Annals of Indian Academy of Neurology
  Users Online: 682 Home | About the Journal | InstructionsCurrent Issue | Back IssuesLogin      Print this page Email this page  Small font size Default font size Increase font size

Table of Contents
Year : 2020  |  Volume : 23  |  Issue : 2  |  Page : 153-154

Phenotypic variability in huntington's disease

Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India

Date of Submission25-Oct-2019
Date of Acceptance27-Oct-2019
Date of Web Publication07-Feb-2020

Correspondence Address:
Prof. Sanjay Pandey
Department of Neurology, Academic Block, Room No 503, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi - 110 002
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_543_19

Rights and Permissions


How to cite this article:
Chouksey A, Pandey S. Phenotypic variability in huntington's disease. Ann Indian Acad Neurol 2020;23:153-4

How to cite this URL:
Chouksey A, Pandey S. Phenotypic variability in huntington's disease. Ann Indian Acad Neurol [serial online] 2020 [cited 2020 Jul 4];23:153-4. Available from:

Huntington's disease (HD) is a hereditary neurodegenerative disorder with an autosomal dominant inheritance pattern. It is characterized by a progressive course of the combination of motor, cognitive, and psychiatric manifestations. It is caused because of expansion of CAG trinucleotide repeat in the huntingtin (HTT) gene encoding the protein HTT on chromosome 4. The exact function of normal HTT protein and the mechanism by which mutant huntingtin (mHTT) gene produces manifestation in HD is still unclear. It has been proposed that the mHTT protein contains abnormal long polyglutamine sequences that result in the formation of HTT protein aggregates, which disrupts normal cell functions and ultimately culminates into neuronal loss and neurodegeneration. Current literature shows an important role in cellular aging and various aging-related genes, inducing the disease-specific phenotypes in HD patients.[1],[2]

In this issue of the Annals of Indian Academy of Neurology, authors have described the clinical spectrum of HD in 76 genetically proven patients from Eastern India.[3] In this study, the mean age of presentation was 43.21 (±10.14; range 23–65) years and the variation in the age of presentation correlated strongly with the number of CAG repeats. Recent studies proposed that the age of presentation is also influenced by the sequence variation outside the HTT region. Identification of such candidate genes, which act as a genetic modifier in the pathogenesis of HD, will allow for the development of treatment options that can modulate the disease process and, thus, delay or prevent the symptom onset in the individuals carrying mHTT gene.[4]

Paternal transmission is around three times more common as compared with the maternal transmission and associated with earlier age of onset owing to the higher CAG repeat instability during spermatogenesis. In the above-mentioned study, 18.7% had apparently unaffected parents. This subgroup of HD patients, without a family history, are likely to represent sporadic or de novo mutation, which is now well-known to contribute at least 5–8% of genetically proven HD cases.[5]

The majority of the HD patients present with motor features and most of them follow a biphasic course with initial hyperkinetic movements like chorea or dystonia, which gradually plateaus and later replaced by the Parkinsonian features as the disease progresses. This biphasic course corresponds to the selective vulnerability and initial loss of medium spiny neurons (MSNs) of the indirect pathway, leading to hyperkinetic movements followed by the involvement of the direct pathway resulting in hypokinetic movements. The dopamine D2 receptors have been implicated for the selective involvement of indirect pathway MSNs as they are expressed by indirect but not direct MSNs; however, the exact reason is still not clear.[6]

Chorea, followed by dystonia, is the most common hyperkinetic movement disorder noticed in HD patients. Rarely tics have been reported in HD patients, however, it is difficult to clearly distinguish between chorea and tics because both share common jerky nature.[7] While parkinsonian features like rigidity and bradykinesia appear late in adult HD, these symptoms are quite prominent in Juvenile variety (age at onset below 20 years) of Huntington's disease (JHD) which accounts for <10% of the Huntington's disease cases.[6]

The cognitive disturbance is often present in HD patients many years before the onset of motor symptoms and is mostly characterized by subcortical dysfunction including impaired emotion recognition, cognitive slowing, visuospatial and executive dysfunction. The features of frontal lobe involvement are relatively uncommon in HD patients.

A wide variety of behavioral manifestations including apathy, anxiety, irritability, depression, obsessive-compulsive behavior, and psychosis are commonly observed in HD patients. The low frequency of initial psychiatric symptoms noticed by the authors in the above-mentioned study might be the reflection of the tendency to hide psychiatric symptoms by the patient and family member because of the social stigma attached to it.

The triad of chorea, cognitive and neuropsychiatric disturbance is considered to be the characteristic of HD, but in the absence of HTT gene mutation, one should consider HD phenocopies as alternative diagnosis including Huntington disease like 2 (HDL-2) and dentatorubral pallidoluysian atrophy, spino-cerebellar ataxia (types 2, 3, 12 and 17), neuroacanthocytosis and C9orf72 expansions.

The tetrabenazine and its modified version deutetrabenazine are the only two drugs specifically licensed by the US Food and Drug Administration (FDA) for use in patients with HD for the treatment of chorea. Currently, there is no effective disease modifying therapy available for HD patients, however various clinical trials are going on to investigate therapeutic strategies to arrest the disease in the premanifest stage. The most promising disease-modifying approaches that are under trial include therapies aimed at lowering levels of mHTT by targeting either the DNA or RNA of the mHTT gene using anti-sense oligonucleotides (ASOs), RNA interference (RNAi) or small molecule splicing inhibitors.[8] Even after decades of decoding the genetic basis of HD, several aspects of this disease continued to puzzle researchers.

   References Top

Victor MB, Richner M, Olsen HE, Lee SW, Monteys AM, Ma C, et al. Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat Neurosci 2018;21:341-52.  Back to cited text no. 1
Pandey S, Dash D. Cellular age in the manifestation of disease-relevant phenotypes in Huntington's disease. Mov Disord 2018;33:1096.  Back to cited text no. 2
Hussain Z, Mukherjee A, Ganguly G, Joardar A, Roy S, Guin DS, et al. Clinical Profile of Genetically Proven Huntington's Disease Patients from Eastern India. Ann Indian Acad Neurol 2009;23:195-200.  Back to cited text no. 3
Gusella JF, MacDonald ME, Lee JM. Genetic modifiers of Huntington's disease. Mov Disord 2014;29:1359-65.  Back to cited text no. 4
Almqvist EW, Elterman DS, MacLeod PM, Hayden MR. High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin Genet 2001;60:198-205.  Back to cited text no. 5
Plotkin JL, Surmeier DJ. Corticostriatal synaptic adaptations in Huntington's disease. Curr Opin Neurobiol 2015;33C: 53-62.  Back to cited text no. 6
Jankovic J, Mejia NI. Tics associated with other disorders. In: Wlakup J, Mink J, Hollenbeck, editors. Tourette Syndrome. Advances in Neurology. Vol 99. Philadelphia: Philadelphia, Lippincott Williams and Wilkins; 2006. p. 61-8.  Back to cited text no. 7
Aronin N, DiFiglia M. Huntingtin-lowering strategies in Huntington's disease: antisense oligonucleotides, small RNAs, and gene editing. Mov Disord 2014;29:1455-61.  Back to cited text no. 8


Print this article  Email this article


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (268 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


 Article Access Statistics
    PDF Downloaded33    
    Comments [Add]    

Recommend this journal