Huntington’s Disease is a neurodegenerative disorder that follows an autosomal dominant pattern of inheritance with complete penetrance. It is caused by a mutation that encodes an increase in CAG repeats, which encodes glutamine, in the N-terminus of the gene encoding Huntingtin (HTT) on chromosome 4. Normal individuals, typically have 9 to 36 CAG repeats, therefore Huntington’s disease is characterized by more than 36 CAG repeats. (Trottier 1995)
Onset of Huntington’s disease typically occurs later in life, around 30 to 40 years of age (though cases of juvenile Huntington’s disease exist). Phenotypically Huntington’s disease is characterized by motor dysfunction, cognitive disorders, personality changes, weight loss, and chorea appearing during typical age of onset. Mutant Huntingtin (mHTT) is a misfolded and toxic protein that alters the transcription and epigenetic regulation of dozens of proteins. (Valor 2014)
Treatment of Huntington’s is very limited and pharmacological drugs used in the treatment and management of Huntington’s predominantly only provide relief from the symptoms; drugs that help control movement disorders. However more potential drug candidates and drug targets are being found and understood faster than ever before. Research using HD models of Huntington’s Disease have provided potential new mechanism for treating Huntington’s disease, such as inhibition of histone deacetylase (HDAC). HDAC is activity is increased by mHTT, which subsequently leads to the inactivation of other genes. Introduction of an HDAC inhibitor can lower HDAC activity back to normal rates. However, to reduce the potential of an overdose from HDAC inhibition, increasing the levels of β-hydroxybutyrate (β-OHB), and endogenous HDAC inhibitor, via a ketogenic diet has been shown to improve the condition of Huntington’s disease and other neurodegenerative disorders. (Valor 2015)
Trottier, Y., D. Devys, G. Imbert, F. Saudou, I. An, Y. Lutz, C. Weber, Y. Agid, E. C. Hirsch, and J. L. Mandel. 1995. “Cellular Localization of the Huntington’s Disease Protein and Discrimination of the Normal and Mutated Form.” Nature Genetics 10 (1): 104–10. doi:10.1038/ng0595-104
Valor, Luis M. 2015. “Epigenetic-Based Therapies in the Preclinical and Clinical Treatment of Huntington’s Disease.” International Journal of Biochemistry & Cell Biology 67 (October): 45–48. doi:10.1016/j.biocel.2015.04.009.
Valor, Luis M., and Deisy Guiretti. 2014. “What’s Wrong with Epigenetics in Huntington’s Disease?” Neuropharmacology, Neuroepigenetic Disorders, 80 (May): 103–14. doi:10.1016/j.neuropharm.2013.10.025.