The Woman Who Walked Into the Sea, published in 2008, is a historical account of Huntington’s disease in America. Alice Wexler, author of Mapping Fate and sister to geneticist Nancy Wexler, painstakingly documents the disease in East Hampton, Long Island families from its earliest historical appearance to the present. The book is rich with documents, and Alice Wexler grounds the history of Huntington’s disease (HD) through individual narratives and discussion of broader social movements.
Wexler argues that early perceptions of HD differed a great deal across communities. Although some individuals with HD were vilified, records of social standing and wealth indicate that others held prominent positions in their communities. She argues that the illness gained clinical interest in the 19th century because of a changing understanding of heredity(1). Heredity became central to practical breeding, conversations about race, and in tracing causation for disease and social ills. George Huntington’s paper on “hereditary chorea” appeared in 1872(2), and by the mid-1880’s, clinical reports of “hereditary chorea” began to appear in many countries.
By the 20th century, heredity became a legitimate focus of scientific inquiry and Huntington’s was the topic of many eugenic studies. Davenport, a prominent biologist based out of the Eugenics Record Office in Cold Spring Harbor, theorized that Huntington’s presence in the United States could be traced back to a few Connecticut colonists. Relying on tenuous diagnoses and hearsay accounts of family histories, this was the first origin theory of HD in the U.S. Another researcher, Vessie, connected the disease to individuals accused of witchcraft, criminal acts, and sociopathic behaviors. His work would not be fully discredited until the 1970’s, and helped legitimate prejudicial associations in the medical literature for decades.
Like many diseases, Huntington’s had been linked to social class in the earliest reports of the disease. Davenport tied HD to other nervous disorders and ‘feeble-mindedness,’ and held that a small number of individuals resulted in an expansion of disease across the US. This strengthened the call for eugenic legislation. The 1920’s through 1940’s were a dark point for people with Huntington’s and other genetic disabilities and diseases(3). For unknown reasons, American publications on Huntington’s disease decreased in the 1920’s, and articles on treatment and therapeutics disappeared. In 1927, the Supreme Court upheld a Virginian program of sterilizing the mentally disabled. In 1935, a committee of the American Neurological Association defended the practice of sterilization with the consent of a patient or their caretakers, and called for restrictions on marriage for conditions like Huntington’s.
Negative portrayals of Huntington’s did not begin with eugenics, but the movement increased these portrayals in medical writings and occasionally in the popular media. However, by the 1970’s, with the backdrop of civil rights, informed consent, and feminism, the cultural landscape around HD had changed. In 1976 and 1977, public Congressional hearings were held to respond to demands of families affected by HD. Some two thousand people, mostly family members, caregivers, and health professionals, came forward to discuss their experiences. Family members placed emphasis on the need for social services and affordable facilities for long-term care. They called for more informed and sympathetic physicians, more research for a treatment and a cure, and the need to end the stigma of talking about the disease.
Wexler’s very thorough book emphasizes how HD can be understood as part of “larger cultural narratives.” She emphasizes that rather than simply dismissing the history as an example of bad science, we need to recognize that substituting scientific fact for superstition does not necessarily reduce stigma and prejudice. For example, knowledge of the Mendelian dominant inheritance of HD and vague notions of a familial curse coexist just as easily with arguments for eugenic sterilization. Wexler writes, “science is always a complex construction that involves arguments about meaning and value.” As we continue to search for treatment and a cure, constructing scientific knowledge in ways that benefit the HD community is tightly linked to our politics and priorities.
(1) Medical literature on HD was considerable by the early 1800’s.
(2) Although HD would be named after him, George Huntington was not the first to describe symptoms of HD. Several 19th century Americans and at least one Norwegian described the illness before him. Medical historians have speculated that early modern European portrayals of chorea and St. Vitus’ dance may have also included cases that would be diagnosed as HD today.
