[Editor's note: This article is from 2007. Some newer treatments and current statistics are not included here. See further information on BrainWeb]
sections include: the genetics of Huntington's, diagnosis and treatment
Huntington’s disease (HD), previously referred to as Huntington’s chorea, is a hereditary neurological disorder. Typically, individuals who have inherited the responsible mutant gene see the first signs of illness in adulthood. The average age at HD onset is about 40, with an average duration of illness of about 20 years. Therefore, the “typical” individual who has inherited the HD gene spends the first two thirds of life healthy and the last one third with emerging and progressive features of HD. It should be noted, however, that the onset of HD may vary from as early as childhood to as late as the eighth decade of life.
The first signs of illness develop gradually over months or years. They consist of changes in movement and dexterity, alterations in personality and mood, and occasionally disordered thought and impaired judgment. The motor symptoms are perhaps the most conspicuous and uniform features of the disease. An individual who has previously been healthy, agile, and adroit gradually develops the symptoms of fidgeting, incoordination, impaired dexterity, and involuntary movement. Over time, dancelike movements referred to as chorea (from the same root as choreography) may appear in the person’s fingers, toes, face, head, neck, or torso. In some individuals, the movements may be very slow and take the form of posturing or dystonia (sustained muscle contractions). General movements often become slow (bradykinetic), leading to impaired coordination and dexterity.
As HD progresses, the person’s movements may become more intense or widespread, altering gait and balance. The involuntary movements frequently affect the muscle groups responsible for speaking and swallowing, resulting in slurred speech and difficulty eating and drinking. Eventually people with HD can no longer balance easily or take care of themselves because of the progressive worsening of their motor functions.
Changes in intellect, another cardinal feature of HD, may precede or follow motor symptoms by months or even years. The first signs of intellectual damage typically include an impaired ability to carry out a fluid sequence of tasks such as preparing a recipe, maintaining a changing work schedule, or overseeing family finances. Eventually a person’s memory, recall, and learning are affected. Many other intellectual operations, such as language and spatial and recognition processing, as well as the general fund of knowledge, may remain relatively well preserved. With time, however, a person’s progressive intellectual decline may affect his or her judgment, analytic skills, and capacity for self-care.
A variety of psychiatric disorders may develop in HD patients, some even preceding the motor symptoms. About 40 percent of HD patients develop features of depression, characterized by apathy, low mood, and poor self-esteem. At times, agitation and irritability may accompany the mood disorders. On occasion, the features of depression are cyclical, with periods of depressed mood alternating with intervals of unrealistic expectations and falsely elevated mood (bipolar disorder). About 10 percent of HD patients develop psychotic features—thought disorders, loss of one’s sense of reality, and paranoid thinking—virtually indistinguishable from schizophrenia.
Individuals and families who are aware of their risk for inheriting the HD gene may engage in “symptom searching.” They may interpret such common mishaps as dropping objects as a harbinger of illness, but we all fumble things sometimes. In contrast, people who are not aware of the HD gene in their family legacy may not recognize the symptoms for many months or years.
The Genetics of Huntington’s
George Huntington, an American physician, first described the clinical features of HD and its hereditary nature in 1872. More recently, the disorder has been definitively tied to a mutant gene. The origin of the HD mutation remains unknown, but it is likely that it arose in Europe several hundred years ago. With increasing migration, the HD gene has been distributed worldwide, but there are areas of high occurrence, such as the Lake Maracaibo region of Venezuela. In the United States, HD affects about 5 to 10 people in every 100,000, and about 30,000 individuals have the clinical features of HD. In addition, approximately 150,000 healthy individuals are at risk of having inherited the HD gene.
Huntington’s disease develops only in individuals who have inherited the gene responsible for this disorder from their mother or father. The HD gene is autosomal, meaning that men and women have equal risk of inheriting HD from an affected parent. The HD gene is also dominant, meaning that each offspring of an HD parent has a 50 percent risk of having inherited the gene. Most important, the HD gene is highly penetrant, meaning that individuals who have inherited it carry a 100 percent lifetime risk of developing the illness.
