Huntington's Disease (HD)
Huntington's disease is a hereditary brain disease which disrupts thinking, mood, behavior, and movement. It is named after Dr. George Huntington, who first described the disorder in his essay, On Chorea, in 1872. HD occurs in all regions of the world and in all ethnic populations. In the United States, HD affects about 2 to 10 per 100,000 people, but in certain regions of the world, like Lake Maracaibo, Venezuela and Moray Firth, Scotland, the prevalence is much higher. Both men and woman may inherit the gene that causes HD. HD usually begins in adulthood but may arise in children.
Chorea consists of involuntary, continuous, abrupt, rapid and brief, irregular movements that flow randomly from one body part to another. The term derives from the Latin word for dance, but chorea is patternless, unlike most forms of dance. Patients can partially and temporarily suppress choreic movements and frequently camouflage some muscle jerks by incorporating them into purposeful activities. Chorea may be disabling because it interferes with voluntary movements, resulting in clumsiness, speech and swallowing difficulty, as well as loss of balance. Although chorea is the clinical hallmark of HD, other movement problems, such as dystonia (sustained muscle contractions resulting in abnormal postures), myoclonus (very rapid jerk-like movements), rigidity (muscle stiffness), and bradykinesia (slowness of movement) often co-exist.
Cognitive decline and various psychiatric symptoms may precede the motor manifestations of HD. The neurobehavioral symptoms typically consist of personality changes, apathy, social withdrawal, anxiety, impulsiveness, depression, mania, paranoia, delusions, hostility, sleep disturbances, hallucinations, or psychosis. Cognitive changes, manifested chiefly by loss of short-term memory, poor judgment, and impaired concentration, occur in nearly all patients with HD; however, some patients with late-onset chorea never develop dementia.
Onset of Disease
The usual peak age of onset is in the 4th and 5th decade, but about 10 percent of HD cases have their onset before age 20 (juvenile HD). Juvenile HD typically presents with the combination of progressive parkinsonism (slowness of movements), dementia, incoordination, and seizures. In contrast, adult HD usually presents with the gradual onset of clumsiness, chorea, and personality changes.
Before the advent of a genetic blood test, the diagnosis of HD was based upon the typical clinical presentation and a positive family history of HD, supported by the findings of atrophy (shrinkage) of the caudate nucleus on brain imaging. Today, DNA testing can reliably diagnose HD and differentiate the disease from other disorders that cause similar symptoms. DNA testing is also available for family members of patients with HD who may not have symptoms but are at risk for the disease. However, because of potential psychological and legal implications of identifying a HD gene mutation in an asymptomatic, at-risk individual, predictive testing should be performed by a team of clinicians and geneticists who are knowledgeable about the disease and genetic techniques and who are sensitive to the psychosocial and ethical issues associated with such testing.
HD is a genetic disorder, inherited in an autosomal dominant pattern, which means that each child of an affected parent has a 50 percent chance of inheriting the disease-causing gene. Individuals who inherit the HD gene almost always develop the symptoms of HD, usually at the same age as their affected parent or earlier.
The gene responsible for HD is IT15, which is located on the short arm of chromosome 4 (4p16.3). This gene produces a protein known as huntingtin, whose function remains unknown. The mutation that causes HD consists of an unstable enlargement of the gene's CAG (cytosine-adenine-guanine) repeat sequence, which results in an abnormal elongation of the huntingtin protein. Normally, the number of CAG repeats is less than 29, while in persons with HD the gene usually contains more than 36 repeats. It is unclear whether individuals with between 29 and 36 CAG repeats, will develop symptoms of HD, but they may transmit HD to their children because the number of repeats grows over successive generations. The degree of repeat expansion over a generation is usually greater when the gene is inherited from one's father. The number of repeats inversely correlates with the age at onset, such that children with HD may have 100 CAG repeats or more. Accordingly, young-onset patients usually inherit the disease from their father while older-onset patients are more likely to inherit the gene from their mother. There is no difference in the mean number of repeats between patients presenting with psychiatric symptoms and those with chorea and other motor disorders, though the rigid juvenile patients have the largest number of repeats.
