Huntington’s disease, often known as Huntington’s chorea, is a late-onset genetic disorder that causes severe neurodegeneration. The condition is inherited in an autosomal dominant manner, though symptoms of the condition do not usually present before the individual’s mid-thirties. Huntington’s is, regrettably, fatal and as yet very few treatment options exist. The nature of the genetic mutation can have dramatic effects on prognosis, though most patients can live for up to two decades after diagnosis, with motor symptoms (uncoordinated movement, dementia and other behavioural disorders) becoming progressively worse.
Huntington’s is a trinucleotide repeat disorder, meaning that the underlying mutation that causes the condition is due to the expansion of a series of three bases (Budworth and McMurray, 2013). In this case, a CAG repeat in the Huntington gene is unstable and is grows in copy number when it is replicated. This usually means that, when the gene is inherited, the number of CAG repeats also increases in number. Unfortunately, there is a strong correlation between the number of repeats and disease severity (McMurray, 2010), so descendants of Huntington’s patients that inherited the aberrant allele will often experience more rapid deterioration in condition. The discrepancy between affected and unaffected individuals is dramatic: normal copies of Huntington have between 3-6 CAG repeats, but in mutated versions of the gene numbers can run into the hundreds.
The exact function of the Huntington gene product, HTT, has yet to be fully elucidated. However, it is believed to have roles in a diverse array of cellular processes including gene expression, transport and ciliogenesis (Kreyer et al., 2011). Knock-outs of the gene are homozygous lethal, indicating that whatever the functions of the protein it is critical to normal cellular homeostasis. HTT is expressed in all cells, though the highest levels of expression are observed in the brain and testes (Li et al., 1993).
The nature of the trinucleotide repeat disorders means that mutated versions of the human protein have an extended polyglutamine (polyQ) domain. Generally, HTT is very highly conserved between species, though it is in this region that variability between homologs exist. As a rule, the minimum number of glutamines among vertebrates is four, with so-called “higher vertebrates” have more residues. Humans have more repeats than any other species (Tartari et al., 2008).
Unsurprisingly, the expansion of the polyQ domain has severe – and devastating – impacts on protein function. Mutated proteins have a dramatically increased propensity to aggregate into insoluble amyloid fibrils (Hatters, 2008). These fibrils can be either directly or indirectly toxic: the aggregation of the proteins inhibits their interaction with other complexes, preventing many critical cellular processes from occurring. Alternatively, the aggregates can force other polyQ proteins out of solution. This interaction has been observed between HTT aggregates and the proteasome, initiating a sort of positive feedback loop: the more HTT, the fewer proteosomes there are to degrade it and other proteins, leading to an increased abundance of those proteins. Regardless of the mechanism, HTT aggregates will eventually lead to cell death.
Due to the high levels of HTT expression in the brain, it is more affected by HTT aggregation than any other part of the body. Early in the development of the disease the basal ganglia – an area of the brain that is important for the control of movement – is affected, though it eventually spreads to the substantia nigra, the cerebellum, and parts of the thymus (Walker, 2007). Interestingly, the substantia nigra is the region of the brain most affected in Parkinson’s Disease, another neurodegenerative condition that leads to severe impairment of motor control. The area is rich in dopaminergic neurons that produce dopamine, the brain’s “motivational” chemical. When these neurons are damaged the levels of dopamine decrease dramatically, meaning that the sufferer has difficulty in initiating or controlling actions.
These abnormal movements – termed “chorea” – are characteristic of Huntington’s disease. Initially they may present as slight, involuntary facial tics but often progress to large, jerky movement of limbs. Sufferers will also have difficulty with speech and food as muscles of the throat and mouth start to waste and degrade. Life expectancy after diagnosis is usually around twenty years, with cause of death being through secondary conditions such as pneumonia or heart disease (Walker, 2007).
With regard treatment, there are regrettably few options for those affected by Huntington’s. Most interventions instead aim to improve quality of life and reduce disease severity, though the efficacy of many such treatments is unclear. As muscle degradation makes communication difficult, many patients will receive speech and language therapy. Regular exercise is also strongly recommended, with some case-control studies finding that regular exercise causes the rate of deterioration to slow in a treatment groups. Though symptoms did eventually progress, the extended period of mobility and proper cognitive function is not insignificant.
There are few approved medications for treating Huntington’s. All approved drugs seek to mitigate symptoms rather than treat the underlying cause. The cognitive deterioration causes many to suffer from depression and mood swings, so anti-depressents are often prescribed. Some antipsychotics – such as olanzapine and sulpiride – and dopamine inhibitors have also been shown to reduce the degree of involuntary movements.
Nevertheless, many hope for a cure. Some progress has been made, particularly in the field of gene therapies. As Huntington’s has a clear genetic basis it is an ideal candidate for developing such treatments. Recently a gene-silencing drug was shown to be effective at targeting HTT in mice and monkeys, with human trials currently underway (American Acadamy of Neurology, 2016). Administration of the drug – called IONIS-HTTRx – reduced the levels of HTT by up to 50% and was shown to both slow and reverse the progression of the disease.
Improved treatments mean that many with Huntington’s can live relatively normal lives for years after their diagnosis, though a cure still remains out of reach. Increased understanding of Huntington’s pathology will help develop novel drug targets, whilst cohort studies can assist in developing palliative treatments for those currently affected by the disease. Several possible treatments are currently being tested, offering a new and real hope for sufferers and their children.
American Academy of Neurology (2016). Potential treatment for Huntington’s disease, found effective, safe in mice, monkeys: Drug enters clinical testing. Science Daily <www.sciencedaily.com/releases
Budworth, H. and McMurray, C.T. (2013). A brief history of triplet repeat diseases. Methods in Molecular Biology 1013:-17
Kreyer, G., Pineda, J.R., Liot, G., Kim, J., Dietrich, P., Benstaali, C., Smith, K., Cordelières, F.P., Spaasky, N., Ferrante, R.J., Dragatsis, I. and Saudou, F. (2011). Ciliogenesis is regulated by a huntintin-HAP1-PCM1 pathway and is altered in Huntington disease. The Journal of Clinical Investigation 121:4371-4382
Hatters, D.M. (2008). Protein misfolding inside cells: The case of huntington and Huntington’s disease. IUBMB 60:724-728
Li, S.H., Schilling, G., Young, W.S., Li, X.J., Margolis, R.L., Stine, O.C., Wagster, M.V. Abbostt, M.H., Franz, M.L. and Ranen, N.G. (1993). Huntington’s disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11: 985-993
McMurray, C.T. (2010). Mechanisms of trinucleotide repeat instability during human development. National Review of Genetics 11:786-799
Tartari, M., Gissi, C., Lo Sardo, V., Zuccato, C., Picardi, E., Pesole, G. and Cattaneo, E. (2008). Phylogenetic comparison of huntington homologues reveals the appearnce of a primative polyQ in sea urchin. Molecular Biology Evolution 25:330-338
Walker, F.O. (2007). Huntington’s disease. Lancet 369:218-228