(3) The eugenic movement began in the late 19th and early 20th century, but the most hostile representation of HD in American medical literature emerged in the decades following World War II.
Though it has been suggested that the frequency of HD is probably low among people of African origin, documentation remains poor and evidence is inconclusive. From the few known cases, however, it has been hypothesized that the HD mutation in Africa has a separate origin from the mutation in Europe or Japan.
There is a substantial frequency of HD in the white and mixed-race populations of South Africa. Most of the families with HD have Dutch or British ancestry, which suggests that they inherited the European HD allele. A 1987 study revealed the HD prevalence among South African blacks to be very low – around 0.6 cases per million people.
Huntington’s disease is believed to have first arrived in South Africa over 300 years ago when Dutch colonists settled into the Western Cape in the 1600’s. Dr. Michael Hayden, a South African researcher, traced back the origins of the disease in this country and noted the following in his groundbreaking research released in the 1980’s:
“Among the 344 persons who arrived on the Dordrecht at the Cape in 1658 was a man called Willem Schalkv.d. Merwe. His family had its origins in Oud-Beyerland, which is in the vicinity of Rotterdam. On 5 May 1661, he became one of the first free burghers at the Cape and in 1668 he married Elsjie Cloeten, daughter of lacob Cloeten who arrived at the Cape with lan van Riebeeck in 1652. The first child of this marriage was a daughter named Sophia after her maternal grandmother. She married Roelof Pasman on 12 November 1684 and they had 5 children before he died in 1695. In 1696 she married Pieter Robberts, who was to become one of the first magistrates in the Cape, and after 1699 they lived on a farm, Rustenburg, in the Stellenbosch district. A search through old manuscripts and documents revealed a map of the Cape of Good Hope, drawn between 1699 and 1713 by a cartographer named Valentyn, in which farms and the names of owners are marked. Over 50 smaller affected families, who link up to form 4 very large Afrikaner families, have been traced over 14 generations to these common ancestors.
Three of these are descendants of the marriage between Sophia v.d. Merwe and Roelof Pasman and the other large affected kindred stems from the later marriage of Sophia to Pieter Robberts.”
Hayden’s research highlights the relatively high prevalence of HD in those of Afrikaner descent and other European ancestry within South Africa. (There is current research in the works to determine the prevalence of other ethnicities within the region.) Hayden’s other research paper, The Prevalence of Huntington’s Disease in South Africa, was a groundbreaking study in the 1980’s, as it was the first attempt to document the prevalence of Huntington’s disease in South Africa. At the time, Hayden used ethnographic studies of the Western Cape to estimate that there were 22 per million in coloured and white populations and 0.1 per million in Black South Africans affected by the disease (Click here for more information). It is important to note that these figures were minimum estimates of prevalence and that much of the research focused on families in the Western Cape where the Dutch settlers first arrived. Further research is in the process of determining more accurate prevalence for the Coloured and Black populations of South Africa.
Furthermore, research from Baine et al. (2013) highlights differences in the HD gene itself, with black patients experiencing more occurrence on haplogroup B (a haplogroup is a genetic population that shares a common ancestor), versus haplogroup A for white and coloured populations in South Africa. The average number of CAG repeats in unaffected black Africans is significantly lower than the mean CAG in white South Africans. However, there have been no studies yet to investigate the reason for this within the black population.
Research is greatly needed across the world to determine current disease prevalence, in addition to research on the genetics of Huntington’s disease in black African communities. These numbers are incredibly important for lobbying government and other funders in order to convince them to allocate resources to affected populations.
Huntington’s Association of South Africa
The Huntington’s Association of South Africa’s (HASA) mission is to “assist families with Huntington’s Disease by providing knowledge and support through support groups, creating awareness about HD through fund-raising and providing financial assistance where possible.” HASA manages support groups in Cape Town and Gauteng and provides many other support services.
