Pathophysiology of Huntington Disease
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Published: Thu, 23 Nov 2017
George Huntington first described Huntington Disease in 1872 as “coming on gradually but surely, increasing by degrees, and often occupying years in its development until the hapless sufferer is but a quivering wreck of his former self” (Visser, 2010). Huntington disease is an inherited genetic disorder, which causes the progressive degeneration of selected nerve cells in the brain. This degeneration of nerve cells results in impairment of both mental capability and physical control which results in death (Visser, 2010). This essay will look at the pathophysiology of Huntington disease in relation to the possible signs and symptoms. While also identifying the risk factors and examining the relevant tests available with regards to screening, diagnosing and monitoring treatment within New Zealand. It will then further explore the treatment options available in New Zealand and treatment developments worldwide.
Pathophysiology of Huntington disease in relation to signs and symptoms
Huntington disease is caused by a genetic fault in a small section located on chromosome 4, which encodes a protein called Huntington (Porth, 2011). However, the function of the Huntington protein is still unknown, yet this protein appears to be important to neurons in the brain (Visser, 2010). This genetic fault results in a segment of DNA, known as a CAG trinucleotide repeat, this segment of DNA is made up of a series of DNA building blocks cytosine, adenine and guanine that appear multiple times in a row (Visser, 2010). The normal copy of this gene contains 6 to 35 copies of the trinucleotide repeat, compared to the faulty gene which contains 40 to 120 copies of the trinucleotide repeat resulting in this gene producing an expansion of Huntington’s gene (Porth, 2011). The larger number of trinucleotide repeats is generally associated with an earlier onset of Huntington’s’ disease. This is shown as adults with Huntington’s disease generally have 40-50 trinucleotide repeats where people with the juvenile form of this disorder tend to have more than 50 trinucleotide repeats (Visser, 2010). Also, Visser (2010) suggests that due to the elongation of the CAG trinucleotide segment, the segment gains a toxic function that disrupts the normal function of neurons and eventually leads to the death of neurons.
Cells are known as building blocks of life that use energy to carry out biological functions, while also producing oxidants that can potentially damage themselves; Yet, these cells can make such chemicals harmless (Visser, 2010). Current studies suggests that the protein Huntington somehow prevents the brain cells from protecting themselves against the toxic chemicals which results in Huntington’s disease causing the localized death of brain and spinal cord cells (Porth, 2011). Basal ganglia are the first neurons to be affected by Huntington disease; these neurons are associated with a variety of functions that modulate motor movements, emotions, cognitive and learning abilities (Porth, 2011). Therefore the deteriation of basal ganglia results in many symptoms which commonly occur around 35 and 55 years of age, however these symptoms will progressively get worse which results in the individual passing away in around 10-20 years (Porth, 2011).
There are early signs and symptoms of Huntington disease which include uncontrolled muscular movements, memory problems and mood changes (Visser, 2010). Yet, these symptoms quickly develop into serious motor impairment conditions such as eye movement disorders, spasticity, dysphagia, dysarthria, myoclonus, and the main impairment chorea which involves rapid, jerking movements that the individual has no control over (Porth, 2011). As Huntington disease develops it results in a cognitive decline, mental slowing which is the inability to remember people and to make decisions for oneself (Porth, 2011). This can all eventually lead to dementia. There are many factors that influence behavioural symptoms which include stress about the disease, family relationships, and as the pathways through the basal ganglia become disconnected which results in a loss of frontal lobe functions (Visser, 2010). The major behavioural symptom is depression with 30% of individuals with Huntington disease experiencing major depressive or dysthymic disorders and 6% resulting in suicide (Porth, 2011). Other behavioural symptoms such as personality changes results in the individual appearing to have no interest in life or the individual having increased anger and irritability which further links to impulsive actions and violence, these actions can cause stress in relationships between family members (Visser, 2010).
