One
Huntington's Disease
'If you were going to be knocked down by a bus tomorrow, you wouldn't want to know, would you?' Valentina asked.
'I would want to know,' I decided. 'I'd spend a lot of time talking to people and then I'd eat everything off the menu in the Ritz!'
We were both laughing but we were also aware that Valentina knew better. Valentina's mother has the genetically determined neurological condition Huntington's disease (HD) and Valentina faced a 50% chance that she had inherited the disorder. She had spent years considering whether or not to be tested, weighing all the pros and cons of having advanced knowledge of a big slice of her medical future. A predictive genetic test could give her some sense of certainty-but, like all predictive diagnostic tests, it would also create a cascade of consequences that many fail to anticipate.
Predictive medicine is diagnosis in healthy people before a disease has had a chance to start. Genetic predictive diagnosis can be used to advise people of a pending health problem decades ahead of time. That means many years of waiting and watching for the first symptom to strike.
Huntington’s disease is an incurable condition that causes progressive physical and cognitive disability. The early signs are often subtle behavioural changes such as mood swings, social withdrawal, loss of impulse control and poor organisation. Psychiatric features are prominent. Depression, mania, obsessive behaviour, and thoughts of death and suicide may feature. Motor symptoms can be present early on but more often come later, resulting in clumsiness, loss of balance, slurred speech and difficulty swallowing. A hallmark of the disease is the development of jerky involuntary muscle twitches called chorea or choreiform movements. In the later stages, sufferers are unable to walk and struggle to eat or speak. Nothing will stop the downhill trajectory to severe disability. The typical age of onset of symptoms is between thirty and fifty, with the eventual death coming roughly ten to twenty-five years later. The first disease gene to be discovered was that for Huntington’s disease. More than anyone else, the HD community understand the gravity of the decision to take a predictive diagnostic test.
Human DNA is arranged into twenty-three chromosome pairs. One pair are sex chromosomes, X and Y, and the other twenty-two numbered pairs are referred to as autosomal. Genes, which make up small sections of the long threads of DNA within a chromosome, are the basic unit of inheritance. They contain all the instructions needed for human development. Genes make proteins which make cells, and we are made of cells. When a gene code contains some form of mistake, a genetic disease can develop. Mistakes in genes were once called mutations but are now called variants.
As soon as the normal structure of DNA was understood, the search for genetic variants that cause disease could begin. The precise faulty gene that causes HD was identified in 1993. It is a monogenic disorder, meaning it's caused by a mistake in only one gene. Polygenic disorders, on the other hand, have contributions from multiple genes. HD is autosomal dominant, so the disease gene is on a numbered autosomal chromosome-chromosome 4-and only one gene in a pair needs to be a disease gene for HD to develop. Monogenic dominant disorders like HD have predictable inheritance because children either get the genetic variant from their affected parent or they don't: a fifty-fifty chance. The HD gene variant is not just a risk factor suggesting that a person might get HD, it is a certainty. The only question is when the symptoms will start and how quickly they will progress.
The discovery of the HD variant brought testing for Huntington's disease into everyday medical practice. From that moment on, any person with a family history of HD could be tested to see if they were also destined to develop the condition. It was clinical medicine's first opportunity to grapple with all the implications of giving healthy people a diagnosis of an impending incurable disease.
Valentina was twenty-eight and pregnant with her first child when she learned her mother was being tested for Huntington’s disease. Valentina’s family had no idea this was on their horizon. Vivian, Valentina’s mother, was adopted. She was never told of any bleak medical secret in her biological family, so when, in her fifties, she started dropping things and developed tic-like muscle twitches and loss of balance, nobody recognised this as the start of HD. Much later, Valentina wondered if her mother’s symptoms actually began many years before. As Valentina remembers it, Vivian had been prone to depressive bouts for many years. She was easily flustered and bad at decision-making. These are exactly the sort of non-specific symptoms that herald the insidious onset of neurodegeneration. When they happened to Vivian, they were attributed to more ordinary mental health problems.
