Huntington’s disease (HD) is a progressive inherited disorder, characterized by degeneration of the brain with its subsequent atrophy, for which no modifying treatment currently exists (Bates, Tabrizi, & Jones, 2014).
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Morbidity and Mortality
The disease is not widespread and affects 5-15 in 100,000 people of Caucasian descent and even fewer Asians. Despite the fact that its occurrence in Africa is unknown, it can be deduced that the disease is still most prevalent among the white population, the reason for which is not fully comprehended. HD affects both male and female patients equally, with a slight preponderance of women (Bates et al., 2014).
A recent study found out that 340 out of 249,811 residents dwelling in nursing homes were diagnosed with Huntington’s disease, which accounted for 0.14%. The majority of them were between 55 and 59 years old; 77.8% were Caucasian; 61% were female (Zarowitz, O’Shea, & Nance, 2014).
The overall mortality rate among the affected is approximately 0.2-0.3 per 100,000 patients annually. Since the disease causes heart and respiratory complications, it is rarely listed among the only or the underlying causes of death. Suicide occurs in about 10% of cases (Bates et al., 2014).
The condition emerges due to a genetic defect in chromosome 4, which causes an expanded CAG (cysteine-adenosine-guanine) repeat. This implies that a part of the DNA is made to appear much more frequently than it normally does (36-120 times as compared to normal 10-28 times). The gene in its healthy state produces huntingtin (a protein) whereas a faulty copy of the gene is much larger and therefore produces enlarged huntingtin, which undermines some of the brain cell functions.
As a result, these cells are gradually being destroyed. Since the disease is inherited, the number of repeats increases each time it affects a new family member. Thus, the higher the number of repeats is, the more likely it is that a patient will reveal the symptoms of the condition at an earlier age (Labbadia & Morimoto, 2013). However, if a person does not get the gene of Huntington’s disease from his/her parents, there is no chance that he/she will pass it to his/her children.
The major risk factor of HD is genetic. The onset is accounted for by CAG instability and CAG-repeat length since these factors determine at what age the disease will reveal itself. CAG-repeat length is also responsible for the level of neuropathological severity of the condition and reduced volume of the brain in the affected individuals. Maternal and paternal transmission can cause CAG repeats either to expand or to contract; however, expansions are met much more frequently (Bates et al., 2014).
As far as progression risk factors are concerned, solely CAG-repeat length is accountable for the rate of deterioration of cognitive, motor, and other neurological functions, earlier hospitalization, and shorter life expectancy. Most researchers agree that the reason for the dominant influence of CAG-repeat length both on the onset and development of the disease (especially at its late stages) is a mechanism of increased toxicity to neuronal tissues that appears as a consequence of the expanded polyglutamine stretch in the protein (Chao, Hu, & Pringsheim, 2017).
There are no known risk factors of Huntington’s disease besides hereditary ones. However, there are some weak and questionable connections of its onset with environmental and demographic factors indicated in a very limited number of studies. As it has already been mentioned, the disease is a little more frequent in males and females of Caucasian ancestry between 55 and 59 years old; and is practically never met in other ethnicities (Zarowitz et al., 2014). Yet, it still occurs due to CAG mutation.
The most evident distortion appears in the striatum (one of the nuclei located in the subcortical basal ganglia of the forebrain): Caudate nucleus (one of the structures that constitute the dorsal striatum) and putamen (the outer part of the lentiform nucleus of the brain) are subjected to severe atrophy (Drouin‐Ouellet et al., 2015). This condition is aggravated by astrogliosis (a pathological increase in the number of astrocytes caused by the destruction of nearby neurons) and selective neuronal loss, which is also found in deeper layers of the cortex. The degrees of cells atrophy in other parts of the brain may vary significantly across patients (Bates et al., 2014).
It is possible to grade the severity of Huntington’s disease judging by the degrees of striatal pathology and neuronal loss. The assigned grades vary from 0 to 4. In grades 0-1, no severe atrophy of striatum is observed. Grade 0 implies that there is a positive family history of the disease and the presence of a typical clinical picture suggesting HD; however, no neuropathology can yet be detected. Grade 1 means that certain neuropathologic distortions can be identified in the patient’s brain with the help of a microscope (Bates et al., 2014).
