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.