For more information, visit http://www.huntingtons.org.za/
Dr. Michael Hayden
Michael Hayden is the world’s most cited author on Huntington’s disease. In the 1980’s, Dr. Hayden led a study of the prevalence of Huntington’s disease in South Africa. Dr. Hayden then moved to Canada and continued to focus on Huntington’s disease research. His lab became the first to successfully cure a mouse of the disease. Currently, he is the Chief Scientific Officer of Teva Pharmaceuticals and continues to advocate for Huntington’s disease research through his work there.
Jessica Selfe is one of the directors of the Huntington’s Association of South Africa (HASA), an organized started in 2004 to better serve the HD population of South Africa. Selfe is gene-positive, but not yet symptomatic. As a result of this awareness and having HD in her family, Selfe is improving access to care through her intense advocacy and devotion, leading to the development of several support groups in Cape Town, Pretoria and Johannesburg. She was also one of the individuals responsible for the hiring of the first social worker for HD families in the country.
Lysle Turner, a South African from the Gauteng province, is a mountaineer and fitness guru who is using his international fame to shine a spotlight on Huntington’s disease. After one of his family members was diagnosed with the disease, Turner decided to use his celebrity status and climb mountains in order to use the publicity to raise money for organizations like the Huntington’s Association of South Africa. In early 2015, Turner attempted to become the first person to scale Everest in honor of Huntington’s disease families, but a major avalanche that closed the mountain halted his efforts. Turner hopes to continue his efforts to raise awareness for HD through his passion for sports.
For Further Reading^
1. Baine, Fiona K., et al. “Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes.” European Journal of Human Genetics 21.10 (2013): 1120-1127.
2. Hayden, M. R., et al. “The origin of Huntington’s chorea in the Afrikaner population of South Africa.” S Afr Med J 58.5 (1980): 197-200.
3. Hayden, M. R., J. M. MacGregor, and P. H. Beighton. “The prevalence of Huntington’s chorea in South Africa.” S Afr Med J 58.5 (1980): 193-196.
Living with HD
- The Huntington’s Disease Society of America (HDSA) is a national organization that works to improve the lives of people with HD and their families. Their website has a wealth of information on how to manage symptoms and live with the disease, with advice on how to find support groups and nursing homes. The HDSA compiles an extensive list of online resources aimed at helping people manage HD, found here.
- Huntington’s disease Advocacy Center (HDAC) is a forum for people to share their experiences with HD, be it as a family member, a caregiver, or a person who has the disease. They also have research updates, and an active political advocacy page.
- The Cure HD blog is written by an HD-positive activist who goes by the pseudonym Gene Veritas. He writes about events in the HD community, with a focus on relevant political events.
Isis Pharmaceutical trials have begun for a much-anticipated antisense drug, ISIS-HTTRx,. ISIS-HTTRx, aims to reduce the amount of mutant huntingtin protein made in the brain. The antisense oglionucleotide drug binds to the mRNA of the harmful huntingtin protein and physically prevents protein production. The drug also recruits an enzyme to degrade the mRNA. (For more information about antisense gene therapy, please see this article.) ISIS-HTTRx, is the first therapy to reach clinical development that targets the production of huntingtin protein.
The 1/2a study is designed to test the safety and tolerability of multiple doses of the drug in adult patients with early manifest HD. Each dose will be administered through a lower back injection, commonly known as a lumbar puncture or ‘spinal tap.’ During this procedure, a needle is inserted between two vertebrae in your lower back and the drug is injected. The study will be randomized so that 75% of the patients will receive ISIS-HTTRx,, and 25% will receive a placebo. This randomization will allow the study to meet the statistical standards required to assess drug safety.
The pharmaceutical trial will enroll 36 patients who pass the additional screening evaluations, and will take place at six centers in Canada, the United Kingdom, and Germany. Only patients who live within four hours ground-travel distance of a study center will be eligible. If the study finds that the drug is safe and well tolerated, further trials will be needed to test for its effectiveness in treating symptoms. Future clinical trials will likely include testing sites in the U.S.