There is still no gross atrophy present. In contrast, in grade 2, striatal atrophy is already detectable although the caudate nucleus is still intact, remaining convex. The atrophy is aggravated in grade 3, affecting the caudate nucleus, which becomes flat at this stage. Further exacerbation of the condition is observed in grade 4. The caudate nucleus is concave, and the patient loses his/her motor and cognitive functions (Drouin‐Ouellet et al., 2015).
The genetic basis of the disease is a mutation of huntingtin that happens in the DNA of the affected individuals and results in abnormal CAG repeats and the production of enlarged huntingtin with a prolonged stretch of polyglutamine residues. Consequently, various pathologies of the brain emerge. However, the particular functions huntingtin performs are unknown, which makes it difficult to identify the reasons for the accumulation of its N-terminal fragments (Drouin‐Ouellet et al., 2015). They form neuronal intranuclear inclusions that are believed to be pathogenic due to their toxicity. Yet, some of the recent studies hypothesize that the inclusions are not necessarily toxic but their translocation into the cell nucleus is sufficient to cause death of the brain cells (Labbadia & Morimoto, 2013).
Thus, all the signs and symptoms observed in patients having HD appear as a result of striatum (or neostriatum) atrophy. This nucleus located in the subcortical basal ganglia is a vital component responsible for the proper functioning of reward and motor systems. This implies that its atrophy results in poor coordination of various motor functions and cognitive aspects (action-planning, motivation, decision-making, reward perception, and reinforcement), which get aggravated from grade 0 to grade 4 (Labbadia & Morimoto, 2013).
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Signs and Symptoms
Since in grade 0 no atrophy is found (typically at the ages between 35 and 45), changes in physical skills and personality are hardly noticeable. At the next stage, distortions of the motor functions appear first. Behavioral and cognitive symptoms do not reveal themselves until grade 3 when the caudate nucleus becomes flat (Bates et al., 2014). Physical symptoms are generally the same while cognitive and behavioral distortions are unique in each particular case.
The most frequently appearing sign of HD is chorea–uncontrollable, jerky movements, initially exhibited as lack of coordination, restlessness, and uncompleted motions. It can also be accompanied by saccadic eye movements, which are also referred to slight abnormalities. More evident symptoms of motor dysfunction appear in grade 3, in 3-5 years after the disease was diagnosed. They include abnormal posturing and facial expression, seizures, difficulties speaking, chewing, and swallowing, uncontrolled motions, physical instability, rigidity or muscle contracture (dystonia) (Labbadia & Morimoto, 2013). These signs indicate that the striatum has been severely affected. Due to the impairment of eating functions weight loss is frequently observed (Bates et al., 2014).
At the same time, the patient’s cognitive abilities are also gradually deteriorating, which particularly concerns executive functions (cognitive flexibility, initiation of appropriate actions and inhibition of inappropriate ones, planning, abstract thinking, etc.). At the late stages, patients start suffering from memory deficits (including deficits of short-term, long-term, procedural, working, and episodic memory) (Bates et al., 2014). All these problems result in subcortical dementia in the majority of cases.
As for neuropsychiatric signs, the most common ones are aggression, reduced emotional expression, difficulties recognizing other people’s emotions, anxiety, compulsive behaviour, depression, and egocentrism. Suicidal thoughts and attempts also appear more often than in healthy individuals (Drouin‐Ouellet et al., 2015). These symptoms profoundly affect normal daily functioning and therefore lead to hospitalization.
In some rare cases, the disease may bring about abnormalities expressed throughout the whole body, such as cardiac failure, muscle atrophy, osteoporosis, impaired glucose tolerance, etc.
HD is diagnosed on the basis of genetic testing and the symptoms described above. The diagnosis typically takes a sequence of steps. First and foremost, a detailed examination of the patient’s physical condition is performed to identify whether the onset has already started. The condition is suspected if random or unintentional movements are observed. In the second stage, a thorough psychological examination takes place to see if cognitive or behavioural functions have been affected (Bates et al., 2014). Although magnetic resonance imaging and computerized tomography can show signs of atrophy of the caudate nuclei, this fact exclusively does not indicate the presence of the condition.