Risk Factors of Huntington disease
Everyone receives two copies of each gene which are singularly known as alleles, one from each parent, that are present in all cells of the body (Lemiere, 2004). Therefore most individuals are born with two normal copies of each allele (Lemiere, 2004). However in the case of hereditary disorders specifically Huntington’s disease, an individual is born with one normal gene and a gene defect which is called a mutation (Lemiere, 2004). Huntington disease has an autosomal dominant inheritance pattern which means that a child of a parent who carries the mutation has a 50% chance of inheriting the mutation (Frank, 2014). If the child inherits the mutation the child will develop Huntington’s disease some point in the individual’s life, and can also pass it on to their children. But if the individual does not inherit the mutation then they cannot pass it on to their children (Frank, 2014). Yet, there are also rare cases where individuals develop Huntington’s disease, without a family history of the condition (Visser, 2010). This generally happens because of a genetic mutation during the father’s sperm development (Visser, 2010).
However, there is a process where fertilized embryos can be tested for Huntington’s disease prior to the embryos being implanted within a mother’s womb called pre-implantation genetic diagnosis (Christian, 2007). This technique allows the parent that carries the Huntington’s disease to avoid passing the genetic condition to their children (Christian, 2007). Pre-implantation genetic diagnosis is completed through in-vitro fertilization (IVF) where the mother’s egg is fertilized with the father’s sperm outside the body (Christian, 2007). The eggs then develop into embryos, after three days of being cultured in the laboratory the technique of embryo biopsy is performed, this test checks the embryo for the Huntington’s disease and therefore all the embryos are then implanted back into the mother (Christian, 2007). New Zealand has been ethically approved for pre-implantation genetic diagnosis however this is only under special circumstances (Christian, 2007). The government only funds pre-implantation genetic diagnosis for 40 couples a year with one single attempt at pregnancy; this funding includes all serious genetic conditions (Christian, 2007).
Relevant diagnostic, screening and monitoring tests in New Zealand
Genetic tests are an example of a diagnostic as it is a procedure performed that establishes if an individual has the presence or absence of Huntington’s disease (Lyon, 2013). Individuals that have symptomatic symptoms of Huntington’s disease may be recommended by health care professionals to undertake a genetic test for the faulty Huntington gene (Visser, 2010). However, there is also predictive DNA testing which is for asymptomatic individuals with a 50% chance of developing Huntington’s disease, these individuals are tested to see if they will be affected or not by the faulty gene in adulthood (Visser, 2010). Both of these genetic tests are accomplished in the same way and can be done in Auckland laboratory (Lyon, 2013). Genetic testing is done by DNA being extracted from the individual’s blood sample, and then the DNA being purified (Lyon, 2013). A technique called polymerase chain reaction is then implicated to locate the two Huntington genes, once found millions of exact copies are made for further analysis (Lyon, 2013). This further analysing is when the DNA is sorted by size to determine the number of CAG repeats in each gene. The three outcomes to the test are based on the CAG repeats (Lyon, 2013). If an individual receives a negative test it means the CAG repeat size is 30 or less and therefore the individual is not at risk of developing Huntingtons disease, but if an individual receives a positive test it means the CAG repeat size is 40 or more and the individual will develop Huntington’s disease generally in adulthood (Lyon, 2013). However if an individual receives uninformative it mean the CAG repeat is in the immediate range between 31-39 and is unclear if the individual will develop Huntington’s disease (Lyon, 2013).
Other tests available are known as screening this is where a series of tests are used to predict the presence of disease in individuals at risk (Lemiere, 2004). These tests include neurological examinations, along with structural and functional imaging. Neurological examinations are performed by a neurologist, which intensively interviews an individual to obtain the medical history and rule out other possible medical conditions (Lemiere, 2004). Some key aspects neurologists use to identify Huntington’s disease include taking a family history as Huntington disease is an inherited disorder and taking note of reflexes, muscle strength and eye movements as some of the earliest manifestations of the disease are “subtle chorea, eye movement and fine motor abnormalities” (Lemiere, 2004). However, Lemiere (2004) suggests that the Huntington gene defect may influence brain function and behaviour during asymptomatic years, this research has been conducted using presymptomatic individuals who have a positive gene defect. These individuals had a volume reduction of “30.9% for the caudate, 29.3% for the globus pallidus and 25.7% for the putamen” (Lemiere, 2004) compared to individuals with a negative gene defect from offspring of Huntington disease patients (Lemiere, 2004). This research shows that the decline of basal ganglia occurs gradually before the onset of Huntington disease symptoms (Lemiere, 2004). Therefore healthcare professionals can use MRI and CT scans of the brain to help determine if patients have Huntington’s disease (Lemiere, 2004).
