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Cause

Huntington disease (HD), a fatal neurodegenerative disorder characterized by progressive deterioration of cognitive and motor functions, is caused by an expansion of a trinucleotide (CAG) repeat encoding glutamine in the protein huntingtin. Neurodegeneration, the loss of structure and function of brain cells, occurs initially and most severely in the medium-spiny neurons of the striatum, and later in the deep layers of the cortex.

Diagnosis

Huntington disease is normally diagnosed in the clinic on the basis of motor performance (onset of chorea). Several other tests may also be performed and measured using the unified Huntington's disease rating scale in order to obtain an overall assessment of disease progression. As HD is an adult-onset disorder, individuals are generally between 35 and 50 years of age when onset of the motor symptoms occur. However, while rare, juvenile cases have been described. Subsequent to the clinical motor diagnosis, DNA testing is done to conclusively determine that it is HD. The DNA test measures the number of CAG repeats present in the HD gene and determines if it falls in the normal or expanded (HD) range. As there is an inverse correlation between CAG size and age of onset, for those individuals that have HD in the family but do not have symptoms, they can elect to have the HD gene test to determine if they will develop HD in the future.

Gene Silencing

One of the main goals in Huntington disease research at the present time is on gene silencing. In HD, an incorrect version of the HD gene is present. This in turn makes an incorrect version of the huntingtin protein (what is called mutant huntingtin).

If we can lower the amount, or get rid altogether, of the mutant huntingtin protein, this would decrease or remove the damage caused by the mutant protein and protect against its toxic effects. A number of techniques are currently being investigated which lower the amount of the mutant huntingtin protein. These are very important experiments and compounds are currently being testing in HD mouse models.

Excitotoxicity

This is a pathological process that involves dysfunction of glutamate receptors, in particular N-Methyl-D-aspartic acid (NMDA) receptors.Excitotoxins bind to these receptors and can cause excitotoxic stress due to high levels of calcium ions entering the cell, protease activation and eventual cell death.

Excitotoxic neuropathological changes are observed in Huntington disease and are considered to be an early event in the pathogenesis of this disease. Efforts are ongoing to screen drug libraries in order to identify inhibitors of excitotoxic stress. Once the compounds have been identified they are then tested in HD mouse models in order to determine if protection and amelioration of the symptoms is observed and to identify compounds that may prove beneficial in human clinical trials.

Excitotoxic neuropathological changes are observed in Huntington disease and are considered to be an early event in the pathogenesis of this disease. Efforts are ongoing to screen drug libraries in order to identify inhibitors of excitotoxic stress. Once the compounds have been identified they are then tested in HD mouse models in order to determine if protection and amelioration of the symptoms is observed and to identify compounds that may prove beneficial in human clinical trials.


Apoptosis

Programmed cell death or apoptosis is a program found within in all cells that once triggered leads to activation of caspases, cleavage of specific proteins and eventual death of the injured cell. This is a fundamental biological process essential for development and normal tissue homeostasis. In neurodegenerative diseases, alterations in components of the cell death machinery occur and enhance apoptosis. There is strong evidence to suggest that apoptotic events play a role in the neurodegeneration observed in HD. Work is ongoing to identify inhibitors and test them in cell and animal models of HD.

There are a number of other important Huntington disease research efforts, including stem cell research, also ongoing. Information on these, and current clinical trials, can be found in the websites below.


Websites for information on HD:

European HD Network: www.euro-hd.net/html/network

CHDI: www.highqfoundation.org

CMMT: www.cmmt.ubc.ca/outreach/hd-clinic

HDbuzz: en.hdbuzz.net

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