Role of Gene Mutation
HD causes neuronal (nerve cell) loss and gliosis (scarring) in the cerebral cortex and the basal ganglia, particularly the caudate nucleus. In advanced disease, degeneration of the hippocampus, angular gyrus and hypothalamus may be seen. GABAergic medium spiny neurons are the most degenerated neurons in HD. Damage is thought to result from a toxic effect of the elongated HD protein, rather than loss of this protein's normal function. Many hypotheses have been proposed to explain how the abnormal protein causes selective loss of nerve cells, but the exact mechanism is not yet fully understood. The mutant huntingtin protein alters intracellular calcium homeostasis, disrupts intracellular trafficking and impairs gene transcription. Aggregates of mutated huntingtin protein may impair energy metabolism leading to neuronal damage. It has been also suggested that certain neurons become "exhausted" as a result of prolonged excitatory neurotransmission. Other studies have provided evidence that HD may cause damage through toxic free-radicals, and for this reason, researchers are studying whether antioxidants may be useful as a therapy for HD. Further insight into the action of this protein should lead to an improved understanding of HD with possible implications for future treatment. A new study found that dysregulation of the PGC-1 Alpha gene, which is involved in energy metabolism, provides variation in the onset of motor symptoms. Understanding the role of this gene is another target for future research.
Since the exact cause of cell loss in HD has not yet been established, only symptomatic treatment is currently available for HD patients. A variety of experimental drugs for HD have been tested at Baylor, but none appear to slow the course of the disease, so the search for truly neuroprotective drugs continues.
Xenazine® (tetrabenazine) is the only FDA approved medication for Huntington's disease and has been the most effective anti-chorea drug in our experience. Tetrabenazine does not cause tardive dyskinesia, but, similar to other neuroleptics, it may cause slowness of movement, drowsiness, restlessness or mood changes. Prior to the drug's general FDA approval, Dr. Jankovic received special permission from the FDA (via an investigation new drug permit) to prescribe tetrabenazine in 1979 and has used the drug has since that time in well over a thousand patients, including those with HD.
Psychosis may improve with neuroleptics (drugs that block dopamine receptors), such as haloperidol, pimozide, fluphenazine, and thioridazine. These drugs, however, can induce tardive dyskinesia (manifested by involuntary movements other than chorea), and should only be used if absolutely needed to control symptoms. Clozapine, an atypical antipsychotic (neuroleptic) drug that does not cause tardive dyskinesia, may be a useful alternative to the typical neuroleptics, but the risk of agranulocytosis (a very low white cell count) complicates its use. Other atypical neuroleptics such as olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon) do not need close monitoring and may be easier to use, but are less effective in controlling chorea. Other medications for memory loss, depression and anxiety also may be useful in some HD patients.
Neurotrophic factors, which play an important role in the cell differentiation and the prevention of cell death are thought to play an important role in neuroprotection in HD, and it is hoped that they will be adopted as a therapeutic tool for HD treatment. A deficiency in such factors affects neuroplasticity of the central nervous system and can ultimately contribute to neural death. It has been found that some of these factors, such as brain-derived neurotrophic factor (BDNF), have a diminished presence in HD mouse models. It is possible a deficit of neurotrophic factor levels in HD is linked to the action of mutant huntingtin protein in the transport of these factors. HD mouse models exploring the role of BDNF, as well as fibroblast growth factor (FGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and neurturin, have shown restoration in neuronal dysfunction, improved behavioral deficits and prolonged survival depending upon the factor, dosage and delivery technique. A recent study also investigated the therapeutic potential of human bone marrow-derived mesenchymal stem cells in HD mouse models with trophic support. Over 10 weeks, a significant reduction in motor function impairment and increased survival rate were found and thought attributable to neural differentiation improvement potential, neurotrophic support and an anti-apoptotic effect. These findings are not generalizable to humans at this time; however, these studies provide continued hope for the development of new therapies for HD.
The Movement Disorders Clinic at Baylor College of Medicine has been designated as a Center of Excellence by the Huntington's Disease Society of America. It is also a member of the Huntington Study Group, a consortium of academic clinicians and researchers interested in finding the cause of neurodegeneration in HD and designing therapeutic trials of new medications.
Huntington's Disease Society of America
505 Eighth Avenue, Suite 902
New York, NY 10018
Phone: (212) 242-1968
Toll free: (800) 345-HDSA (4372)
Toll free: (888) HDSA-506 (helpline number)
Fax: (212) 239-3430
Huntington Study Group
2604 Elmwood Avenue, Suite 335
Rochester, NY 14618-2295
Toll free: (800) 487-7671 (North America)
Fax: (585) 672-9912
J. Jankovic, M.D., Director
HDSA Center of Excellence
Movement Disorders Center
Baylor College of Medicine
Department of Neurology
6550 Fannin St., Suite 1801
Houston, TX 77030
©2011 Joseph Jankovic, M.D.
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