Functional neuroimaging techniques such as Position emission tomography (PET) and fMRI, which are now used experimentally in a number of hospitals, can help reveal the presence of the disease even before any physical symptoms start to appear.
Genetic blood testing is usually conducted to find out whether there is a mutation in the individual’s copies of the huntingtin gene. Basically, the test counts the number of CAG repeats:
- if there are more than 40, the result is positive, which implies that the patient carries an expanded copy of the gene and is likely to develop the condition one day in his/her lifetime;
- 36-39 repeats indicate that the symptoms will appear much later (approximately by the age of 65);
- 27-35 repeats are not associated with HD in the tested patient; yet, it is still possible for the symptoms to appear in the offspring;
- fewer than 26 repeats mean that the test is negative (Bates et al., 2014).
Genetic testing can be performed only when the patient is at least 18 years old. This type of diagnostics does not allow identifying when the first symptoms of the condition will become visible.
Another option is to carry out prenatal testing to check if the mutation gene is present in the embryo. For this purpose, they either extract a sample of amniotic fluid surrounding the fetus (the procedure is called chorionic villus sampling) or test it without extraction (the process is referred to as amniocentesis) (Labbadia & Morimoto, 2013). Genetic testing is typically resorted to when one of the parents suffers from HD.
Currently, there is no cure for HD. Neither is there any effective operational interventions that lead to full recovery. That is why all the options available are aimed to decrease the severity of the condition. Occupational, physical, and speech therapies are used to mitigate the symptoms. An affected person needs nutrition management owing to weight loss and swallowing difficulties. To make liquids safer to swallow, thickening agents can be added to prevent choking.
If the process starts threatening the patient’s life, it is possible to resort to percutaneous endoscopic gastronomy (a feeding tube attached to the abdomen). At an early stage, non-medication-based ways of treatment are sufficient to manage the symptoms. Physical therapists usually recommend breathing exercises, assisted walking, stretching, etc. (Wilson & Aubeeluck, 2016). With the progress of the disease, tetrabenazine, benzodiazepines, and neuroleptics are implemented for treating chorea (involuntary movements).
Antiparkinsonian drugs are suitable for managing rigidity and hypokinesia (loss of muscle movement) (Bates et al., 2014). Psychiatric symptoms are treated as in the general population: Depression can be managed by mirtazapine while antipsychotic medications are used for behavioral problems and psychosis.
Complications and Sequelae
Complications and Sequelae of HD include a number of secondary disorders caused by the disease (sometimes indistinguishable from its symptoms). Although the disease is not fatal, its complications significantly reduce life expectancy. The most frequently appearing ones are pneumonia and heart failure. Furthermore, patients may also suffer from gastrointestinal and respiratory problems. Other complications include schizophrenia, manic-depressive disorder, incontinence, chronic brain failure, choreoathetosis, etc. (Bates et al., 2014).
Bates, G., Tabrizi, S., & Jones, L. (Eds.). (2014). Huntington’s disease (No. 64). Oxford, UK: Oxford University Press.
Chao, T. K., Hu, J., & Pringsheim, T. (2017). Risk factors for the onset and progression of Huntington disease. Neurotoxicology, 61(2), 79-99.
Drouin‐Ouellet, J., Sawiak, S. J., Cisbani, G., Lagacé, M., Kuan, W. L., Saint‐Pierre, M.,… Calon, F. (2015). Cerebrovascular and blood–brain barrier impairments in Huntington’s disease: Potential implications for its pathophysiology. Annals of Neurology, 78(2), 160-177.
Labbadia, J., & Morimoto, R. I. (2013). Huntington’s disease: Underlying molecular mechanisms and emerging concepts. Trends in Biochemical Sciences, 38(8), 378-385.
Wilson, E., & Aubeeluck, A. (2016). Knowledge in practice: The specialist nurse role in Huntington’s disease. British Journal of Neuroscience Nursing, 12(4), 185-189. Web.
Zarowitz, B. J., O’Shea, T., & Nance, M. (2014). Clinical, demographic, and pharmacologic features of nursing home residents with Huntington’s disease. Journal of the American Medical Directors Association, 15(6), 423-428. Web.