This is exciting news for the HD community! For future updates about this trial, please visit clincialtrials.gov or hdtrialfinder.org.
In Eternal on the Water Jonathan Cobb meets the love of his life, Mary, while kayaking in backcountry Maine. Their perfect love is shortened by Mary’s illness of Huntington’s disease (HD). Published in 2010, this book is a fictional account of Jonathan and Mary coming to terms with the consequences of HD and the difficult decisions they have to make.
Summary: (Spoiler Alert!)
The book is primarily told from Jonathan’s perspective as he relates his and Mary’s love story to a police officer after Mary’s dead body is found on the Allagash River. The story begins when the two unexpectedly meet while kayaking on the same river years earlier. Jonathan is taking a break from his teaching job to follow Thoreau’s path down the river and Mary is lecturing group of girls with special needs about ravens, her academic specialty.
The two are quickly united by their love for nature when Mary reveals that she has a family history of HD. She has never been tested but feels certain she carries the disease. It quickly becomes clear that Jonathan and Mary are soul mates. However, Mary is hesitant to get involved with Jonathan because she potentially has a debilitating and life-ending disease.
Although Mary does not want to know her genetic test results, she agrees to let her mother disclose her results to Jonathan. Confident that Mary is the love of his life, Jonathan does not let her positive HD status deter them from having a happy life together. The story follows the couple through their travels in Indonesia and home in New England.
As the years pass, Mary begins to develop symptoms of HD. After watching her father struggle to the end with the disease, she decided long ago that once her quality of life began to deteriorate, she would end her life. She asks Jonathan and her family to support her in this decision. The book ends with a celebration of Mary’s life, as she floats for her final time down the Allagash River.
Portrayal of Huntington’s disease:
Huntington’s disease and associated challenges figure prominently in this work of fiction. Mary informs Jonathan about the genetic disease beginning on page 97.
“I often tell people my father died of a heart attack in a Chinese restaurant, but that’s not true. He died of Huntington’s when he was forty-one” (97).
Mary accurately describes the symptoms, prognosis, and discovery of the gene for HD. Despite her candid acceptance of her fate, she keeps the disease a secret from most people. This decision reflects the history of stigma associated with Huntington’s and highlights the intensely personal nature of coming to terms with having HD in one’s family.
“What if the test comes out and I learn I won’t make it to forty? Or even thirty-five? How do you go on after that? I try to live my life fully right this instant. Every instant” (99).
The book addresses the difficulties of deciding whether or not one should be genetically tested. Mary eventually decides to be tested for the sake of her loved ones, but she doesn’t want to know her own results. For Mary, the downside of a positive test is too great. She copes with the possibility of having HD by living each day to the fullest. This contrasts with her brother’s decision to know his results. For Freddie, “knowledge is power” (272). Look here for more information on the genetic testing (http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/genetic-testing/), and specifically deciding not to be tested (http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/genetic-testing/#what-if-i-decide-not-to-be-tested).
“When she was about ten we – my husband and I- we asked the hospital to run the tests” (150).
An additional concern with genetic testing is consent. Mary’s mom reveals that although Mary doesn’t know her status, she and her husband secretly had her screened as a child. Her mom references the difficulties in getting the test by saying, “We had to move heaven and earth to get it done”(150). Genetic testing guidelines stress that the decision to undergo genetic testing should only be made if an individual can give informed consent. The HDSA Genetic Testing Guidelines stress that minors should not be tested unless there is a medically compelling reason to do so. The book deviates from what would be considered normal testing procedures. For further information on genetic testing, please read more here (http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/genetic-testing/).
“I have already arranged things so I can’t have children” (98).
