Huntington's Disease (HD)

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What is Huntington’s disease (HD)?

Huntington's disease (HD) 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.

What are the motor symptoms of HD?

Chorea consists of involuntary, continuous, abrupt, rapid, brief, irregular movements that flow randomly from one body part to another. The term derives from the Latin word for a circular 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, and loss of balance. Although chorea is the clinical hallmark of HD, other movement problems, such as dystonia (more sustained muscle contractions resulting in abnormal postures), myoclonus (very rapid jerk-like movements), rigidity (muscle stiffness), bradykinesia (slowness of movement) often co-exist.

What are the non-motor symptoms of HD?

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.

When and how does HD usually start?

The usual peak age of onset is in the 4th and 5th decade, but about 10% 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.

What causes HD?

HD is a genetic disorder, inherited in an autosomal dominant pattern, which means that each child of an affected parent has a 50% 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; although, as expected, the rigid juvenile patients have the largest number of repeats.

How is HD diagnosed?

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.

How does the gene mutation lead to disease?

HD causes neuronal (nerve cell) loss and gliosis (scarring) in the cerebral cortex and the basal ganglia, particularly the caudate nucleus. 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. One hypothesis suggests that aggregates of mutated huntingtin protein impair energy metabolism leading to neuronal damage. It has been also suggested that in HD, as a result of prolonged excitatory neurotransmission, certain neurons become “exhausted.” 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.

How is HD treated?

Since the exact cause of cell loss in HD has not yet been established, only symptomatic treatment is currently available for HD patients. 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), so they 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 its 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. In our experience the most effective anti-chorea drug is tetrabenazine. Tetrabenazine does not cause tardive dyskinesia, but, similar to other neuroleptics, it may cause slowness of movement, drowsiness, restlessness or mood changes. Tetrabenazine is not yet readily available in the United States, although it may be approved by the Food and Drug Administration (FDA) in 2008. Dr. Jankovic, however, received special permission (an investigational new drug permit) from the FDA to prescribe tetrabenazine in 1979 and has used the drug has since that time in well over a thousand patients, including those with HD. Other medications for memory loss, depression and anxiety also may be useful in some HD patients with these problems. A variety of other experimental drugs for HD have been tested at Baylor, but none appear to slow the course of the disease, so the search for true neuroprotective drugs continues.

The Movement Disorders Clinic at Baylor College of Medicine has been designated as a Center of Excellence by the HD 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.

Selected References

Fahn S, Jankovic J. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2007:1-652. (Accompanied by a DVD of movement disorders).
Helder DI, Kaptein AA, van Kempen GMJ, et al. Impact of Huntington’s disease on quality of life. Mov Disord 2001;16:325-330.
Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001;57:397-404.
Jankovic J. Huntington’s disease. In: Noseworthy J, editor-in-chief, Neurological Therapeutics: Principles and Practice, 2nd Edition, Informa Healthcare, Milton Park, Abingdon, Oxon, UK, 2006:2869-2881.
Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders, 5th edition, Lippincott Williams and Wilkins, Philadelphia, PA, 2007:1-720. (Accompanied by a CD video atlas).
Jankovic J, Shannon KM. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice, 5th Edition, Butterworth-Heinemann (Elsevier), Philadelphia, PA, 2008.
Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabenazine on chorea associated with Huntington disease. Mov Disord. 2007;22:10-3.
Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington disease with 29 trinucleotide repeats. Mov Disord. 2007;22:127-30.
Marshall FJ, Walker F, Frank S, Oakes D, Plumb S, Factor SA, Hunt VP, Jankovic J, Shinaman A, Shoulson I, and the Huntington Study Group.Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006;66:366-72.
Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treatment for Huntington’s disease-associated chorea. Clin Neuropharmacol 2002;25:300-302.
Paulsen JS, Ready RE, Hamilton JM, et al. Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry 2001;71:310-314.
Tan E-K, Jankovic J. Bruxism in Huntington’s disease. Mov Disord 2000;15:171-173.
Thomas M, Le W, Jankovic J. Minocycline and other tetracycline derivatives: A neuroprotective strategy in Parkinson’s disease and Huntington’s disease. Clin Neuropharmacol 2003;26:18-23.
Tibben A. Predictive testing for Huntington's disease. Brain Res Bull. 2007;72:165-71.
Walker FO. Huntington's Disease. Semin Neurol. 2007;27:143-50.

Appendix

Huntington’s Disease Society of America (HDSA)
158 West 29 th Street, 7 th Floor
New York, NY 10001
Tel: 212-242-1968
Fax: 212-239-3430
http://www.hdsa.org

Huntington Study Group
Tel: 800-942-0424
http://www.huntington-study-group.org

International Huntington Association
Gerrit Dommerholt
Callunahof 8, 7217 ST Harfsen
The Netherlands
Tel: 31-573311595
Fax: 31-703500050
http://www.hdlighthouse.org

J. Jankovic, M.D., Director
HDSA Center of Excellence
Movement Disorders Center
Baylor College of Medicine
Department of Neurology
6550 Fannin, Suite #1801
Houston, Texas 77030

Other related websites:
http://clix.to/HDSupportInfo
http://www.wemove.org

For additional information visit http://www.bcm.edu/neurology/pdcmdc/