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Huntington’s disease (HD) is at the center of one of the most remarkable stories of discovery in medical history. In 1872 George Huntington, a North American general practitioner, published the first unambiguous description of the unrelenting neurodegenerative disorder in The Medical and Surgical Reporter. The title of his article was simply “On Chorea” referring to the strange involuntary contorted movements made by people with HD. His description of this type of chorea as a specific hereditary disorder became quickly and widely accepted. Careful pedigrees of generations of HD families around the world have since confirmed his theory by documenting that 50% of the children of a parent with HD, will develop HD if they live long enough. That is, HD is an autosomal dominant hereditary disorder.
Simply put, HD is caused when one gene (or allele) of a usually healthy gene pair we all carry is abnormally elongated. This HD gene mutation is dominant, so that anyone who carries it will develop HD. Each child has a 50% chance of inheriting the mutated allele from a parent who has it, even if the parent has not yet developed any HD symptoms. On the bright side, the child also has a 50% chance of inheriting the HD parent’s healthy allele, in which case the child will never develop HD and will never pass it on. Until it is known for certain whether or not a descendant of a person with HD has inherited the HD mutation, that individual is said to be “at risk.” For example, when Woody Guthrie was diagnosed with HD, his children’s risk for developing HD became 50%, and if any of those children had children, they would immediately be at risk as well, but their risk would be 25%. If one of Woody’s children decided they wanted to know if they carried the gene and therefore would certainly develop the terrible disease, they could now undergo a predictive genetic test (although this wasn’t available when Woody Guthrie was diagnosed). If this predictive test was positive for the HD gene (or if they developed any HD symptoms) any children they had would now have a 50% risk of having the disease. If the predictive test showed that they did not carry the HD gene, their risk and the risk for any children of theirs would drop to zero.
HD symptoms usually become apparent between the ages of 35 and 45, although there may be subtle signs of the disease long before this. In rare cases, the symptoms do not become apparent until much later, even into the seventies. Chorea is the most common and prominent motor symptom and is usually amongst the earliest symptoms to develop, due to damage to the basal ganglia, a deep structure in the brain involved in motor movement. These random and abrupt movements usually progress over the course of the disease from restlessness with only a mild, intermittent exaggeration of expression and gesture, to fidgeting movements of the hands, to an unstable, writhing, dance-like gait, or a continuous flow of disabling, violent, “crazy-looking” movements. Sustained muscle contractions resulting in twisting, repetitive movements and abnormal postures are also common. Tremor can also occur in HD, although this is more often associated with Parkinson’s disease (PD), another movement disorder, but one that is not usually genetically determined. Other motor abnormalities that HD and PD have in common are rigidity and a slowness of movement that can result in freezing, a terrible symptom where the HD patient is unable to move. Gait abnormalities are obvious in patients who have had HD for some years, with a wide-based staggering gait—often mistaken for drunkenness—being a common feature. Fortunately, choreic movements largely cease during sleep, although in the latter stages of HD the patient may be sleepy during the day and wakeful at night.
Eye movement abnormalities occur early in the disease in most patients and gradually worsen, resulting in an increasing problem with focusing the eyes. Slurred speech is common, and early in the disease speech rate and rhythm are often abnormal, worsening over time until speech becomes unintelligible. Some patients become mute even before their motor disability is very severe. Eating difficulties involving inappropriate selection of food, inappropriate rate of eating, retention of food in the mouth after swallowing, and regurgitation. Choking and asphyxia are also common and distressing symptoms.
As HD progresses, other parts of the brain are affected, including the outermost neuronal layer of the brain—the cortex—and especially the frontal cortex, resulting in patients experiencing cognitive symptoms and ever-worsening “executive” impairments, including difficulties in abstract thinking and planning ahead, and problems shifting thoughts from one topic to another. In the latter stages of HD, serious loss of weight and muscle bulk occur in spite of an adequate diet and feeding. This is not simply the result of constant excessive movement but appears to be an integral aspect of HD.
