Huntington’s disease (HD) is caused by a cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT); a gain-of-function mutation leading to the production of toxic mutant huntingtin (mHTT) protein.1 The degree of symptom severity, disease stage, and markers of neuronal damage have been shown to correlate with levels of the mHTT protein in the cerebrospinal fluid in individuals with HD. This toxic mHTT causes progressive neuronal degeneration, ultimately leading to neuronal cell death.1-4
The production of this toxic mutant huntingtin protein leads to progressive neuronal degeneration, ultimately leading to neuronal cell death.5 Levels of mHTT protein in cerebrospinal fluid have been shown to correlate with disease stage, symptom severity and markers of neuronal damage in people with HD.5
The exact mechanism by which mHTT protein causes neuronal death is still being elucidated; however, research suggests that it may interfere with a number of cellular processes such as DNA transcription and axonal transport.6
Researchers identified that the number of CAG trinucleotide repeat expansions in the huntingtin gene (HTT) has been shown to correlate with the age of disease onset.2,3 It is known that a CAG repeat length of ≥40 results in definite HD,1,7-10 CAG repeat length inversely correlates with age of onset,3,7 and other genetic and environmental factors may also affect disease progression.3,11
A blood test can be performed to determine the CAG repeat length.2,12 More information can be found on the NIH website.
Hear from researchers Nancy Wexler and Lauren Byrne on why the identification of the fundamental cause of HD was so significant, and how that finding informs today’s research into potential disease-modifying therapies that may slow or stop disease progression.
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