Over the past century researchers recognized that HD results from the mutated gene’s delayed but gradual adverse impact on particular regions of the brain responsible for the automatic (unconscious) operations controlling movement and intellect. Within the past two decades, the gene responsible for HD has been located in a region of DNA on the short arm of chromosome 4. This discovery has allowed healthy adults who are at risk for inheriting the HD gene to learn whether or not they carry it. Because there are no treatments to prevent, postpone, or slow the disorder, however, there are few practical rewards to knowing that one has the gene. Therefore, only a small proportion of individuals at risk for HD have decided to undergo DNA testing.
How the HD gene is triggered to cause selective brain neurons to die prematurely remains unclear. The gene is present in all tissues, but only certain regions of the brain are vulnerable. The basal ganglia and particularly the striatum (consisting of the caudate and putamen nuclei) are the regions most susceptible to the gene’s deleterious effects. Specific groups of cells in the striatum lose normal function and vitality, and eventually degenerate and are replaced by brain scar tissue (composed of glia, which fill in the space where the neurons they were supporting have died). The resulting shrunken basal ganglia can be seen through such neuroimaging techniques as computed tomography (CT) and magnetic resonance imaging (MRI). The selective degeneration of brain cells is progressive and parallels the onset and progression of illness and disability.
Diagnosis and Treatment
Although we can detect the presence or absence of the HD gene, a skilled and experienced neurologist or psychiatrist must still conduct a clinical evaluation of an individual to diagnose HD itself. A key to recognizing and confirming the disorder is a detailed and accurate family history that goes back for as many generations as possible. If an individual has a family history of HD, the presence of a movement disorder that cannot be explained otherwise, by medications or illness, confirms the diagnosis.
Although disorders of intellect and mood commonly occur in HD, and sometimes precede the characteristic difficulties with movement, they are not as specific or uniform in their appearance as the movement disorder. Furthermore, mood disorders like depression are common in the general population. Therefore, we do not use the isolated appearance of such disorders to confirm the diagnosis of HD.
Individuals who have features resembling HD but do not have (or cannot provide evidence for) a family history of the illness must undergo a rather deliberate and extensive evaluation. Neuroimaging tests such as CT and MRI may show evidence of loss of tissue (atrophy) in the area of the basal ganglia and striatum. With the necessary consent and counseling, these individuals may also be tested for the HD gene. The results of that testing will usually clarify whether the person’s symptoms are indeed due to HD.
We do not have medications to halt or slow the progression of HD. There are pharmacological treatments, including antipsychotic (dopamineblocking) drugs, to help suppress involuntary movements. The benefits of these medications are often transient, however, and they can have such adverse effects as excessively slowed movements, apathy, and problems with swallowing and speaking.
There are also drugs to treat some of the psychiatric disorders that accompany HD. People can manage depression effectively for many years using a variety of antidepressant medications; the new selective serotonin reuptake inhibitors (SSRIs) seem to be well-tolerated and effective antidepressants for HD. For individuals who develop psychotic features, a range of antipsychotic medications may help improve thinking, behavior, and functioning.
There are other, nonpharmacological interventions to help people with HD and their families, including genetic counseling; group and individual psychotherapy; and physical, speech, and occupational therapy. Effective care depends on counseling, a supportive environment, and help for the family as well as the individual. One concern for HD families is confidentiality, particularly for healthy individuals who are coping with the ramifications of their genetic risk and considering such aspects of life as having children, working, and buying insurance.
There remains no effective treatment to stem the degeneration of brain cells from HD and the progressive impairment and disability that result. However, we can see promise for the future in the remarkable revolution in our understanding of the HD gene over the last two decades. That advance gives us hope for developing a treatment to postpone or prevent the onset of HD. Researchers are also examining a variety of pharmacological and neurosurgical treatments. The outlook for substantive therapeutic gains within the next decade is good.
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