Huntington Disease (HD)

Huntington disease (HD) is a rare, inherited, neurodegenerative disorder affecting the central nervous system, resulting in progressive atrophy of the basal ganglia and cerebral cortex. The hallmark characteristics of HD involve a combination of motor, cognitive, and psychiatric symptoms.1

Role of HD in the Advancement of Molecular Genetics

Given its genetic etiology, HD has served a pivotal role in the advancement of human genetics over the last 40 years. In 1872, George Huntington’s careful observations and tracing of family histories incorporated the observations of his father and grandfather who were also general practitioners who served the same families living in one community for generations. These observations indicated that HD was passed down from generation to generation without skipping a generation.2

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Huntington’s contemporary, Gregor Mendel, published his seminal work on dominant and recessive patterns of inheritance in pea plants, which became the foundation for modern genetics just 7 years prior in 1865.3 Based on Mendel’s work, it was determined that HD followed an autosomal dominant pattern of inheritance in which any child born to a parent with the affected gene has a 50% chance of inheriting the condition.4

Given the obvious familial inheritance of the condition, the genetic etiological underpinnings of HD became the subject of intense, collaborative research following the Centennial Symposium on Huntington’s Disease held in 1972.5 A research team led by Nancy Wexler and James Gusella successfully localized the genetic defect to human chromosome 4 through genetic linkage analysis and gene-mapping techniques using common DNA polymorphisms in 1983. HD became the first autosomal disease to be genetically mapped.6-8

The identification of the HD gene, later renamed the HTT gene, and its successful localization to the p16.3 region on chromosome 4 inspired multiple studies of similar nature to identify the genetic etiologies for other conditions, later culminating in the Human Genome Project.7 

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Pathogenesis of Huntington Disease

Genetic mapping helped to determine where the genetic defect causing HD was located, but it failed to explain the pathogenesis of the disease. After another decade of technological advancements in DNA cloning, sequencing, and gene mapping, researchers were able to determine the exact cause of HD when they identified a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion located on the first exon of the newly renamed HTT gene.9,10

The gene mutation causing HD involves an unstable segment of DNA with CAG trinucleotide repeat expansions of variable length per application of polymerase chain reaction (PCR) testing. The length of the CAG repeat expansion was found to correlate with the age of onset for HD symptom manifestation based on partial or full penetrance, according to the following classifications7:

  • Normal: less than 27 CAG repeats
  • High normal: 27 to 35 CAG repeats
  • Partial penetrance of HD: 36 to 39 CAG repeats
  • Full penetrance of HD: more than 40 CAG repeats

No matter what length of CAG repeat expansion is found, HD age of onset may vary over several decades; however, as the length of CAG repeats increases, the average age of onset decreases.7

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This HTT gene mutation affects the biosynthesis of the huntingtin protein. Although the function of the huntingtin protein is not fully understood, it is theorized that it plays an important role in the preservation of neurons in the brain.11 

HD results from the death of medium-sized spiny neurons of the striatum that use γ-aminobutyric acid (GABA).7 Pyramidal neurons that project from the cerebral cortex to the striatum as well as striatal neurons that project to the external segment of the globus pallidus and the substantia nigra within the basal ganglia degenerate in presymptomatic patients with HD.7,12,13 

Multiple research studies indicate a glial component contributing to HD pathogenesis, suggesting the involvement of reactive microglia in the striatum and cortex, which progressively accumulate in both the early and late stages of HD. These reactive microglia (identified by localizing thymosin β-4, which is elevated in reactive microglia) seem to play a role in neuronal cell death in neurodegenerative diseases such as HD.7,14

These specific regions of the brain demonstrate varying rates of neurodegeneration across individuals with HD. This is evidenced by brain imaging that depicts varying degrees of brain volume loss within different brain compartments, including the cerebral cortex, putamen, caudate nucleus, and telencephalic white matter, compared to normotypical individuals.7,15,16

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Huntingtin Protein

The genetically mutated huntingtin protein is misfolded with a much longer polyglutamine (polyQ) sequence than normal near the amino-terminus of the protein. These abnormal proteins form toxic aggregations that are deposited within brain neurons, compared to the more diffuse localization seen in individuals unaffected by HD.7,17 

