Clinical Symptomatology of Huntington’s Disease
Huntington’s disease (HD) is a dominantly inherited autosomal neuropsychiatric degenerative disease with a fatal prognosis, caused by a mutation—the expansion of C-A-G (cytosine-adenine-guanine) triplet repeats 40 and more repetitions on the short arm of fourth chromosome. The product of the mutation is an aberrant protein called huntingtin with an enlarged polyglutamine stretch. The prevalence of HD is approx. 1:10–15,000. The typical onset of HD is in the fourth decade, with a minority of cases starting in childhood or adolescence (juvenile HD) or in patients older than 65 years of age (late onset HD).
Early symptoms of classical form are usually nonspecific: behavioral changes, personality disorders, affective symptoms, etc. The affected person begins to be apathetic, emotionally flattened, losing interest in any hobbies. Other patients show jealousy, paranoid suspicions, obsessive thoughts, and compulsive acts. The patients have difficulties with work-related activities, partly due to the early appearance of executive dysfunction, and partly due to apathy and lack of concern. Typical motor symptoms are choreatic and/or dystonic dyskinesias, the impairment of voluntary movements, gait disorder, dysphagia, and dysarthria.
In the progression of HD cognitive disturbance appears leading to severe dementia. During the course of the disease, chorea is individually progressive, eventually decreasing in intensity, spontaneously subsiding and converting to dystonia, and finally to akinesia. The progression of HD leads inevitably to the marantic, cachectic state with a total loss of voluntary movement.
The first signs in juvenile form are difficulties with school activities related to psychomotor retardation, motor dyscoordination, voluntary movement impairment, and cognitive deterioration. Behavioral changes are characteristic for JHD: outbursts of anger, aggression, antisocial tendencies as well as obsessive thoughts and compulsive acts. Psychotic manifestations are more common than in adults with HD. Chorea is rare, dystonia and/or rigidity with akinesia dominate. Gait disorder with postural instability and frequent falls arises rapidly. Myoclonus of the head and trunk, postural and kinetic tremor of the upper extremities as well as supranuclear gaze palsy are frequently present. Epileptic seizures could be present.
Late onset form has a relatively benign course and most patients live to the average age of the healthy population. The principal and incipient manifestation is chorea, whose distribution and character do not differ from the classical form of the disease, but is less intensive and progresses more slowly. Apathy, depression, and irritability are frequent behavioral manifestations. Isolated cognitive deficits are usually present (especially dysexecutive syndrome and short-term memory impairments), but to the lesser degree than in the classical form. Severe dementia does not usually develop.
Clinical diagnosis is confirmed using a genetic test. Adult and healthy people at risk could ask for the predictive genetical testing, but a specific protocol is needed. Children and adolescents are typically not tested. Prenatal testing is also available. A preimplantation genetic diagnosis can determine the health of the embryo without knowing the genetic risk factors of the parents.
KeywordsHuntington’s disease CAG triplet Chorea Dementia Behavior
- 2.Huntington G. On chorea. Med Surg Reporter. 1872;26:317–21.Google Scholar
- 4.The Huntington’s Disease Colaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;2:971–83.Google Scholar
- 11.Rubinsztein DC, Leggo J, Voles R, Almquist E, Biancalana V, Cassiman JJ, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington’s disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996;59:16–22.PubMedPubMedCentralGoogle Scholar
- 12.Leeflang EP, Zhang L, Tavaré S, Hubert R, Srinidhi J, MacDonald ME, Myers RH, de Young M, Wexler NS, Gusella JF, et al. Single sperm analysis of the trinucleotide repeats in the Huntington’s disease gene: quantification of the mutation frequency spectrum. Hum Mol Genet. 1995;4:1519–26.CrossRefGoogle Scholar
- 21.Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain. 2003;126:946–55.CrossRefGoogle Scholar
- 28.Paulsen JS, Long JD, Ross CA, Harrington DL, Erwin CJ, Williams JK, Westervelt HJ, Johnson HJ, Aylward EH, Zhang Y, Bockholt HJ, Barker RA, PREDICT-HD Investigators and Coordinators of the Huntington Study Group. Prediction of manifest Huntington’s disease with clinical and imaging measures: a prospective observational study. Lancet Neurol. 2014;13(12):1193–201.CrossRefGoogle Scholar
- 29.Solomon AC, Stout JC, Weaver M, Queller S, Tomusk A, Whitlock KB, Hui SL, Marshall J, Jackson JG, Siemers ER, Beristain X, Wojcieszek J, Foroud T. Ten-year rate of longitudinal change in neurocognitive and motor function in prediagnosis Huntington disease. Mov Disord. 2008;23:1830–6.CrossRefGoogle Scholar
- 43.Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington’s disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001;4:219–26.Google Scholar
- 45.Epping EA, Kim JI, Craufurd D, Brashers-Krug TM, Anderson KE, McCusker E, Luther J, Long JD, Paulsen JS, PREDICT-HD Investigators and Coordinators of the Huntington Study Group. Longitudinal psychiatric symptoms in prodromal Huntington’s disease: a decade of data. Am J Psychiatry. 2016;173(2):184–92. https://doi.org/10.1176/appi.ajp.2015.14121551. Epub 2015 Oct 16.CrossRefPubMedGoogle Scholar
- 53.van Duijn E, Craufurd D, Hubers AA, Giltay EJ, Bonelli R, Rickards H, Anderson KE, van Walsem MR, van der Mast RC, Orth M, Landwehrmeyer GB, European Huntington’s Disease Network Behavioural Phenotype Working Group. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY). J Neurol Neurosurg Psychiatry. 2014a;85(12):1411–8.CrossRefGoogle Scholar
- 59.Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Wang C, Stout JC, Ross CA, Aylward E, Carlozzi NE, Queller S, Predict-HD Investigators of the Huntington Study Group. “Frontal” behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci. 2010;22(2):196–207.CrossRefGoogle Scholar
- 75.Cornejo-Olivas MR, Inca-Martinez MA, Espinoza-Huertas K, Veliz-Otani D, Velit-Salazar MR, Marca V, Ortega O, Cornejo-Herrera IF, Lindo-Samanamud S, Mora-Alferez P, Mazzetti P. Clinical and molecular features of late onset Huntington disease in a peruvian cohort. J Huntingtons Dis. 2015;4(1):99–105.PubMedGoogle Scholar