The story mainly centers on the long-term consequences of having HD. For Mary, the long-term consequences motivate her hesitation to begin a serious relationship and her choice not to have children. If one parent has HD, there is a 50% chance of passing on the disease each time they conceive. The decision to have children is deeply personal for HD patients. However, Mary’s decision glosses over the fact that there are many methods available to help someone ensure their child does not inherit Huntington’s. In addition to adoption and sperm donation, pre-implantation genetic diagnosis also exists, for which a couple undergoes in-vitro fertilization for an embryo that has been screened for genetic diseases. A fetus can also be screened prenatally for HD and other genetic disorders. This is a morally complex decision that the book only briefly touches on. See this article for more information on family planning. (http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/family-planning/).
I’m not going to run and jump off a bridge, but in time, when it’s right for both of us, I’ll leave” (240).
Suicide ideation is one of the most pressing and difficult issues facing the HD community. Mary decides to take her life in this novel. She is candid with Jonathan about her decision to commit suicide and expects his support. She says, “You will let me go and that’s what needs to happen now”(320). The book depicts a heartbreaking choice, made seemingly easy by the unwavering support of loved ones. The reality is likely far more complicated, but it is an important issue to address.
Eternal on the Water is an idealistic portrayal of one couple’s struggle with HD. The touching story centers on their love for nature, always returning back to the Allagash, where Mary is ultimately ‘eternal on the water.’ Despite this romantic perspective, the book examines real challenges both HD patients and their loved ones face. While some of the details on the topic of consent required for genetic testing and on the seemingly inevitable decision not to have children are debatable, the book is a heartbreaking look at the impacts of HD. It is a celebration of love and life, no matter how fleeting.
1. Bryan’s Dad Isn’t Who Lila Remembers
2. Bryan’s Dad Visits Dr. Kealy
3. Bryan Wants Ordinary Back
4. Bryan’s Dad Plays the Game
5. Like Father Like Son?
Prion-Like Behavior in the Huntingtin Protein:
Protein aggregates are a hallmark feature of Huntington’s disease (HD), as well as a number of other neurodegenerative diseases. These protein aggregates, composed of misfolded proteins that clump together, are traditionally thought to develop in vulnerable neurons individually. However, recent research suggests that these misfolded proteins may be transmitted from neuron to neuron.
Transmission of disease-causing proteins between cells is not new in the scientific literature. The idea of an infectious agent composed only of proteins, called prions, was first proposed in 1967, and is now known to cause a number of neurodegenerative diseases in animals and humans. Prions cause other proteins to fold into the wrong shape. Some research suggests that proteins demonstrating prion-like behavior may play a role in other neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Amyotrophic Lateral Sclerosis (ALS). This destructive process mainly appears in functioning, connected neural networks. Unlike prions, proteins involved in these neurodegenerative diseases are not infectious between individuals or species . A study published in Nature in August 2014 by Pecho-Vrieseling et al.  suggests that the protein that creates protein aggregates in HD patients, mutant huntingtin (mHTT), may spread from cell to cell. This study provides valuable insight into what is currently understood about the role of protein aggregates and HD.
The study examines whether mHTT can spread among and propagate in vulnerable neurons using R6/2 HD mouse models and normal human stem cells. The researchers used genetically modified mice that express human mHTT fragments (only small portion of mHTT containing the polyglutamine stretch) and have accelerated HD-like pathophysiology. They began by implanting human neuronal progenitor cells without mHTT (derived from normal human stem cells), into HD mouse brain slices. The researchers determined that the human cells were successfully integrated in the brain slice as functional neurons. Then, they demonstrated that the healthy human cells were able to acquire aggregates of mouse mHTT protein and underwent similar changes as the sick mouse cells, including fewer projections from neurons and loss in medium spiny neurons.
Finally, in order to investigate if mHTT was transmitted from cell to cell via synapses, the researchers treated co-cultures of human neurons and HD mouse brain slices with a neurotoxin, botulinum toxin, which blocks vesicle fusion with the plasma membrane and prevents the neurons from releasing neurotransmitters. In the presence of this neurotoxin, the HD mouse neurons contained mHTT aggregates but the human cells did not. This evidence suggests that mHTT is transmitted along the cortical striatal pathway and is transmitted across neurons via synapses.
If mHTT is passed from neuron to neuron, it could have important implications on therapeutic interventions because the propagation can be experimentally blocked. In the past, neural transplants have been tested as a therapeutic for HD patients. If mHTT is indeed able to escape between cells, this could lead to a failure of neural transplants in HD patients. The biological mechanisms by which misfolding proteins are transmitted to functioning neural networks in this study are still unclear. The authors of the paper speculate that mHTT transfer depends on synaptic activity, and suggest that mHTT is transmitted at the synapse. However, much more research is still needed to determine whether this prion-like process actually affects human HD onset and/or progression.
This recent study adds to the understanding of the development of protein aggregates in HD by demonstrating that in certain lab conditions, mHTT can escape one cell and enter another. It is possible that cell-to cell propagation of mHTT may be another factor in the development of protein aggregates in HD. However, although this work is very well done and novel, it is unclear whether this process has any relevance to disease development. The role of protein aggregates in HD development is still widely debated.
Arrasate, Montserrat and Steven Finkbeiner, “S. Protein aggregates in Huntington’s disease. Exp. Neurol. 2012, 238,:11-11.
 Griffith, J.S. “Nature of the Scrapie Agent: Self-replication and the Scrapie.” Nature 2 Sept. 1967: 1043-1044.
Guo, Jing L. and Virginia M Y Lee. “Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases.” Nature Medicine (2014) 20: 130-138.
Aguzzi et al. “Cell Biology: Beyond the prion principle.” Nature, 18 Jun. 2009, 459: 924-925.
Pecho-Vrieseling et al. “Transneuronal propagation of mutant huntingtin
contributes to non-cell autonomous pathology in neurons.” Nature Neuroscience Aug. 2014; 1(8): 1064-1072.
On September 13th, the UCSF Memory and Aging Center hosted the 11th Annual Huntington Disease Research Symposium. The symposium featured scientists discussing their work in basic science and clinical HD research. It was a great opportunity for HD patients and families to meet local researchers, become more informed about progress in HD research, and learn about ways get involved.
Stem cells figured heavily in the basic science portion of the symposium. Steve Finkbeiner from the Gladstone Institute of UCSF kicked off the conference by discussing among other things, the use of skin or blood samples from HD patients to make stem cells, which then can then be differentiated into brain cells. This process preserves the patient’s genetics and may help more directly test the efficacy of prospective therapies. These stem cells are called induced pluripotent stem cells and induced neuronal stem cells, respectively. Scientist Vikki Wheelock discussed a different kind of stem cell, mesenchymal stem cells, and the potential ability to engineer non-HD mesenchymal stem cells to deliver drug treatments. These stem cells come from adult bone marrow.
Many of the researchers rely on bioinformatics and the use of new research methods like optogenetics to make advancements in understanding HD. For example, Alexandra Nelson discussed her efforts to understand HD’s effects on the brain using optogenetics, a technique that a lab at Stanford pioneered. Optogenetics takes advantage of light sensitive proteins in algae. The genes for these proteins can be packaged inside of a virus and injected into an animal’s brain to make nearby neurons light-sensitive. Through this technique, Alexandra Nelson hopes to understand how the living cells that survive HD can be harnessed to deal with the symptoms.
Three researchers from the Memory and Aging Center at UCSF, Michael Geschwind, Natasha Boissier, and Erica Pitsch, discussed the clinical side of HD research. Overall, despite the acknowledgement of the scientists that many of these treatments and advancements are in preliminary stages, and that clinical research may be halted if it is determined to be ineffective or unsafe, hope was in the air at the symposium.
More Information about the Scientists Involved
 Steve Finkbeiner
 Vicki Wheelock
 Alexandra Nelson
 Michael Geschwind
 Natasha Boissier
 Erica Pitsch
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