A brain scan was what first alerted Vivian's neurologist to the possibility of HD and the need to refer Vivian for a genetic test. Vivian didn't take the suggestion very seriously. She was sure that somebody in the adoption services would have told her that she had a parent with HD and because they didn't, she convinced herself it was not her diagnosis. Only later did the family learn that Vivian's father had spent years in a psychiatric institution. In the past, before HD was fully understood or easy to diagnose, some sufferers languished in psychiatric units without a diagnosis. Not knowing she was at risk, Vivian was absolutely certain her tests for HD would come back negative. She was so dismissive of the test that Valentina wasn't particularly concerned either and didn't even think to ask about the result.
The day that Vivian found out she had HD, Valentina's future and the future of her unborn child changed dramatically. All of Valentina's siblings' and nieces' and nephews' lives changed, too. Each of Vivian's four children went from being perfectly healthy young people to having a fifty-fifty chance that they would eventually develop an incurable neurodegenerative disease, while Vivian's grandchildren had an immediate 25% chance of being affected. The wife of Valentina's brother Luca was pregnant too, with their second child. Valentina's younger sister Camila was about to get married and had yet to start a family. The eldest of the siblings, Evangeline, already had three daughters and a son.
Vivian waited until Valentina's baby daughter, Ella, was born before they told her that the genetic test had been positive for HD. It came as a complete shock.
'I knew exactly what it meant when I heard about the diagnosis,' Valentina said, thinking back to that time. 'I like medical programmes and books. I'd heard of HD and I knew it was bad.' Vivian's symptoms had probably begun in her early forties. If Valentina had inherited the gene variant that causes HD, she would most likely start showing signs of the disease around the same age as her mother, giving her maybe another fifteen years of good health.
Vivian's diagnosis had an immediate impact on Valentina. She had always been a light-hearted, glass-half-full type of person, but she changed. She began having panic attacks. Before long, she needed antidepressants to control her mood and she has continued taking them since.
'When this is in the family, the children need to be prepared from a young age,' Valentina advised me. 'For us, there was no preparation and we all had so many decisions to make and so quickly.'
Valentina and her siblings were each at the point of starting or expanding their families. They were developing their careers, buying houses. Should they keep their plans the same or change them to accommodate the new possibility? Of the four children, surely at least one, probably two, would have inherited their mother's disorder.
'Did you think about getting tested straight away?' I asked.
'I thought about it, but hardly at all. I had a baby to look after and that was my priority. My brother Luca was the one who insisted he wanted to be tested immediately. But he didn't do it in the end. He still hasn't.'
Valentina and I were speaking twenty-two years after she learned of her mother's diagnosis. Valentina had waited twenty years to have the test that would let her know if her mother's fate was also her own.
'What stopped you testing for so long?' I asked. My first impulse as I began exploring predictive genetic diagnosis for this book was to assume I would take the test at the first opportunity-just as I was sure that I would want to know about the metaphorical bus that would soon knock me down. Valentina and her siblings did have an immediate thought to test but, ultimately, they all put it off. I wondered what changed their minds.
'Hope,' Valentina answered. 'If you don't test, you can hope you don't have it and you cling to that. You don't want to know because you want to have a free life. Hope will carry you a long way.'
Nonetheless, Valentina's life was shattered by her mother's diagnosis. She sought the support of a psychologist. It didn't help. Valentina's worry was too specific and the non-specialist counsellor didn't understand the decision Valentina was facing. Only when Valentina found someone who specialised as a genetic counsellor did she get some peace of mind. Genetic counsellors are not psychologists. They are experts in genomic medicine, skilled in calculating genetic risk, explaining inheritance patterns, predicting risks of genetic disease, advising on genetic testing and, crucially, helping people to understand and live with uncertainty. Valentina's genetic counsellor was the first person who fully grasped the complexity of her decision. They challenged her impulse to test, helping her realise she wasn't ready. She was a young mum. She would prefer to get on with her life. Valentina, supported by her husband, found ways to manage the worst of her panic. Although, even on the happiest of days, anxiety always lingered in the back of her mind.