Many patients with HD experience psychiatric symptoms. Depression is common, especially in the early stage of HD when the patient is fully aware of their condition and their grim and unalterable prognosis. Suicide rates are almost four times higher than in the healthy population. Many other psychiatric and behavioral problems are also common—the vast majority of HD sufferers regularly show signs of one or more of low mood, agitation, irritability, apathy, anxiety, an inability to inhibit inappropriate behaviors, and euphoria. Delusions and hallucinations are problems for a small number of HD patients. Other symptoms that cause concern for families, and which probably often arise from the psychiatric symptoms already mentioned, include moodiness, aggression, violent behaviors, hypersexuality, paranoid suspicions, lying, stealing, a loss of interest in personal appearance, marked self-neglect, and mutism. As the patient becomes more demented and loses insight, apathy may increase and depression decrease.
In the final stage, patients are severely physically disabled and demented, and thus totally dependent on others. About twenty percent of HD patients become incontinent near the end. Death usually results from a combination of weight loss, immobility, a tendency to aspirate food, and an increased vulnerability to pneumonia, cardiovascular disease, and other diseases.
There is currently no cure for HD and no way to delay its progression, and the only way to stop it affecting generation after generation of an HD family is by ensuring that no children are born with the gene. Thus couples where one partner is at risk for HD are increasingly opting for assisted fertilization options. For example, the genetic makeup of the fertilized eggs can be determined and an embryo without the HD gene re-implanted in the mother. Other alternatives including adoption, using a non-HD sperm or egg donor, or choosing not to have children are also increasingly used. All these decisions require genetic counseling, and in some countries, cultures, or religions, and in third world countries, none of these alternatives are permitted, acceptable, or available, often resulting in couples risking the birth of a child with the HD gene.
Studies have shown that 90% of people at risk for the HD gene decide NOT to have the predictive test. Clearly for most people the 50% chance that you will discover that you have the gene is worse than not knowing and retaining the hope that you will not have it. In most countries, while it is permitted to test an embryo for the HD gene, once a child is born, parents cannot choose to have him or her tested; children must be old enough to decide for themselves, usually in their late teenage years or older.
In common with a number of other medical conditions, the stimulus for setting up research and support institutions for HD came initially from individuals who had themselves been personally affected by the disease. “The Hereditary Disease Foundation,” which promotes research into HD, was initiated by Dr. Milton Wexler after his wife died from HD and is continued by his daughter, Dr. Nancy Wexler. The foundation has played a central role in the remarkable study that began in 1979 of a large HD population living by the shores of Lake Maracaibo in Venezuela. This group is the best example of how quickly a dominantly inherited genetic disorder can take over a small, isolated community. Painstaking research has revealed that one ancestor with HD who lived in the early 1800s has so far left more than 18 thousand descendants, 14 thousand of whom are still alive today and many of whom have HD or are at risk for it. This detailed and unique pedigree was a crucial factor in locating, in 1983, the approximate location of the gene involved in HD. In 1993 after further painstaking work by many research groups in the US and UK, a group lead by Harvard Medical School researcher, James Gusella, isolated the precise causal gene and identified the mutation of the gene that causes the disease. At this point an expanded group, called the “Huntington’s Disease Collaborative Research Group,” published its findings. This group was a collaboration of six US and British research teams, and although Gusella’s team isolated the gene, the credit was rightly given to the entire collaboration, as the research that preceded the gene’s precise identification was an essential aspect of the discovery. This truly collaborative effort is a superb example of how medical and other scientific research should be conducted—a cooperative endeavor motivated by the determination to find the truth and make a difference, rather than by competition and the desire for personal aggrandizement.
Marjorie Guthrie, the wife of the iconic American folksinger, Woody Guthrie, who developed HD symptoms around 1952 and died in 1967 when he was only 55, founded the “Committee to Combat Huntington’s Disease,” which led to the formation of the “Huntington’s Disease Society of America.” The aim of this society is to promote education, research, and services for families of HD sufferers. (Much of the above information about HD has been excerpted from my book Trouble In Mind: Stories from a Neuropsychologist’s Casebook.” The true and moving story of an amazing family and how they coped with HD (and it has an uplifting ending!) can be read in that book—the chapter is named for one of Woody Guthrie’s songs, in his and Marjorie Guthrie’s honor: “Hard, Ain’t It Hard: A Family’s Fight with Huntington’s Disease.”) Recent novels featuring HD include Lisa Genova’s book Inside the O’Briens, which is the intense story of a Boston family and their struggle with the disease, and my own new novel A Drop in the Ocean in which HD plays a part (but is not the central theme as it is in Genova's novel).
