Neurodegenerative Diseases: Huntington Disease

  • Serge Weis
  • Michael Sonnberger
  • Andreas Dunzinger
  • Eva Voglmayr
  • Martin Aichholzer
  • Raimund Kleiser
  • Peter Strasser


Huntington disease (HD) is an autosomal dominant disorder with full penetrance and rare de novo mutations. Early changes include mild motor decline with clumsiness and slowed gait, progressive changes include dystonia and chorea, parkinsonian symptoms, slow and stiff gait, dysphagia, tremor, and depression and suicidal ideation. In the late stages, rigidity, severe bradykinesia, dysphagia, inability to swallow, seizures, and inability to walk or speak predominate.

On MR imaging, atrophy of the striatum (especially caudate nucleus), cortical gray matter, globus pallidus and thalamus are the predominant features.

Loss of medium-sized spiny GABA-substance P- or GABA-enkephalin-positive neurons which project to the globus pallidus and pars reticulata of the substantia nigra is noticed in the caudate nucleus. Small spiny neuropeptide Y, somatostatin and NADPH-diaphorase-positive interneurons as well as large non-spiny cholinergic interneurons are not involved. Other affected regions include the globus pallidus, ventrolateral thalamus, and subthalamic nuclei. In the cerebral cortex, slight loss of pyramidal neurons in layers III, V and VI of the frontal lobe, CA1 region of the hippocampus and concomitant reactive astrogliosis might be seen.

HD is characterized by an expansion of the CAG repeat in exon 1 in the huntingtin gene (HTT) mapped to short arm of chromosome 4q16.3 which encodes the protein huntingtin. Huntingtin plays several roles in regulating the dynamics of autophagy, is expressed in innate immune cells and plays as wild-type huntingtin a role in the intracellular transport of vesicles and organelles.

The number of repeats can increase from one generation to the next one (normal alleles: 26 or fewer repeats; intermediate alleles: 27–35 repeats; individual not at risk to develop the disease, risk of having an affected child). HD-causing alleles: 36 or more repeats (reduced penetrance: 36–39 repeats; full penetrance: 40 or more repeats). Environmental factors, genetic modifiers, and other factors determine the development of the disease over time. Maternal or paternal transmission is possible, whereby the paternal transmission is associated with higher number of repeats.

Treatment consists in managing rigidity (baclofen and diltiazem), chorea (haloperidol or atypical antipsychotics), and myoclonus (valproate). HD is a progressive disorder with a mean duration of disease of 17 years (2–45 years).

Selected References

  1. Adam OR, Jankovic J (2008) Symptomatic treatment of Huntington disease. Neurotherapeutics 5(2):181–197. Scholar
  2. Anglada-Huguet M, Vidal-Sancho L (2017) Pathogenesis of Huntington’s disease: how to fight excitotoxicity and transcriptional dysregulation. In: Tunalı NE (ed) Huntington’s disease – molecular pathogenesis and current models. InTech, Rijeka, pp 37–73. Scholar
  3. Apolinario TA, Paiva CL, Agostinho LA (2017) REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review. Genet Mol Res 16(2).
  4. Arning L (2016) The search for modifier genes in Huntington disease – multifactorial aspects of a monogenic disorder. Mol Cell Probes.
  5. Dayalu P, Albin RL (2015) Huntington disease: pathogenesis and treatment. Neurol Clin 33(1):101–114. Scholar
  6. Ho VB, Chuang HS, Rovira MJ, Koo B (1995) Juvenile Huntington disease: CT and MR features. AJNR Am J Neuroradiol 16(7):1405–1412Google Scholar
  7. Martin DD, Ladha S, Ehrnhoefer DE, Hayden MR (2015) Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci 38(1):26–35. Scholar
  8. Montoya A, Price BH, Menear M, Lepage M (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31(1):21–29Google Scholar
  9. Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, Scahill RI, Leavitt BR, Stout JC, Paulsen JS, Reilmann R, Unschuld PG, Wexler A, Margolis RL, Tabrizi SJ (2014) Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204–216. Scholar
  10. Rub U, Vonsattel JP, Heinsen H, Korf HW (2015) The neuropathology of Huntington’s disease: classical findings, recent developments and correlation to functional neuroanatomy. Adv Anat Embryol Cell Biol 217:1–146Google Scholar
  11. Sturrock A, Leavitt BR (2010) The clinical and genetic features of Huntington disease. J Geriatr Psychiatry Neurol 23(4):243–259. Scholar
  12. Sturrock A, Laule C, Decolongon J, Dar Santos R, Coleman AJ, Creighton S, Bechtel N, Reilmann R, Hayden MR, Tabrizi SJ, Mackay AL, Leavitt BR (2010) Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease. Neurology 75(19):1702–1710. Scholar
  13. Thomas EA (2016) DNA methylation in Huntington’s disease: implications for transgenerational effects. Neurosci Lett 625:34–39. Epub 2015 Nov 11Google Scholar
  14. Tomé S, Dandelot E (2017) Genetic modifiers of CAG.CTG repeat instability in Huntington’s disease mouse models. In: Tunalı NE (ed) Huntington’s disease – molecular pathogenesis and current models. InTech, Rijeka, pp 1–20. Scholar
  15. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384Google Scholar
  16. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577Google Scholar
  17. Vonsattel JP, Keller C, Del Pilar Amaya M (2008) Neuropathology of Huntington’s disease. Handb Clin Neurol 89:599–618. Scholar
  18. Vonsattel JP, Keller C, Cortes Ramirez EP (2011) Huntington’s disease – neuropathology. Handb Clin Neurol 100:83–100. Scholar
  19. Warby SC, Graham RK, Hayden MR (1993) Huntington disease. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews(R). University of Washington, Seattle, WAGoogle Scholar
  20. Zheng Z, Diamond MI (2012) Huntington disease and the huntingtin protein. Prog Mol Biol Transl Sci 107:189–214. Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Serge Weis
    • 1
  • Michael Sonnberger
    • 2
  • Andreas Dunzinger
    • 3
  • Eva Voglmayr
    • 2
  • Martin Aichholzer
    • 4
  • Raimund Kleiser
    • 2
  • Peter Strasser
    • 5
  1. 1.Division of Neuropathology, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  2. 2.Department of Neuroradiology, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  3. 3.Department of Neuro-Nuclear Medicine, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  4. 4.Department of Neurosurgery, Neuromed CampusKepler University Hospital, Johannes Kepler UniversityLinzAustria
  5. 5.PMU University Institute for Medical & Chemical Laboratory DiagnosticsSalzburgAustria

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