Huntington Disease


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Huntington Disease

 

Definition

Huntington disease (HD) is a progressive neuro-degenerative disease causing uncontrolled physical movements and mental deterioration. The disease was discovered by George Sumner Huntington (1850–1916), an Ohio doctor who first described the hereditary movement disorder in 1872.

Description

Huntington disease is also called Huntington chorea or hereditary chorea. The word chorea comes from the Greek word for "dance" and refers to the involuntary movements of the patient's feet, lower arms, and face that develop as the disease progresses. It is occasionally referred to as "Woody Guthrie's disease" for the American folk singer who died from it. Huntington disease (HD) causes progressive loss of cells in areas of the brain responsible for certain aspects of movement control and mental abilities. A person with HD gradually develops abnormal movements and changes in cognition (thinking), behavior and personality.
The onset of symptoms of HD usually occurs between the ages of 30 and 50; although in 10% of cases, onset is in late childhood or early adolescence. Approximately 30,000 people in the United States are affected by HD, with another 150,000 at risk for developing this disorder. The frequency of HD is 4-7 cases per 100,000 persons.

Causes and symptoms

Huntington disease is caused by a defect in the HD gene (an inherited unit which contains a code for a protein), which is located on the short arm of chromosome 4. The gene codes for a protein called huntingtin, whose function is not known as of early 2005. The nucleotide codes (building blocks of genes arranged in a specific code which chemically forms into proteins), contain CAG repeats (40 or more of these repeat sequences). The extra building blocks in the huntingtin gene cause the protein that is made from it to contain an extra section as well. It is currently thought that this extra protein section, or portion, interacts with other proteins in brain cells where it occurs, and that this interaction ultimately leads to cell death.
The HD gene is a dominant gene, meaning that only one copy of it is needed to develop the disease. HD affects both males and females. The gene may be inherited from either parent, who will also be affected by the disease. A parent with the HD gene has a 50% chance of passing it on to each offspring. The chances of passing on the HD gene are not affected by the results of previous pregnancies.
The symptoms of HD fall into three categories: motor or movement symptoms; personality and behavioral changes; and cognitive decline. The severity and rate of progression of each type of symptom can vary from person to person.
Early motor symptoms include restlessness, twitching and a desire to move about. Handwriting may become less controlled, and coordination may decline. Later symptoms include:
  • dystonia, or sustained abnormal postures, including facial grimaces, a twisted neck, or an arched back
  • chorea, in which involuntary jerking, twisting or writhing motions become pronounced
  • slowness of voluntary movements, inability to regulate the speed or force of movements, inability to initiate movement and slowed reactions
  • difficulty speaking and swallowing due to involvement of the throat muscles
  • localized or generalized weakness and impaired balance ability
  • rigidity, especially in late-stage disease
Personality and behavioral changes include depression, irritability, anxiety and apathy. The person with HD may become impulsive, aggressive or socially withdrawn.
Cognitive changes include loss of ability to plan and execute routine tasks, slowed thought, and impaired or inappropriate judgment. Short-term memory loss usually occurs, although long-term memory is usually not affected. The person with late-stage HD usually retains knowledge of his environment and recognizes family members or other loved ones, despite severe cognitive decline.

Diagnosis

Diagnosis of HD begins with a detailed medical history, and a thorough physical and neurological examination. The family's medical history is very important. Magnetic resonance imaging (MRI) or computed tomography scan (CT scan) imaging may be performed to look for degeneration in the basal ganglia and cortex, the brain regions most affected in HD.
Physicians have recently developed a Uniform Huntington's Disease Rating Scale, or UHDRS, to assess a patient's symptoms and the speed of progression of the disease.
A genetic test is available for confirmation of the clinical diagnosis. In this test, a small blood sample is taken, and DNA from it is analyzed to determine the CAG repeat number. A person with a repeat number of 30 or below will not develop HD. A person with a repeat number between 35 and 40 may not develop the disease within their normal lifespan. A person with a very high number of repeats (70 or above) is likely to develop the juvenile-onset form. An important part of genetic testing is extensive genetic counseling.
Prenatal testing is available. A person at risk for HD (a child of an affected person) may obtain fetal testing without determining whether she herself carries the gene. This test, also called a linkage test, examines the pattern of DNA near the gene in both parent and fetus, but does not analyze for the triple nucleotide repeat (CAG). If the DNA patterns do not match, the fetus can be assumed not to have inherited the HD gene, even if present in the parent. A pattern match indicates the fetus probably has the same genetic makeup of the at-risk parent.