The monitoring of treatment is extremely important in Huntington’s disease and dependently relies on the motor, behavioural and cognitive aspects of the individual (Frank, 2014). After the onset of Huntington disease the individuals’ functional abilities gradually worsen over time due to the Huntington gene mutation that causes a localized death of neurons which helped to regulate the motor movements, emotional and cognitive abilities (Frank, 2014). The loss of these abilities requires the individual to seek help for all activities of daily care, yet later in the disease the individual will be confined to a bed with the inability to speak (Frank, 2014). This gradual decline of the individuals’ condition makes it important for health care professional to monitor the individuals’ treatments and adjust the treatment accordingly to the disease progress (Frank, 2014). Further, the drugs used in treatment of Huntington’s disease has the potential to cause significant side effects that can worsen symptoms of the disease (Frank, 2014). Therefore it is critically important for health care professionals to monitor the risk- benefit ratio effect the treatment has on an individual (Frank, 2014).
Treatment available in New Zealand and further treatment developments worldwide
Currently, there is no cure for Huntington disease, but medications, psychotherapy, speech and physical therapy can be implemented to help minimize symptoms while also allowing the individual to adapt to their condition (Frank, 2014). Medications to help treat movement disorders in New Zealand include Xenazine this medication helps to suppress chorea, but has possible side effects of aggravating depression (Frank, 2014). Also, the use of certain antipsychotic drugs such as haloperidol and clozapine can help alleviate choreic movements and further controlling hallucinations and violent outbursts, but the possible side effects can worsen dystonia and muscle rigidity (Frank, 2014).
Due to the loss of frontal lobe functions as an effect of the disease, there needs to be increased psychiatric support for individuals with Huntington’s disease (Visser, 2010). This support can come from medications that support depression such as antidepressants which include fluoxetine, sertraline and esctislopram (Frank, 2014). This treatment of depression can further help to improve the symptoms of sleep disturbance, social withdrawal and lack of interest in general life (Frank, 2014). However, using antidepressants can include the side effects of insomnia, diarrhoea, nausea and sexual problems (Frank, 2014). Other medications to help individuals can be antipsychotic and mood stabilizing drugs which help to supress violent outbursts, highs and low mood swings, the common side effects of these medications include weight gain, tremor and gastrointestinal problems (Frank, 2014).
Psychologists can provide talking therapy for an individual with Huntington disease, this therapy allows the individual to understanding the conditions effects, while further discussing the problems and feeling the individual has (Frank, 2014). Such problems the individual could be concerned about are talking, eating and swallowing this is because Huntington disease impairs the control of muscles of the mouth and throat (Frank, 2014). A speech therapist can address these issues and improve the individual’s ability of communication by implementation communication devices (Frank, 2014). Physical therapy is also an important part of Huntington disease as the exercises provide help improve strength, balance and coordination, which further results in the individual maintain mobility for as long as possible and minimizing the possible falls (Frank, 2014).
Even though there is no treatment the research field is still dynamic there are a high number of on-going or recently completed studies in relation to Huntington disease (Frank, 2014). Also, in the USA there has been a break through approach called gene-silencing (Carrol, 2013). This approach relies on the fact that DNA is not directly copied from the protein, but is made up from a chemical RNA first; this RNA message is chopped up and thereby stops the cell making the Huntington protein (Carrol, 2013). Although this approach does not stop the individual from carrying the Huntington disease and, therefore the individual can still pass the gene on, this approach stops making the protein that attacks the brain cells (Carrol, 2013). Another breakthrough development happened in the UK this is of a tool called CRISPR (clustered regularly interspaced short palindromic repeats) that targets and cuts out specific small pieces of RNA (Carrol, 2013). This tool is used in the approach genome editing. This approach is different to gene silencing as it corrects the defect, which results in the individual not having the genetic defect and therefore produce babies without Huntington disease (Carrol, 2013).
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