This polyQ expansion leading to misfolding of the huntingtin protein disrupts the ubiquitin-proteasomal degradation system required for cellular homeostasis involving protein recycling and energetics.7,18 Many studies indicate the presence of gain-of-function phenotypes, although some studies report loss-of-function effects due to the mutated polyQ expansion of the huntingtin protein.7 It is still unclear as to how this process interferes with neuronal function and viability; this is a topic of ongoing research.17 

Studies suggest that the huntingtin protein may be involved in chemical signaling, transporting materials, binding to proteins and other structures, protecting cells from apoptosis, and possibly repairing DNA damage. In addition to microglial inflammation, other pathogenetic mechanisms of HD neurodegeneration likely involve abnormalities of cytoskeletal and axonal transport, mitochondrial dysfunction and suppression of energy metabolism, systemic failure of transcription, and decreased biosynthesis of brain-derived neurotrophic factor.1,19

Once the underlying etiological mechanisms of HD are discovered and fully understood, more targeted and effective treatments can be researched and developed.

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  1. Illarioshkin SN, Klyushnikov SA, Vigont VA, Seliverstov YA, Kaznacheyeva EV. Molecular pathogenesis in Huntington’s disease. Biochemistry (Mosc). 2018;83(9):1030-1039. doi:10.1134/S0006297918090043
  2. Huntington G. On chorea. J Neuropsychiatry Clin Neurosci. 2003;15(1):109-112. doi:10.1176/jnp.15.1.109
  3. 1865: Mendel’s peas. National Human Genome Research Institute. Updated April 22, 2013. Accessed August 12, 2023.
  4.  Huntington’s disease. National Institute of Neurological Disorders and Stroke. Accessed August 12, 2023.
  5. Wexler A, Wild EJ, Tabrizi SJ. George Huntington: a legacy of inquiry, empathy and hope. Brain. 2016;139(8):2326-2333. doi:10.1093/brain/aww165
  6. 1983: first disease gene mapped. National Human Genome Research Institute. Updated April 26, 2013. Accessed August 12, 2023.
  7. Hong EP, MacDonald ME, Wheeler VC, et al. Huntington’s disease pathogenesis: two sequential components. J Huntingtons Dis. 2021;10(1):35-51. doi:10.3233/JHD-200427
  8. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983;306(5940):234-238. doi:10.1038/306234a0
  9. Gusella JF, Lee JM, MacDonald ME. Huntington’s disease: nearly four decades of human molecular genetics. Hum Mol Genet. 2021;30(R2):R254-R263. doi:10.1093/hmg/ddab170
  10. MacDonald ME, Ambrose CM, Duyao MP, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72(6):971-983. doi:10.1016/0092-8674(93)90585-E
  11. Huntington disease. MedlinePlus. Updated July 1, 2020. Accessed August 12, 2023.
  12. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A. 1988;85(15):5733-5737. doi:10.1073/pnas.85.15.5733
  13. Albin RL, Reiner A, Anderson KD, et al. Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol. 1992;31(4):425-430. doi:10.1002/ana.410310412
  14. Sapp E, Kegel KB, Aronin N, et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol. 2001;60(2):161-172. doi:10.1093/jnen/60.2.161
  15. Nopoulos PC, Aylward EH, Ross CA, et al; PREDICT-HD Investigators Coordinators of Huntington Study Group (HSG). Cerebral cortex structure in prodromal Huntington disease. Neurobiol Dis. 2010;40(3):544-554. doi:10.1016/j.nbd.2010.07.014
  16. Squitieri F, Cannella M, Simonelli M, et al. Distinct brain volume changes correlating with clinical stage, disease progression rate, mutation size, and age at onset prediction as early biomarkers of brain atrophy in Huntington’s disease. CNS Neurosci Ther. 2009;15(1):1-11. doi:10.1111/j.1755-5949.2008.00068.x
  17. Hatters DM. Protein misfolding inside cells: the case of huntingtin and Huntington’s disease. IUBMB Life. 2008;60(11):724-728. doi:10.1002/iub.111
  18. Imarisio S, Carmichael J, Korolchuk V, et al. Huntington’s disease: from pathology and genetics to potential therapies. Biochem J. 2008;412(2):191-209. doi:10.1042/BJ20071619
  19. HTT gene. MedlinePlus. Updated July 1, 2020. Accessed August 12, 2023.

Reviewed by Hasan Avcu, MD, on 8/15/2023.