DEFINITION

Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder characterized by progressive motor and cognitive dysfunction, as well as psychiatric disorders.

• HD onset is typically mid-life (30-50 with outliers in either direction) with an insidious and progressive course[1].
  • It is a fatal disorder for which there are no disease-modifying therapies, though symptomatic treatments are available.
• HD is caused by a CAG expansion mutation in the huntingtin (HTT) gene that affects the N-terminal polyglutamine of the encoded huntingtin protein.
  • The length of the CAG repeat explains 50-70% of the variance in age of onset and the rate of disease progression. Longer repeats tend to be associated with earlier onset and more rapid progression, but there are many exceptions as well, likely due to genetic modifiers and other factors.
  • CAG repeat count > 39 leads to HD with full penetrance.
  • New approaches for staging HD based on CAG repeat length as well as emerging biomarker data have been proposed but are not in use yet[2].
• The precise mechanisms connecting mutant huntingtin to neurodegeneration are not completely understood; proteotoxic interference with various cellular processes are thought to contribute.
  • Several agents that seek to exert disease-modifying effects by lowering Htt levels—notably anti-sense oligonucleotide (ASO) formulations—are in development, but results so far have been disappointing[3]. Improvements are being made in the ASO and trial designs.
• Pathologically, HD causes selective degeneration of the striatum (especially caudate), though many other regions subsequently atrophy as the disease progresses.
  • Regional brain atrophy can be detected approximately 15 years before HD manifests clinically[4].
  • Somatic expansion of CAG or CTG repeats in striatal neurons, along with genetic variants that impact DNA repair mechanisms, may partly explain their relatively accelerated degeneration[5][6][7].
• Cognitive impairment due to Huntington disease is classified under the neurocognitive disorders (NCDs) section of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)[8].