Huntington’s Disease: Causes, Symptoms and Treatment

Huntington's disease (HD) is a rare autosomal dominant inherited progressive neurological disorder characterised by damage neuron cells. Although genes responsible for HD can be found in every individual, but only expanded HD will cause disease. HD occurs due to the presence of HTT gene mutation that generates the CAG trinucleotide repeat expansion. A healthy individual will consist of 10 to 35 CAG repeats, while HD patients normally comprises 40 or more CAG repeats. This leads to the excess production of huntingtin proteins which altered the formation of functional proteins, thus inducing the accumulation of toxic fragments which gradually harms the neurons. Since Huntington’s disease is an autosomal dominant inherited disease, the offspring of the affected individual will have 50% chance to inherit the disease even when only one of the parental gene was affected. The course of this illness is commonly known to be 15 to 20 years. Infections, injuries and heart failure are the most common causes of death for Huntington’s disease patient.

Symptoms

Huntington's disease is characterised by involuntary movements, memory loss, and impaired cognitive, language and coordination abilities. There are 2 main types of the HD which separate based on the age of onset. The early-onset form is also known as the Juvenile Huntington’s disease which the patients start to show symptoms during childhood or adolescence. Juvenile HD is commonly characterized as having the disease symptoms at age 20 or younger. This constitutes nearly 7 per cent of cases. Early signs of juvenile HD are associated with poor performance in learning, seizures and problems in action including, but not limited to, irregular walking and speaking slowly.

Aside from the Juvenile which is rare, the adult-onset is more common as most of the HD symptoms starts to show at age of an individuals from 30 years and above. Basically, HD comes with mild symptoms at first such as difficulty concentrating, behaviour and mood effects or clumsiness. As the time passing, the issues of the memory loss, coordination of limbs, thinking ability, depression or even normal living abilities such as swallowing and breathing will become worse and worse due to the reduced functional on brain to control muscles movements.

Incidence/ Epidemiology

Generally, both men and women have an equal chance of inheriting Huntington’s disease from their ancestor. However, in terms of the seriousness of the disease, an ANCOVA analysis of the motor and functional assessment on 20 to 60 years old Huntington’s disease patients showed that the rate of progression of the disease is slightly higher in women than men. Huntington’s disease is more likely to affect Europe, North America, and Australia descent compared to Asian descent, with an overall prevalence of 5.70 per 100,000 for the former and an overall prevalence of 0.40 per 100,000 for the latter. This finding is supported by Rawlins et al. and Baig et al. in 2016.

Causes of Huntington’s Disease

In 1872, George Huntington was the first person which give a comprehensive description of adult-onset HD. [HeidiIn,2008]. The HD gene, Htt had been mapped out by James F.Gusella to a human chromosome in 1983 [Gusella et al.,1983]. The Htt gene was found on the chromosome 4 (4p16.3) which effecting the neurons production puzzling throughout in the brain while the specific role of Htt in not clear. Different from the normal individuals, HD patients consist of the multiples repeat of trinucleotide that believed to cause toxicity to the brain cells, specifically the basal ganglia and parts of cortexare. This could be proved by the affected motion control and thinking capability are mainly coordinated through basal ganglia and cortex. The aggregation of protein caused by the Htt gene was due to the excess glutamine residues translated by the repeated CAG and caused mHtt to folded abnormally which consequently forms more proteins aggregates. One of the signature sign of HD was the presence of dead neurons mainly found in the striatum. One of the most significant potential pathways for pathogenesis of HD is transglutaminase. Transglutaminase causes neuronal aggregation. The discovery of transglutaminase pathway leads to the introduction of cysteamine which inhibits the pathway.

Diagnosis

Nowadays, the most common and accurate form of diagnosis for Huntington’s disease is by genetic screening of blood sample. People who contain 36 to 39 copies of CAG repeats in the HTT gene are considered at high risk as this group of people might or might not develop the symptoms. On the other hand, a person who contains more than 40 copies of the CAG repeats will develop the disease as they contain a full penetrance gene. Given that huntington’s disease is an inherited neurological disease, neurologists will also investigate the pedigree of the individual, carry out linkage testing, and examine individual’s physical function before leading to a final diagnosis.

Treatment Available

Nowadays, the pathophysiological pathways of the mutated HD that lead to cognitive and psychiatric changes is still unclear. This is the reason why seeking a disease-modifying treatment is very challenging. Hence, there is yet a viable disease-modifying therapy available for HD. Currently, drug prescribed for HD patient only helps to relieve the non-motor symptoms caused by HD. For instance, Tetrabenazine (TBZ) is the only FDA approved drug for HD which relieves chorea symptoms. While other medications such as dopamine antagonists are commonly suggested as a treatment for chorea, neither of the drugs are proven to be effective in randomized, double-blind nor placebo-controlled trials to reduce chorea symptoms. This highlighted the importance of discovering a more effective treatment for this progressive and complex disorder that to be known to cause a range of non-motor issues. All the trial research that aims to identify potential HD therapy mainly focus on targeting mHtt which was proved to be the responding gene. This is important in understanding the signalling pathway that leads to cell death and the pathways that reduce and inhibit mHtt.

During late 90’s, Melino et al. 1998 and Lesort et al., 2000 raised the potential of transglutaminase inhibitor like cysteamine which promotes neuroprotective effect as a disease-modifying treatment for neurological diseases. This statement is enhanced by Institut Curie who demonstrated the potency of cysteamine in treating Huntington’s disease specifically. Cysteamine is a reduced form of cysteamine that can be found in mammalian cell as a product of coenzyme A metabolism. The nature of cysteamine passing through the blood-brain barrier, makes it a high expectancy candidate of HD therapeutic applications. Effect of cysteamine on HD was initially focused on the mechanism to inhibit transglutaminase as this is believed to be the core pathology that causes toxic to the brain cells. Cysteamine functions by catalysing y-glutamyl crosslinks between protein. Despite it was proven in latest studies that inhibiting the transglutaminase does not prevent neurodegeneration in HD, cysteamine is still a strong candidate as a disease-modifying treatment for HD as the majority of the studies showed positive results in terms of neuroprotective, antioxidant and prolonged life-span.

Conclusion

In fact, the uncertain of the ways that how exactly the presence of mutated huntingtin gene that brings in the toxicity to the brain cells is still unclear which make the research on the treatment more challenging. It is also believed that the based on the increased numbers of the CAG repeats, the earlier the onset of the symptoms of disease, known as anticipation phenomenon. Huntington’s disease is an inherited condition characterised by progressive destructive to the brain. The disease is caused by mutated HTT genes. Currently, there is no cure for HD. Tetrabenazine or antipsychotic drugs which associated with significant side effects have been used to control the clinical symptoms of Huntington’s disease by modulating the neurotransmitters. Cysteamine, which is a transglutaminase inhibitor has been proposed as a potential treatment for Huntington’s disease.