There were also big decisions to be made. Valentina and her husband, Jonathan, never doubted they would have more than one child. Her brother Luca also wanted more children. Camila, the youngest, had not even started her family yet. But choosing to have a child naturally, who would automatically have a 25% chance of developing an incurable condition that foreshortens life, was not easy for any of them.
One way that predictive genetic diagnosis has certainly benefitted people is that it offers a means by which families with a monogenic condition can dramatically lower the chance of passing it on. Pre-implantation genetic testing (PGT) is used to check embryos for genetic mistakes. It means having a child by IVF. Only those embryos with a normal chromosome 4 are implanted. At the time that Valentina and her husband were making the decision to have their second child, PGT cost £30,000. The NHS now provides it for free to people with a family history of select monogenic disorders. PGT, like any IVF procedure, is much less likely to result in a successful pregnancy than natural conception. It can also be a gruelling process for the prospective mother.
Valentina and her husband agonised over the decision. They were counselled about the pros and cons of PGT. They decided they would prefer to have a child naturally.
'It wasn't the money,' Valentina told me. 'Or it wasn't just the money. I couldn't imagine sitting my children down one day and telling one child that they were OK, that they'd been chosen. Then having to tell Ella that she had a fifty-fifty chance of HD. I never wanted to put my children in that situation. It was a conversation I knew I couldn't have.'
Valentina felt a lot of guilt about deciding to have a child who could later develop HD. But it is actually a common decision for people in her position to make. Her brother Luca did the same. They wanted all their children to feel equal. Camila, who had no children when she learned of her mother's diagnosis, chose to have PGT.
Valentina gave birth to baby Jake, five years after his older sister, Ella. Valentina was thirty-three and still hadn't tested.
During all these hard decisions, the siblings watched their mum become significantly more symptomatic. It was painful to see. Vivian was often aggressive and argumentative. She had violent outbursts. Verbal assaults on Vivian's father evolved into physical attacks. Valentina, who lived nearby, was often called in to help calm things down. Some fights were so furious that the police were called. Vivian was abusive to complete strangers. If she encountered a person who was mildly overweight she called them 'f**king fat'. She made racist comments that were entirely out of character. Her mood was very low. She once tried to throw herself out of an upstairs window. These are all extremely common behaviours for someone with advancing HD.
Vivian's physical disability also accumulated slowly. She developed chorea-constant, unpredictable, fidgety movements. Her balance deteriorated and so did her speech. Ultimately, the family had no choice but to move her into a nursing home for specialised care.
'I started to dread visiting her. I was seeing my future and my kids' future,' Valentina told me. 'It was very difficult because I adore my mum. We're very close. It was hard to see her get worse for her sake, but she was also a constant reminder of what might be ahead.'
As Valentina watched her mum go downhill, she became more and more anxious, particularly once she began to detect symptoms in herself. Her sister Evangeline, four years older than Valentina, had noticed the same. They were clumsy. They dropped things. Their moods were changeable. The sisters spent hours on the phone talking about symptoms. They tried to reassure each other. Valentina insisted that Evangeline was mistaking premenstrual symptoms for HD. In one of those conversations, Evangeline got annoyed with Valentina. They argued. Evangeline told Valentina to stop giving her false reassurance because she knew she had it. She just knew.
Evangeline was soon proven right. Six years ago, she tested positive for the HD gene. By then, her four children were in their late teens and early twenties. With Evangeline's positive test, her children's chance of having HD jumped from 25% to 50%.
Valentina was devastated for her beloved sister, to whom she had always been close. And it didn't help that Valentina also had all the symptoms that Evangeline and her mother had experienced. She got flustered if she had to do two things at once. She veered to one side. She walked into walls. She had mood swings just like her mother. Sometimes, Valentina didn't want to go out because she felt so dizzy and off balance, and she feared it had become noticeable to others. She travelled a lot for work and her symptoms were at their worst in airports. The precise timings and documents involved in catching a flight were too much for her. Just approaching check-in she became flustered, which would spiral into a feeling that she couldn't cope. She dreaded trips abroad. As her symptoms accumulated, Valentina still agonised over the decision to test. Without the positive test she still had hope, but she knew she couldn't put it off forever.
Copyright © 2025 by Suzanne O'Sullivan. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
