Introduction

Huntington’s disease (HD), named after Dr George Huntington, a physician who first described the disease, is an autosomal dominant, inherited neurodegenerative disorder.¹ HD is characterised by progressive motor dysfunction, cognitive decline, and psychiatric disturbances.¹ Its cause is a known specific genetic mutation, which research has made well-understood.^1,2 This knowledge of the genetic cause and the role of genetics in HD has been crucial in enabling early diagnosis, treatment development, and genetic counselling.²

This article aims to shed some light on the genetic mechanisms that underlie HD, exploring how specific mutations result in the disease, and how the genetic inheritance pattern influences pre-disposition to the rare disease.

Phenomenology of HD

HD is a rare neurodegenerative disease, with a low prevalence of approximately 10 to 12 individuals per 100,000 of European ancestry.^3,4 The onset of HD is defined as the manifestation of significant motor or neurological symptoms, and on average occurs around the age of 40.³ However, it has been identified that the extent of genetic mutations affects the onset and severity of disease. The genetic mutation behind HD is an increase in the number of trinucleotides repeats in a specific gene, the HTT gene. The greater the number of repeats, the earlier the onset and the worse the severity of the disease, thus showing the importance of genetics in HD.³

The genetic background of Huntington’s Disease

The HTT gene

The HTT gene, also known as the Huntingtin gene, is located on the short arm of chromosome 4.^5,6,7 Mutations that cause HD occur in the HTT gene.^5,6 This is because the HTT gene encodes a protein called huntingtin, which is required for the proper functioning of neurons, particularly in the brain. Although the exact role of the huntingtin protein in neuron function has not been fully understood or concluded, it is currently believed to play a role in signalling, cellular transport, and importantly, a protective role for neurons, to prevent damage.^5,6,7

The mutation responsible for HD entails an abnormal expansion of a CAG (cytosine, adenine, and guanine) trinucleotide repeat in the HTT gene.^5,6 Typically, this trinucleotide repeats sequence ranges from 10 to 35 repeats.^5,7 However, those suffering from HD have been found to have CAG repeats that have expanded to 36 copies or more.^5,6,7 The increase in the copies of CAG repeats leads to the production of the huntingtin protein that is abnormally long, and is toxic to neurons, through the formation of abnormal aggregates.^5,6,7 These abnormal aggregates are believed to disrupt various essential cellular processes, which results in neuronal dysfunction, and ultimately cell death. This is most prevalent in regions of the brain responsible for motor control and cognition, such as the basal ganglia and cortex, which dictates the common symptoms of HD: uncontrolled movement, cognitive decline, and behavioural changes, among others.^5,6,7

Expansion of CAG repeats

As previously stated, the genetic hallmark of HD is the expansion of CAG repeats within the gene for the huntingtin protein (HTT gene). The codon CAG produces the amino acid glutamate; hence, the expansion of CAG repeats results in an abnormal polyglutamine tract in the huntingtin protein.⁸ Research has identified that  the level of CAG repeat expansion is directly correlated with the severity and onset of HD.⁸

• Normal allele: consists of 10-35 CAG repeats. Individuals with this range of repeats do not develop HD
• Intermediate allele: 36-39 CAG repeats. Individuals with this range of repeats are at risk of developing HD, but will not definitively develop it
• Pathogenic allele: 40 or more CA repeats. Individuals with this range of repeats will develop HD, and the greater the expansion of repeats, the earlier the disease onset is likely to occur

The inheritance pattern of HD

HD follows the inheritance pattern of an autosomal dominant disease, meaning that an individual only needs to inherit one copy of the mutated HTT gene from their parent to develop HD.^5,6,7 If a parent is a carrier of the mutated gene, each offspring has a 50% chance of inheriting the mutation and developing HD.^5,6,7

As the disease follows a dominant inheritance pattern, it does not ‘’skip’’ generations, which also means that if the offspring do not inherit the mutated gene, they pose no risk of developing it themselves or passing it on to their offspring.^6,7 This inheritance pattern is unique in comparison to other neurodegenerative disorders, which often display more complex and convoluted causes.^5,6,7

Genetic testing for HD: Predictive Testing

A crucial part of managing HD cases is predictive testing, which can be utilised to determine whether an individual has inherited the mutated form of the HTT gene, even before the onset of disease.² This form of testing is particularly significant for individuals who may be at risk of HD, due to a family history of the condition, who aren’t showing any symptoms but wish to know whether they possess the mutated HTT gene before having children.² There is controversy concerning predictive testing for HD, regarding ethical and psychological issues.^2,5,7

There is yet to be a cure developed for HD and those with the mutated HTT gene are inevitably going to experience the symptoms of HD, as it is a dominant disease. Hence, being informed that you are a carrier of the pathogenic mutation can elicit emotional and psychological consequences. As such, genetic testing for HD is often accompanied by extensive genetic counselling to ensure that individuals are supported throughout the process and fully understand the implications of the test results.^2,6

Research on genetic mechanisms and therapies

Given that a single, well-understood genetic mutation causes Huntington’s disease, developing therapies to target this gene has become a focal point for research in treating HD.

Gene silencing techniques

Gene silencing techniques reduce the expression of the mutant HTT gene, which are currently a promising approach for treating HD. One potential treatment involves the use of antisense oligonucleotides (ASOs), which are small DNA-like molecules that bind to the mRNA produced by the mutant HTT gene, which prevents it from being translated into its toxic protein. Early clinical trials of ASOs, for example, Tominersen (IONIS-HTTRx) have shown great promise in reducing the level of mutant huntingtin protein in the brain, thus reducing the symptoms associated with the disease.⁹

CRISPR and gene editing

CRISPR-cas9 is a revolutionary gene-editing tool, which holds immense potential to correct the genetic defect that results in HD.^9,10 It is currently still in the early stages of research; however, scientists are exploring where it could be used to target and excise the expanded CAG repeats in the HTT gene, which would essentially ‘’cure’’ the disease at its source.^9,10 The main challenges associated with this are delivering the technology safely and effectively to the brain to target the correct cells.^9,10

Summary

Huntington’s disease is a neurological disorder caused by a single mutation in the HTT gene. As such, the role of genetics in the disease is crystal clear. The discovery of the genetic mechanism behind HD’s development has revolutionised our understanding of the disorder, allowing us to develop methods for early diagnosis through genetic testing, and paving the way for potential treatments, such as genetic therapies. While there is unfortunately no cure for HD currently, continuous research into gene therapies is promising and offer hope for future generations.