DNA when cells divide struggle to accurately copy highly repetitive stretches of DNA. Sometimes they lose their place and slip or stutter, sticking in or removing a few extra repeats here and there. It’s a bit like trying to read the same word repeated many times over and over in a book – you’ll probably lose your place and forget exactly how many you’ve read.
Intriguingly, the number of repeats is directly linked to the chances of developing the disease. Fewer than 35 CAG repeats and you won’t get it, between 36 and 39 and you might be lucky or not, but more than 40 repeats leads to the onset of Huntington’s around the age of 40. And around 8 per cent of cases occur in people under 20, usually linked to having 60 or more repeats.
But despite finding the Huntingtin gene and identifying the triplet expansion, researchers have little clue about what Huntingtin actually does in normal cells in the brain and the rest of the body, let alone how an extra bunch of glutamines in the protein causes the disease (if indeed it’s the protein that’s causing the problem…)
Maybe all those extra glutamines make the protein very sticky so it gums up the inner workings of brain cells. Perhaps the defective Huntingtin protein dilutes out important functions that are normally carried out by the healthy version. There’s also evidence to suggest that a strange little shortened form of Huntingtin might be the rogue agent at work.
A further nine hereditary neurological diseases have since been found that are due to expansions of those three little letters, CAG, all in unrelated genes. And in all cases it’s still not entirely clear why the increased array of repeats causes the condition.
Although knowing about the genetic fault responsible for Huntington’s disease means that members of affected families can opt for genetic testing if they wish, as well as techniques like prenatal testing and preimplantation genetic diagnosis if they wish to start a family, what they really want is an effective treatment for people living with the condition right now.
There is some hope in the form of an exciting gene therapy technique being pioneered by Professor Sarah Tabrizi at UCL and an international team of collaborators. She’s been running small clinical trials of antisense oligonucleotides – short genetic messages that cancel out the repetitive Huntington’s gene so that the faulty protein doesn’t get made.
People got very excited by her early results, announced in December 2017, which showed that the highest doses of the treatment could lead to a 40 per cent reduction in the amount of faulty Huntingtin present in the fluid around the patients’ brains.
But that’s just the start of it. Tabrizi’s trial was only designed to test delivery and safety of the treatment, and she still needs to prove that it actually makes a difference to patients’ symptoms and outcomes in the short or longer term. Other researchers are investigating whether new gene editing techniques like CRISPR could be used to snip out the extra repeats.
Getting gene therapy and CRISPR tools into enough nerve cells in the brain to make a difference is a big challenge, but it seems to be the best approach on the table right now. Dedicated researchers, charities and family organisations are pulling together to write a new ending for the story of Huntington’s disease.
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