Treatment

There is no cure for HD, nor any treatment that can slow the rate of progression. Treatment is aimed at reducing the disability caused by the motor impairments, and treating behavioral and emotional symptoms.
Physical therapy is used to maintain strength and compensate for lost strength and balance. Stretching and range of motion exercises help minimize contracture, or muscle shortening, a result of weakness and disuse. The physical therapist also advises on the use of mobility aids such as walkers or wheelchairs.
Motor symptoms may be treated with drugs, although some studies suggest that anti-chorea treatment rarely improves function. Chorea (movements caused by abnormal muscle contractions) can be suppressed with drugs that deplete dopamine, an important brain chemical regulating movement. As HD progresses, natural dopamine levels fall, leading to loss of chorea and an increase in rigidity and movement slowness. Treatment with L-dopa (which resupplies dopamine) may be of some value. Frequent reassessment of the effectiveness and appropriateness of any drug therapy is necessary.
Occupational therapy is used to design compensatory strategies for lost abilities in the activities of daily living, such as eating, dressing, and grooming. The occupational therapist advises on modifications to the home that improve safety, accessibility, and comfort.
Difficulty swallowing may be lessened by preparation of softer foods, blending food in an electric blender, and taking care to eat slowly and carefully. Use of a straw for all liquids can help. The potential for choking on food is a concern, especially late in the disease progression. Caregivers should learn the use of the Heimlich maneuver. In addition, passage of food into the airways increases the risk for pneumonia. A gastric feeding tube may be needed, if swallowing becomes too difficult or dangerous.
Speech difficulties may be partially compensated by using picture boards or other augmentative communication devices. Loss of cognitive ability affects both speech production and understanding. A speech-language pathologist can work with the family to develop simplified and more directed communication strategies, including speaking slowly, using simple words, and repeating sentences exactly.
Early behavioral changes, including depression and anxiety, may respond to drug therapy. Maintaining a calm, familiar, and secure environment is useful as the disease progresses. Support groups for both patients and caregivers form an important part of treatment.
Experimental transplant of fetal brain tissue has been attempted in a few HD patients. Early results show some promise, but further trials are needed to establish the effectiveness of this treatment.
Tetrabenazine (Nitoman), a drug that has been considered investigational in the United States, appears to benefit some patients with HD by controlling the involuntary movements of chorea. It works by lowering the levels of dopamine and other neurotransmitters in the brain. The Food and Drug Administration (FDA) granted tetrabenazine fast-track and orphan drug status in the United States as of 2004. It is not yet manufactured in the United States but can be obtained from the United Kingdom.
In 2004 the Food and Drug Administration (FDA) also approved deep brain stimulation (DBS) as an acceptable treatment for HD and other movement disorders. In DBS, the surgeon implants a battery-operated medical device called a neurostimulator, which delivers electrical impulses to the areas of the brain that govern movement. In the case of Huntington's patients, the part of the brain that is targeted is a structure called the globus pallidus. It is thought that DBS works by increasing the flow of blood to this area. A group of Canadian researchers reported in 2004 that some patients with HD are better able to control their movements after DBS of the globus pallidus.
Psychotherapy is often recommended for individuals who know themselves to be at risk for the disease. Some persons want to know their risk status while others prefer not to be tested. Psychotherapy may be useful in helping at-risk persons decide about testing as well as coping with the results of the test.

Prognosis

The person with Huntington disease may be able to maintain a job for several years after diagnosis, despite the increase in disability. Loss of cognitive functions and increase in motor and behavioral symptoms eventually prevent the person with HD from continuing employment. Ultimately, severe motor symptoms prevent mobility. Death usually occurs between 10 and 30 years after disease onset, typically as the result of pneumonia or a fall. Progressive weakness of respiratory and swallowing muscles leads to increased risk of respiratory infection and choking, the most common causes of death. Future research in this area is currently focusing on nerve cell transplantation.

Key terms

Basal ganglia — A structure at the base of the brain composed of four groups of nerve cells, responsible for body movements and coordination.
Chorea — Brief and purposeless involuntary movements of the lower arms, feet, and face.
Chromosome — The structures that carry genetic information. Chromosomes are located within every cell, and are responsible for directing the development and functioning of all the cells in the body. The normal number is 46 (23 pairs).
Cortex — The part of the brain responsible for thought, memory, and sensory perception.
Dystonia — A movement disorder characterized by sustained muscle contractions that result in writhing or twisting movements and unsual body postures.
Globus pallidus — A pale-colored spherical structure within the basal ganglia. Deep brain stimulation of this area is helpful in controlling the chorea of some patients with HD.
Huntingtin — A protein of unknown function encoded by the HD gene. The repeated CAG sequence in a defective HD gene causes the body to produce an abnormal form of huntingtin. It is not yet known why the abnormal form of huntingtin affects only certain regions of the brain.
Orphan drug — A term for a drug that treats a rare disease, defined by the Food and Drug Administration (FDA) as one that affects fewer than 200,000 Americans. The FDA has an Office of Orphan Products Development (OOPD), which offers grants to researchers to develop these products.
Tetrabenazine — A drug given to control chorea that appears to benefit HD patients.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD., editors. "Disorders of Movement." Section 14, Chapter 179 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

