Huntington disease

Olga Waln MD (Dr Waln of Houston Methodist Neurological Institute has no relevant financial relationships to disclose.)
Joseph Jankovic MD, editor. (

Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, received research and training funding from Allergan, F Hoffmann-La Roche, Medtronic Neuromodulation, Merz, Neurocrine  Biosciences, Nuvelution, Revance, and Teva and consulting/advisory board honorariums from Abide, Lundbeck, Retrophin, Parexel, Teva, and Allergan.

)
Originally released February 22, 1994; last updated October 24, 2019; expires October 24, 2022

This article includes discussion of Huntington disease and Huntington chorea. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Huntington disease is a genetic autosomal dominant neurodegenerative disorder caused by an expansion of a trinucleotide repeat in the gene encoding huntingtin (HTT) on chromosome 4. It is characterized by motor, behavioral, and cognitive symptoms, with the onset usually in mid-adulthood. Although the onset of disease is currently defined by its motor manifestations, the presence of cognitive and behavioral features prior to motor symptoms is increasingly recognized. A combination of non-motor and motor symptoms inevitably progresses to produce functional impairments, important targets for symptomatic treatment, and clinical trial outcomes. Only symptomatic treatment is currently available to minimize severity of motor and non-motor symptoms, affecting quality of lives of the patients and caregivers. The area of research to develop potentially disease-modifying therapies in Huntington disease has been growing in the past few years, with many preclinical and clinical trials underway. The development of biomarkers in Huntington disease is also an area of increasing interest that becomes even more important in the anticipation of development of disease-modifying therapies. Predictive (prior to symptoms) genetic testing protocols take a wide range of information on Huntington disease genetics, inheritance, symptoms, and progression into account. In this article, the author explores the advances and possible therapeutic targets in the treatment of this devastating disease.

Key points

 

• Cognitive and behavioral changes may occur years prior to the onset of definitive motor signs.

 

• Changes in sleep, weight loss, and autonomic dysfunction are now recognized as primary and treatable Huntington disease symptoms.

 

• Impacting functional outcomes and quality of life are increasingly important symptomatic care and clinical trial goals.

 

• Management of Huntington disease involves an interdisciplinary whole-family approach, utilizing expertise in neurology, psychiatry, neuropsychology, rehabilitation and wellness, and nutrition in addition to genetic and social issues.

 

• Presymptomatic and confirmatory genetic testing is best utilized with the support of genetic counseling as well as regional and international guidelines.

 

• Treatment of Huntington disease currently remains symptomatic, but potential new therapeutic targets are being actively explored in both manifest and nonmanifest populations.

Historical note and terminology

The clinical syndrome was delineated in the English literature in 1872 by George Huntington (Wexler et al 2016a), who reported:

Hereditary chorea. . .confined to certain and fortunately a few families, and has been transmitted to them, an heirloom from generations away back in the dim past. It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror. . . There are three marked peculiarities in this disease: 1. Its hereditary nature. 2. A tendency to insanity and suicide. 3. Its manifesting itself as a grave disease only in adult life".

The degeneration of the striatum was recognized as the essential neuropathologic feature around the turn of the century (Anton 1896; Lanois and Paviot 1897; Alzheimer 1911). The genetic mutation linked to Huntington disease was found on chromosome 4 in 1983, making Huntington disease the first genetic disease mapped using DNA polymorphisms (Gusella et al 1983). In 1993, a collaborative group of researchers announced the identification of a gene with unstable trinucleotide repeat located on chromosome 4p16.3 (Anonymous 1993). This discovery was the result of a multinational, multidisciplinary research project focused on a unique cluster of affected families in Venezuela diagnosed back in the 1950s by a local physician, Americo Negrette, author of the first monograph ever published on Huntington disease called “Corea de Huntington,” which was published in Spanish in 1963 (Hereditary Disease Foundation website) (Wexler et al 2016a).

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