Huntington's Disease (HD)
by Giuliano Binetti
In 1872 G. Huntington described the variety of chorea that came to bear his name. His description contains all the essential features considered disgnostic of Huntington’s Disease (HD): a progressive disorders combining chorea with behavioral disturbances and dementia, transmitted via an autosomal dominant inheritance pattern. Huntington’s disease is the prototypic neurogenetic disorder, one of the first to be mapped (1983) and subsequently cloned (1993), and the model on which presymptomatic genetic testing is based.
Symptoms and course
It is usually apparent in the forth or fifth decades, but may occur at almost any age. No clear sex preponderance is evident. Low prevalence rates have been noted in Japan and among African and American blacks, and most patients are of northern European ancestry.
The clinical triad of movement disorder, psychiatric features, and eventual dementia will be well known to neurologists. Chorea is the first manifestation in about two thirds of patients, initially a mild fidgetiness apparent only to the careful observer, which gradually progresses and may be the only clinical manifestation of HD for several years. Personality change and eye movement disorders including slow saccades, and head thrusting or blinking to generate saccadic eye movements, are also common early features. A wide range of movement disorders including parkinsonism, loss of postural stability, and dystonia eventually supervene, leading to increasingly functional impairment. Progressive weight loss, often resulting in cachexia, is common. The juvenile onset form of HD may present with parkinsonism, the so-called Westphal variant, while late onset forms may cause chorea alone.
The majority of the patients exhibit neuropsychiatric symptoms, the most prevalent being dysphoria, agitation, irritability, apathy, and anxiety. Symptoms range from mild to severe and are unrelated to dementia and chorea. The cognitive disturbances associated to HD may begin early in the disease course and include deficit in attention and concentration, memory retrieval, “executive” functions, and psychomotor speed. The constellation of cognitive and behavior deficits associated with HD forms a so called “subcortical dementia syndrome” tht is distinct from the frank amnesia, aphasia, apraxia, and agnosia that embodies the cortical dementia syndrome associated to disorders such as Alzheimer disease. Death most often results from dysphagia through aspiration pneumonia or suffocation, usually between 10 and 20 years after the onset of symptoms. Suicide is also a common cause of death. Juvenile onset patients have a distinctly poorer prognosis than adults, with a high incidence of seizure disorders late in the course and a much shorter life expectancy. The onset of HD at later life is associated with a slower progression of symptoms.
The most important issue in the management of HD is the education of the patient and family about the disease and the implication of the diagnosis for other family mambers. The organisations are invaluable sources of information and support for HD families, as well as help with chronic care patients.
Causes and risk factors
Huntington's disease results from a genetic mutation on the fourth chromosome. This abnormality causes the death of vital nerve cells in a region of the brain known as the basal ganglia. HD is an autosomal dominant disorder, which means that each child of a parent with the disease has a 50 percent risk of inheriting the illness.
The huntington gene (IT15 gene) is considered virtually 100 percent “penetrant,” meaning that anyone who inherits the faulty gene will inevitably develop the disease. All “carriers” eventually become “patients.”
Prevalence of HD: People Currently Living with Disorder (US data: 30.000).
The IT15 gene is composed of 67 exons and encodes a protein of 3,144 amino acids, called huntington. Exon 1 contains a CAG trinucleotide repeat that encodes the amino acid glutamine, followed by another repeat that encodes proline. In unaffected individuals, there are 10–34 CAG repeats. In those affected by HD, there are more than 40 repeats. In those with 35–39 repeats, the disease is variably penetrant. The age of onset of the disease varies inversely with the number of CAG repeats. Individuals with juvenile onset usually have over 55 repeats, and they usually inherit the gene from their father.
The expansion is thought to occur via slippage during the DNA replication process. Expansion of a polyglutamine (CAG) trinucleotide repeat beyond the critical threshold of 36 repeats results in disease, and forms the basis of the polymerase chain reaction based genetic test. Inheritance is dominant with full penetrance, meaning that almost all mutation carriers will eventually develop the disease, except those with 36–39 repeats where penetrance is reduced.Predictive genetic testing of asymptomatic at-risk relatives of affected patients is governed by international guidelines. Prenatal testing in known mutation carriers is routinely available, while linkage based exclusion testing is available to those at-risk women who do not wish to know their own gene status. The latter depends on termination of a pregnancy where linkage shows the fetus to have the same 50% genetic risk as the mother.
Care and treatment
Chorea may respond to dopamine antagonists, both presynaptic (Tetrabenazine or reserpin) and postynaptic (neuroleptics such as haloperidol). The high incidence of serious adverse reactions to these agents limits their use where the movements disorder are truly disambling.
Ongoing research/Clinical trials
Current research is exploring possible drug treatments, which would prevent the accumulation of anomalous proteins in cells. Other research efforts include the development of a mouse model for Huntington's disease and the CARE-HD study, a clinical drug trial underway at about 20 Huntington Study Group sites. Researchers are evaluating the combination of a medication (remacimide) and co-enzyme Q-10. Both basic (laboratory) and clinical (testing of medications and treatments) research continues to pursue avenues to facilitate new drug testing and experimental surgical techniques.
International Huntington Association Callunahof 8 7217 ST Harfsen The Netherlands Tel: +31 - 573 - 431 595) Fax: +31 - 573 - 431 719 firstname.lastname@example.org www.huntington-assoc.com/
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- Feigin A, Zgaljardic D. disease: implications for experimental therapeutics.Curr Opin Neurol. 2002 Aug;15(4):483-9.
- McMurray CT. Huntington's disease: new hope for therapeutics.Trends Neurosci. 2001 Nov;24(11 Suppl):S32-8
Last Updated: vendredi 09 octobre 2009