Montgomery, E. B., Jr. "Deep Brain Stimulation for Hyperkinetic Disorders." Neurosurgical Focus 17 (July 15, 2004): E1.
Moro, E., A. E. Lang, A. P. Strafella, et al. "Bilateral Globus Pallidus Stimulation for Huntington's Disease." Annals of Neurology 56 (August 2004): 290-294.
Revilla, Fredy J., MD, and Jaime Grutzendler, MD. "Huntington Disease." eMedicine November 3, 2004. http://www.emedicine.com/NEURO/topic81.htm.
Richartz, E. R., and C. Frank. "A Psychodynamic Approach in Counselling Vulnerable Persons for Chorea Huntington—A Case Report." [in German] Psychiatrische Praxis 31 (July 2004): 255-258.
Seneca, S., D. Fagnart, K. Keymolen, et al. "Early-Onset Huntington Disease: A Neuronal Degeneration Syndrome." European Journal of Pediatrics 26 (August 2004): e-pub.

Organizations

Huntington Disease Society of America. 140 W. 22nd St. New York, NY 10011. (800) 345-HDSA.
National Institute of Neurological Disorders and Stroke (NINDS). NIH Neurological Institute, P. O. Box 5801, Bethesda, MD 20824. (800) 352-9424 or (301) 496-5751. http://www.ninds.nih.gov.
National Organization for Rare Disorders (NORD). 55 Kenosia Avenue, P. O. Box 1968, Danbury, CT 06813-1968. (203) 744-0100. Fax: (203) 798-2291. http://www.rarediseases.org.
United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFOFDA. http://www.fda.gov.

Other

Food and Drug Administration (FDA). "Grants Awarded by the OOPD Program." http://www.fda.gov/orphan/grants/previous.htm.
National Institute of Neurological Disorders and Stroke (NINDS). "Huntington's Disease: Hope Through Research." NIH Publication No. 98-49. Bethesda, MD: NINDS, 2005. http://www.ninds.nih.gov/disorders/huntington/detail_huntington.htm.
National Institute of Neurological Disorders and Stroke (NINDS). "NINDS Deep Brain Stimulation for Parkinson's Disease Information Page." Bethesda, MD: NINDS, 2004. http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm.

Hun·ting·ton cho·re·a

(hunt'ing-ton), [MIM*143100]
a neurodegenerative disorder, with onset usually in the third or fourth decade, characterized by chorea and dementia; pathologically, there is bilateral marked atrophy of the putamen and the head of the caudate nucleus. Autosomal dominant inheritance with complete penetrance, caused by mutation associated with trinucleotide repeat expansion in the Huntington gene (HD) on chromosome 4p.

Hunt·ing·ton cho·re·a

(hŭn'ting-tŏn kŏ-rē'ă)
A neurodegenerative disorder, with onset usually in the third or fourth decade, characterized by chorea and dementia; pathologically, there is bilateral marked atrophy of the putamen and the head of the caudate nucleus. Autosomal dominant inheritance with complete penetrance, caused by mutation associated with trinucleotide repeat expansion in the Huntington gene (HD) on chromosome 4p.
Synonym(s): hereditary chorea, Huntington disease.
[L. fr. G. choreia, a choral dance, fr. choros, a dance]

Huntington,

George, U.S. physician, 1850-1916.
Huntington chorea - an inherited degenerative disorder of the cerebral cortex and corpus striatum. Synonym(s): chronic progressive chorea; degenerative chorea; hereditary chorea; Huntington disease
Huntington disease - Synonym(s): Huntington chorea
References in periodicals archive ?
The investigators also showed that increasing levels of RCAN1-1L rescues cells from the toxic effects of Huntington disease, a result that could someday lead to new avenues of treatment.
Further proof of protection by RCAN1-1L will be required in-vivo, or in actual Huntington disease patients," Ermak added.
Ray Dorsey, Professor of Neurology at the University of Rochester and the Principal Investigator on the trial added: "We are very pleased that the results of the Reach2HD study have shown that PBT2 is well tolerated and generally safe over six months in individuals with early to mid-stage Huntington disease.
We are very thankful for the involvement of the research participants and investigators in this study and look forward to future trials of this promising therapy for one of the cardinal features of Huntington disease.
Based on the promising results of our Phase 2 trial of dimebon in Huntington disease, we are pleased to advance dimebon into late-stage clinical development," said Lynn Seely, M.
Orphan drug designation entitles Pfizer and Medivation to a seven-year period of marketing exclusivity in the United States for dimebon if it is approved by the FDA for the treatment of Huntington disease.
Huntington disease is a familial disease, passed from parent to child through a mutation in a gene.
is a non-profit organization pursuing a biotech approach to rapidly discover and develop drugs that prevent or slow Huntington disease.
ActiveSight's Fragment-based Lead Discovery technologies strengthen our diversified portfolio of parallel drug discovery and development campaigns for Huntington Disease," said Robert Pacifici, Ph.
We are pleased to have the opportunity to work with CHDI to discover new treatments for Huntington Disease," said Duncan McRee, Ph.
has signed a license agreement enabling it to provide behavioral phenotyping and compound evaluation services using the transgenic R6/2 mouse model for Huntington Disease.

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