What Causes Huntington’s Disease?

 by Muhammed Sahil

(source: Wiki Commons)

Huntington’s disease is a rare disease which causes the progressive breakdown of nerve cells in the brain. Currently the number of people diagnosed with Huntington’s disease is around 6000.

HD is caused by a faulty gene attached to chromosome pair number 4 (one of the 23 pairs of human chromosomes that carry the entire genetic code of the individual). Genes are present in every cell of our body and their role is to provide instructions to our cells. Our genes provide the genetic information required to make proteins. The faulty gene that causes HD repeats a particular coding sequence called Cytosine-adenine-guanine (CAG). The protein, that the mutated gene manufactures damages the nerve cells in our brain. Every individual has the HTT gene which provides the instructions for making a protein called huntingtin. It’s exact function is unknown but it’s thought to play a vital role in nerve cells in the brain and is important for normal development before birth. This protein is found in many body tissues but has the highest levels of activity in the brain. A mutation to the HTT gene increases the size of the CAG segment in the HTT gene. People with HD have 36 to more than 120 CAG repeats. If an individual has 36-39 CAG repeats it’s not certain that they will develop any signs or symptoms of HD. However people with 40 or more repeats will almost always develop this disease.

The larger segment of CAG means the sufferer produces an extensive long version of the huntingtin protein. This expanded protein breaks down into smaller toxic fragments which bind together, accumulating in neurons, thus leading to the disruption of the normal function of these cells. One of the functions of the unaffected huntingtin protein as shown by some studies, is that it plays a role in repairing damaged DNA but the new abnormal protein can no longer repair DNA, so it may lead to an accumulation of DNA damage in nerve cells, particularly during ageing. The areas of the brain involved in coordination of movement/controlling emotions and thinking (the cerebral cortex and striatum) are also affected due to the destruction of the nerve cells. As this is a neurodegenerative disease, the symptoms build up over time.

If a parent has the Huntington’s disease gene, there’s a 50% chance that their children develop the gene, which can further pass on to any children they have. If unaffected, they can’t pass on the disease to any children they have. If both parents have inherited the faulty gene, there's a 75% chance of any of their children inheriting it.

Symptoms 

Symptoms for HD usually occur between the age of 30 and 50 but can appear as early as 2 or as late as 80. 

HD causes a variety of problems such as:

• abnormal involuntary movement of the arms, legs, head, face and upper body

• a decline in thinking and reasoning skills, including concentration, memory, judgement and the ability to plan/organise

• Individuals with HD are also affected mentally as the destruction of nerve cells in the brain leads to changes in their mood, leading to depression, anxiety, anger and irritability

• Obsessive compulsive behaviour is also a common symptom found in sufferers meaning they tend to repeat the same activity or question continuously

 As symptoms begin, the disease progresses gradually, meaning an individual will continually have to adapt to changes as the disease worsens. 

Currently there’s no cure for HD and there’s also no way to stop its progression but individuals can learn to manage their symptoms effectively, to improve their quality of life. Therefore it’s important to remember that the medication/therapy available doesnt stop or slow down the condition, but can only reduce the symptoms it causes.

The treatment and support currently available for the issues that it causes include:

•  physiotherapy to help with movement and balance

•  speech and language therapy for feeding and communication problems

• occupational therapy for assistance with everyday tasks

• antidepressants for depression

• Medicines to help ease mood swings/irritability 

• Medicine to reduce the number of involuntary movements

Future treatment?

Currently research is ongoing into new treatments with the main focus on gene silencing drugs.

Recently in 2019, Neurology specialists in Southampton took part in a study (which is still currently going on), to slow down the progression of HD by “switching off” the faulty gene. Patients with HD at Southampton general hospital are being offered to participate in the study with the aim of slowing down the progression of HD through silencing the gene. The drug is given to patients via an injection into the spine. This study is a continuation from a previous smaller trial which had shown promising results.

The drug being trialed is composed of antisense oligonucleotides which work by stopping the production of the Huntingtin protein from the faulty gene and so prevents its destructive effect. Dr Christopher Kipps who’s a neurologist at University Hospital Southampton NHS Foundation Trust and is leading the study in Southampton said that this drug has been tested over many years in the small scale trial with promising results but now with the much larger sample consisting over over 600 patients, doctors will have greater knowledge about how effective this drug is in reducing the level of Huntingtin protein in the brain and “in turn hopefully limiting or reducing the long term motor, psychological and psychiatric effects of the disease.” 

Participants will regularly have MRI scans so doctors can determine whether or not the drug can prevent the loss of brain tissue which is usually seen as the HD progresses.

Despite the study being a long process, if proven safe and successful, it could potentially be a major breakthrough for people with HD.