Huntington's disease: a clinical review

Abstract

Huntington's disease (HD) is a fully penetrant neurodegenerative disease caused by a dominantly inherited CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. In Western populations HD has a prevalence of 10.6–13.7 individuals per 100 000. It is characterized by cognitive, motor and psychiatric disturbance. At the cellular level mutant huntingtin results in neuronal dysfunction and death through a number of mechanisms, including disruption of proteostasis, transcription and mitochondrial function and direct toxicity of the mutant protein. Early macroscopic changes are seen in the striatum with involvement of the cortex as the disease progresses. There are currently no disease modifying treatments; therefore supportive and symptomatic management is the mainstay of treatment. In recent years there have been significant advances in understanding both the cellular pathology and the macroscopic structural brain changes that occur as the disease progresses. In the last decade there has been a large growth in potential therapeutic targets and clinical trials. Perhaps the most promising of these are the emerging therapies aimed at lowering levels of mutant huntingtin. Antisense oligonucleotide therapy is one such approach with clinical trials currently under way. This may bring us one step closer to treating and potentially preventing this devastating condition.

Cannabidiol: A budding industry!

“…Huntington's disease has a prevalence of approximately 11-14 individuals per 100 000 in Western populations. It is the result of a dominantly inherited defect in the gene encoding the protein huntingtin, which causes a loss of protein function leading to neuronal dysfunction and death (McColgan & Tabrizi 2018). There is the suggestion from an animal model study of Huntington's disease that CBD may prevent damage to striatal neurons (Sagredo et al 2007), one of the main brain areas affected by the disease, and from an in vitro study that CBD may reduce huntingtin-induced cell death (Aiken et al 2004).…”

Antisense Oligonucleotide Gene Therapy for Neuromuscular Disorders

“…Huntington's disease Huntington's disease (HD) is a neurodegenerative disorder caused by expansion mutations in the huntingtin gene (17). The mutation stimulates the huntingtin protein to accumulate in toxic aggregates that induce degeneration of the striatum along with progressive motor deficits and cognitive dysfunction.…”

Hunting for the mutant without the MAP(K)

“…Although there have been extensive efforts towards understanding the pathological mechanisms of each disorder, development of effective diseasemodifying therapeutics has proven unsuccessful, owing to a multitude of factors including the overall complexity of each disease, the extended asymptomatic prodromal disease period before treatment administration, and many others. Currently, treatment of neurodegenerative diseases is limited almost entirely to symptom management, aiding with particular motor, cognitive, and psychiatric aspects of each disease [1]. As the prevalence of neurodegenerative disorders continues to rise, a better understanding of the underlying disease mechanisms is essential to guide disease-modifying therapy development.…”