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Prevention and Treatment of Huntington's Disease
1. Introduction
Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia, thereby affects a person's ability to think, talk, and move .It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. The disease is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin, which means any child of an affected parent has a 50% risk of inheriting the disease. In the rare situations where both parents have an affected copy, the risk increases to 75%, and when either parent has two affected copies, the risk is 100% (all children will be affected). Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or Westphal variant HD.
The worldwide prevalence of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, and is lower in the rest of the world, e.g. one per million people of Asian and African descent. Additionally, some localized areas have a much higher prevalence than their regional average.
2. Signs and symptoms
Symptoms of Huntington's disease commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age. In the early stages, there are subtle changes in personality, cognition, and physical skills. The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages. Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking. Eating difficulties commonly cause weight loss and may lead to malnutrition. Sleep disturbances are also associated symptoms. Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.
Cognitive abilities are impaired progressively. Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions. As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity) and working memory. Cognitive problems tend to worsen over time, ultimately leading to dementia. This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g. Alzheimer's disease.
Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, the latter of which can cause or worsen addictions, including alcoholism, gambling, and hypersexuality. Difficulties in recognizing other people's negative expressions have also been observed. The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%. For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization.Suicidal thoughts and suicide attempts are more common than in the general population.
Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.
3. Causes
All humans have the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT genes causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene, and hence its severity, can be influenced by the sex of the affected parent.
(1). Genetic mutation
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin. However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics. This altered form, called mHtt (mutant Htt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these type of neurons, and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD. 36–40 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed. With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.
(2). Inheritance
Huntington's disease is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of gender, and the phenotype does not skip generations.
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. Since penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.
Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present. This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD. Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.
Individuals with both genes affected are rare, except in large consanguineous families. For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the phenotype and the rate of progression. Offspring of an individual who has two affected genes will inherit one of them and therefore definitely inherit the disease. Offspring where both parents have one affected gene have a 75% risk of inheriting HD, including a 25% risk of inheriting two affected genes. Identical twins, who have inherited the same affected gene, typically have differing ages of onset and symptoms.
4. Management and Treatment
There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms. For many of these treatments, comprehensive clinical trials to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses and a person's ability to tend to his own needs reduces, carefully managed multidisciplinary caregiving becomes increasingly necessary.
Tetrabenazine was developed specifically to reduce the severity of chorea in HD, it was approved in 2008 for this use in the US. Other drugs that help to reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results. Hypokinesia and rigidity can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid.
Psychiatric symptoms can be treated with medications similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotic drugs are recommended for psychosis and behavioral problems.
Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow. Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking. If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management.
Although there have been relatively few studies of exercises and therapies that help rehabilitate cognitive symptoms of HD, there is some evidence for the usefulness of physical therapy, occupational therapy, and speech therapy. Patients with Huntington’s disease may see a physical therapist for non-invasive and non-medication ways of managing the physical symptoms of HD. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. The Tinetti Mobility Test has been found to be a valid outcome measure for determining whether a patient with HD is at risk for falling, as its scores correlated with the Unified Huntington Disease Rating Scale motor scores (r = –0.751, p<0.0001). Patients with TMT scores below 21 are at higher risk of falling. Other valid and responsive tools for assessing risk of falling in individuals with HD include the Functional Reach Test, