What’s in a name? How Huntington’s disease gene carriers are seen by themselves and by others

In 1999 I received the results of a genetic test that showed I had 40 CAG repeats on the huntingtin gene inherited from my mother, who died of Huntington’s disease in 2006 after a two-decade struggle with the disorder.

Everybody has this gene, which first appeared 800 million years ago in a species of amoebae. Huntingtin helps our cells function properly.

The gene’s CAG repeats refer to the sequence of three nucleotide bases – cytosine, adenine, and guanine, all building blocks of DNA – on the DNA molecule. Most people have 27 or fewer repeats. The gene I inherited from my father had fewer than 20.

My mother’s high CAG count caused her to start experiencing HD symptoms – typically manifested as emotional distress, cognitive loss, and involuntary movements – in her late forties.

The term “CAG repeats” and my mother’s count of 40 were two of the very first facts I learned about HD after receiving news of her diagnosis in late 1995.

The geneticist used the same terminology when he revealed my test results.

However, as he told me and many other recipients of HD test results, “a positive test result is not a diagnosis.” While everybody with 40 or more repeats will develop HD in his or her lifetime, scientists cannot yet predict the exact moment and type of disease onset.

According to John Warner, Ph.D., the director of biostatistics for CHDI Management, Inc., which carries out the day-to-day mission of the non-profit, HD drug-discovery biotech CHDI Foundation, Inc., 95 percent of those individuals with 40 CAG repeats will experience disease onset between the ages of 50 and 74. (A future article will explore the statistical meaning of the CAG count in greater detail.)

With an ominous test result at age 39 but no symptoms, I needed to construct a definition of my genetic predicament for both myself and for others.

As I said recently in an interview, unlike treatments for certain kinds of cancer, I cannot irradiate my defective huntingtin gene to destroy it. It’s part of me, literally residing in every cell.

Because of its genetic nature, HD also requires a far more nuanced kind of diagnosis. Subtle symptoms can exist for years before the more noticeable symptoms commence.

'Gene-positive'

For many years, I referred to myself as “gene-positive for Huntington’s disease,” a term I heard often in HD family and scientific circles. I also used phrases such as “tested positive for HD.”

“Gene-positive” echoed the term “HIV-positive” used by the AIDS community. It meant not only that I had tested positive for a condition, but that I inevitably faced its dire consequences.

Thus, “gene-positive” resonated with the deep stigma, discrimination, and alienation suffered by members of both the AIDS and HD communities.

“Gene-positive” further implied an activist stance. As with the early years of the fight against AIDS, we in the HD community needed to tell the world we needed treatments and the resources to find them.

I experienced all of these feelings in the late 1990s and early 2000s, as I immersed myself in advocacy work for the Huntington’s Disease Society of America.

They remain with me today as we still await the discovery of an effective treatment.

Changing perceptions

As my knowledge about HD increased, and as I came into ever closer contact with HD researchers in labs and at events such as the annual CHDI-sponsored HD Therapeutics Conference, both my perceptions of HD and the terms I used to describe my situation changed.

As I learned to my first visit to CHDI in 2009, many scientists see gene-positive individuals as genetically and, at least at the cellular level, even functionally compromised from birth.

I started to hear scientists used the word “premanifest” to describe asymptomatic, gene-positive individuals.

Soon I would be introduced to “prodrome” and “prodromal”. A precursor or forerunner to the disease, prodrome refers to the period before onset.

However, I could never imagine using such a technical term to describe myself to others.

Scientists and physicians also used “asymptomatic” and especially “presymptomatic” to describe people like me. I have frequently used the former to indicate to people that I face the danger of HD but am fine for now.

Other phrases I have used or heard include: HD gene carrier; HD gene mutation carrier; asymptomatic HD gene carrier; disease-gene carrier; tested positive for the genetic defect that causes Huntington’s disease; and carry the gene for Huntington’s disease.

Living with the ‘phantom gene’

At the World Congress on Huntington’s Disease in Rio de Janeiro last September, HD activist, historian, and author Alice Wexler, Ph.D., noted that much recent scientific discussion has focused on defining when HD actually begins.

During a panel on coping with HD, Dr. Wexler asked how global HD advocate Charles Sabine and I – both gene-positive but asymptomatic – viewed ourselves as individuals living with the “phantom gene” and in what circumstances would consider ourselves as having HD.

“It changes for me depending on where I am,” I replied. “If I’m at a conference like this: ‘Oh, my God! I have HD.’ Because I see all these studies and brain scans and searches for biomarkers … and references to me as prodromal…. There’s a tendency of the scientific community to see gene carriers as diseased from Day One.”

In settings such as my doctor’s office, I felt different, I said. “My doctor’s telling me: this time you got a clean bill of health.”

Charles, agreeing with my outlook and saying that he “treasured” his current good health, answered the question in a “wider, more metaphysical sense.”

“We are not just someone who’s had a bit of bad luck,” Charles said about having inherited the HD mutation. “We are a part of history. I have absolutely not a single shred of doubt in my mind that, whether it’s 20, 50, or a 100 years [off], that this disease will be managed just like HIV-AIDS can be now.”

You can watch the entire exchange in the video below.

Living with a 'Phantom Gene': Two Huntington's Disease Gene Carriers Discuss Their Perceptions from Gene Veritas on Vimeo.

A new shorthand

The latest conception emerged at the CHDI-sponsored HD therapeutics conference in Palm Springs, CA, last month, where Andrea Varrone, M.D., Ph.D., of the Karolinska Institutet (Sweden) gave a presentation whose title included the phrase “Huntington’s disease gene expansion carriers.”

That phrase very accurately describes someone like me, because it specifically identifies the cause of the disease: an expansion of the huntingtin gene. However, the term does not by itself identify whether a person is symptomatic or asymptomatic.

Nevertheless, it’s good shorthand for the concept of expanded CAG repeats.

However, both the phrase and its acronym, HDGEC, are a mouthful! They might not resonate with the community, and even less so with the general public, which is more familiar with the idea of a “mutated gene” than with the term “expanded gene.”

‘You don’t look like an HD person’

The abundance of terms to describe asymptomatic HD gene carriers reminds me that those of us in this predicament are undergoing “the new and harrowing human experience of living in the gray zone between a genetic test result and the onset of a disease foretold.”

Scientists have demonstrated that changes in the brain occur ten and even 20 years before onset – meaning that my brain may already be seriously compromised, even though I function just fine.

Inexorably, perniciously, but silently, HD attacks the brain.

However, it’s not discernible from the outside.

“You don’t look like a person who has Huntington’s disease,” a health professional told me recently as I contemplated him writhing with pain and discomfort from a knee operation that forced him to wear a brace and use crutches.

There is no particular way for a premanifest person to look! Moreover, no “crutch” yet exists to help the presymptomatic HD brain recover from the initial assault on the cells.

As an HD gene carrier and advocate for this orphan neurological disorder, I continually face the challenge of explaining the seriousness of the disease and its many social implications.

Along with other neurological disease communities, we in the HD community are still searching for the right formula to project the urgency and significance of our predicament.

A temporary escape

Often those of us in the gray zone prefer not to deal with HD. Unlike others in the community, we don’t yet face the minute-by-minute struggle with symptoms.

At the local HD support group meeting this week, I was the only at-risk individual to appear. Even so, the facilitator and her replacement-in-training for the at-risk section (which normally includes both tested and untested asymptomatic individuals) held a session with me. I wanted to help bring the new person up to speed on the history of the support group and the needs of the at-risk section.

We noted that the support group’s caregiver section is usually the largest of the three subdivisions, followed by the section for those already affected.

The at-risk is usually the smallest – even though at-risk individuals outnumber affected individuals nationally by a ratio of at least five to one.

I sympathize completely with the occasional need to “escape” from HD, so I understand why other at-risk people didn’t attend the meeting. However, I am hyper-aware of the need for more individuals to participate in research studies and clinical trials to create effective treatments.

The transition to patient status

The facilitators and I also discussed the difficult choice individuals and facilitators must make in transitioning newly affected individuals out of the at-risk section and into the affected section.

I’ve witnessed this transition for a number of people. I can’t imagine how hard it is.

Once the symptoms begin, the terminological ambiguity ends. They are now “affected” or “symptomatic” individuals. They are “HD patients.”

I anxiously await the moment when an effective treatment would not only ameliorate these and other patients’ symptoms, but also prevent onset in asymptomatic gene carriers.

‘It’s really getting real’: payoffs in the effort to treat Huntington’s disease

The path to treating Huntington’s disease – a potential major breakthrough in the history of science and medicine – is becoming clearer.

That was the takeaway message from the Ninth Annual HD Therapeutics Conference, organized by the CHDI Foundation, Inc. and held February 24-27 at the Parker hotel in Palm Springs, CA. Spending tens of millions of dollars annually, CHDI is a non-profit, virtual biotech founded solely to discover HD treatments. Some 300 participants from academia, the pharmaceutical industry, and biotech firms took part, as well as a number of patient advocates, including Olympic rowing medalist Sarah Winckless, who delivered the keynote address.

“The tagline would have to be ‘it’s really getting real,’” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI Management, Inc., in an interview with me at the conference. “What I’m seeing at this conference already is the culmination of very large, very long-term efforts – things that have taken years and thousands of person hours, patients’, caregivers’, researchers’, and physicians’ – finally coming together in ways that are really conclusive and really helpful.”

All that work has involved numerous questions about the disease and potential ways to treat it, Dr. Pacifici explained.

“All of those things sadly have an incredibly high attrition rate,” he observed. “The fact that we’re getting answers is the thing that makes me the most excited. Sadly, sometimes we don’t like the answer. Sometimes the answer is: ‘That doesn’t work.’ But that’s still very useful for researchers.”

Winnowing out the useless approaches allows researchers to “refocus our resources on something that we feel has a better chance of bearing fruit,” Dr. Pacifici said.

Sitting one evening with a group of CHDI researchers, I expressed the natural concern of the HD community – a concern sometimes tinged with impatience and frustration: could the rapidly expanding knowledge about HD result in an endless search for treatments fueled by questions that simply produce new questions rather than treatments?

They answered with an emphatic no. Echoing Dr. Pacifici, they said that real solutions were in the works.

The conference did seem more coherent in comparison with the previous three I had attended. Indeed, as one senior CHDI advisor observed in response to my observation, Huntington’s researchers now have an understandable “story to tell” about the disease and the research.

You can watch my interview with Dr. Pacifici in the video below. Just below the Pacifici interview, Portuguese speakers can watch my interview about the conference with Dr. Mônica Haddad of Brazil.

'It's Really Getting Real': Payoffs in the Effort to Treat Huntington's Disease from Gene Veritas on Vimeo.

A esperança de tratar a doença de Huntington: Dra. Mônica Haddad fala sobre a conferência da CHDI from Gene Veritas on Vimeo.

Confirming the shots on goal

Just three days before the conference, CHDI and Genzyme Corporation announced an agreement to jointly develop a “novel gene-silencing therapeutic for Huntington’s disease” using an adeno-associated virus, which does not cause disease, as a delivery system.

The venture expands CHDI and other research projects’ portfolio of potential treatments for HD, several of which are in the early stages of clinical trials or aim to begin trials soon.

In Dr. Pacifici’s words, the growing number of drug targets means there are more “shots on goal” in the quest for treatments.

CHDI is concentrating on “validating” (confirming) the targets to assure that as many potential remedies as possible have a chance of becoming effective, safe treatments, Dr. Pacifici explained.

“It’s important for any drug discovery organization, because when you select a target, that’s what underpins the rest of the (drug discovery) activity,” he said.

No organization has yet discovered how to validate targets “exactly,” he said. However, CHDI is especially working hard to insure that a “particular target is really tethered” to the HD disease process and not some other disease or process, he added.

“While nobody has the magic bullet there, it was really impressive to see the variety of approaches that were taken,” Dr. Pacifici said of the talks on target validation.

These included X. William Yang’s report on his latest research with transgenic HD mice, Ernest Fraenkel’s study of the impact of the mutant huntingtin gene at the molecular level, and CHDI scientist Jim Rosinski’s efforts to unify and interpret the totality of biological data on HD by employing a systems biology approach.

You can watch an excerpt from Dr. Fraenkel’s presentation, Dr. Rosinski’s full presentation, and most of the other talks by viewing my 2014 CHDI video album.

Finding a modifier gene, delaying onset

Jim Gusella, Ph.D., one of the lead discoverers of the HD gene in 1993, described the work of a large international team to find a so-called modifier gene, which might act as a trigger for the disease and affect the rate of progression.

Such a gene could also become the target of a treatment, Dr. Pacifici explained.

“Imagine coming up with a drug that can delay your age of onset by 30 years,” he said, referring to the wide variability in age of onset for people with the same degree of mutation. “That would be fabulous.”

The Gusella team’s search for the modifier gene points to “a couple of specific sites on human chromosomes,” Dr. Pacifici said. In contrast with the numerous studies done in mice and other organisms, this project “was generated with human data. So we don’t have to worry about the predictive value of those studies.”

Dr. Pacifici described the 20-year quest for the modifier gene as “a great example of how the community pulls together and the generosity of the families affects the progress of research. Without your blood, without your DNA sequences, without your permission, there’s no way these types of studies could be done.”

The team analyzed DNA from more than 4,000 HD gene carriers and affected individuals. The study also required the ongoing commitment of participants to allow researchers to track their symptoms.

“We need to make the correlation as to when the motoric age of onset (the start of involuntary movements) occurred,” Dr. Pacifici explained. “That’s invaluable and incredibly appreciated. Hopefully now people can understand why participation in trials like this leads to such exciting discoveries.”

New potential therapies

A session on “novel therapeutic approaches” focused on potential remedies different from the traditional concept of oral medication.

Jan Vesper, M.D., presented the promising results of his pilot trial using deep brain stimulation, which involves the placement in the brain of metal capsules covered with electrodes. Long-time HD specialist Gill Bates, Ph.D., discussed her new research on the muscle deterioration involved in HD mice and the potential use of a myostatin inhibitor to remedy the problem as well as perhaps ameliorate the involuntary movements typically suffered by patients.  Beth Stevens, Ph.D., explained the importance of restoring proper function of microglia (cells performing as the immune system of the nervous system) in pruning synapses, the connections between brain cells.

‘A horrible, lifelong case of jet lag’

Changes in people’s behavior could provide another way to ameliorate HD, Dr. Pacifici noted.

Along those lines, Christopher Colwell, Ph.D., presented critical new research on the circadian rhythm – our sleep clocks – and how its disrupted function in HD might worsen symptoms.

“Think of Huntington’s almost as a horrible, lifelong case of jet lag,” Dr. Pacifici said in describing the implications of Colwell’s and others’ work in this area. “By entraining (synchronizing) the clocks in your mind and the clocks in your various organs to stay in sync with each other – by using things like when you eat, when you go to sleep, when you exercise, what kind of light you’re exposed to – you could compensate for some of the mechanisms that go awry in Huntington’s disease. That type of regimen could be a therapy, or an add-on to a therapy, rather than something as traditional as a pill.”

Dr. Colwell’s engaging talk provided a wealth of ideas about the circadian rhythm and keeping it healthy. You can watch his presentation in the video below.

Circadian disruptions in Huntington's disease: mechanisms and possible treatment options from Gene Veritas on Vimeo.

Alpar Lazar, Ph.D., Stephen Morairty, Ph.D., and Tom Warner, Ph.D., provided additional evidence about the importance of the sleep cycle.

Assuring the drug does its job

In the session on “huntingtin lowering biomarkers,” several presenters described cutting-edge techniques for measuring the efficacy of potential therapies designed to attack HD at its genetic roots and reduce the effects of the mutant huntingtin protein. Those projects include the above-mentioned CHDI-Genzyme venture and the Isis-Roche-CHDI partnership.

“What you’d like to do is make sure that after you administer one of those drugs, that the drug has done its job,” Dr. Pacifici explained. “We don’t want to wait for five years to measure hundreds of people only to find out that the drug never did its primary job, which was to lower huntingtin levels.”

Along with an expert task force, CHDI has developed a series of ways to determine huntingtin-lowering efficacy in humans within a period of weeks, he said.

“Because we want to know what’s going on in the human brain, and we can’t go in there and take a little chunk of brain out every couple of weeks, we have to figure out a way of non-invasively making those measurements,” Dr. Pacifici continued.

The techniques include quantitative EEG (a kind of brain mapping), magnetic resonances pectroscopy, assessment of dysfunction in the mitochondria (the powerhouses of the cell), and measurement of huntingtin in bodily fluids such as cerebral spinal fluid.

Scientists are developing ways to measure other types of potential HD remedies such as phosphodiesterase inhibitors (aka “Viagra for the brain”).

As the HD field moves towards clinical trials, CHDI has increasingly emphasized the need for the exchange of information between scientists in the lab and physicians and others focused on patients and clinical trials, Dr. Pacifici commented. Such teamwork will enhance the possibility of finding treatments, he said.

Supporting Enroll-HD

The conference also featured several activities promoting Enroll-HD.

First announced in 2010 and officially launched in 2012, the CHDI-sponsored Enroll-HD is building a worldwide registry of HD patients, HD gene carriers, untested at-risk individuals, family members, and volunteers. It aims to facilitate scientific understanding of HD, identify potential participants in clinical trials, and therefore speed the process of finding therapies.

In a pre-conference meeting of Enroll-HD physicians and administrators on February 23, participants focused on ways to use the project to improve patient care. On February 24, Enroll-HD’s international steering committee met to discuss administrative matters.

On February 25, the CHDI conference featured a practical lunchtime session that provided an update on program details like the number of participants.

A ‘matchmaker’ facilitating clinical trials

In order to deepen understanding of Huntington’s, Enroll-HD looks at individual and family histories of HD “over a long period of time,” Joe Giuliano, CHDI’s director of clinical operations and the chief Enroll-HD administrator, said in an interview on February 24.

“The vision for Enroll-HD is to provide a clinical research platform that can be used by the community of HD researchers around the world to do clinical studies, and it can be used by pharmaceutical sponsors to do clinical trials,” Giuliano explained. “It’s an enabling tool to help answer important questions about Huntington’s disease using clinical research.”

Giuliano described the program’s three levels: the international administration, the wide range of sites based in local communities (run by physicians and other health workers), and the HD families.

“It starts with families,” Giuliano said. “Enroll-HD is really a study for all the family to participate in.

“Enroll-HD is a great opportunity for us to come together as a global research community. The clinical trials that are going to lead ultimately to new therapies for Huntington’s disease are going to be conducted in global clinical trials…. The more people we can get in Enroll-HD, the more powerful the study can become, for example, for recruiting for clinical trials. Enroll-HD can help identify participants … who are eligible for clinical trials.”

This potential makes Enroll-HD “very attractive” for pharmaceutical companies to collaborate with the program, Giuliano said.

Enroll-HD is a “matchmaker” putting together researchers, patients, drug companies, and others, he continued.

Anybody in the HD community can participate, including unaffected relatives of HD people. “By joining Enroll-HD, you’re being very proactive in a lot of different ways,” he said. “You’re providing the possibility that you may be eligible for a future clinical trial.”

The larger the pool of potential participants, the faster trials can take place, he concluded.

You can watch my interview with Giuliano in the video below.

For other coverage of the conference, visit www.HDBuzz.net.

Coming soon: a detailed report and more videos on Enroll-HD.

What is Enroll-HD? An interview with Joe Giuliano from Gene Veritas on Vimeo.