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.
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• Huntington disease is characterized by a combination of progressive motor, cognitive, and psychiatric symptoms.
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• Mutant huntingtin protein that results from CAG repeat expansion affects many cellular processes including gene transcription, posttranslational modification, protein clearance, axonal trafficking, and mitochondrial function.
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• 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 (302), 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; 153; 04). 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 (101). In 1993, a collaborative group of researchers announced the identification of a gene with unstable trinucleotide repeat located on chromosome 4p16.3 (06). 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) (302).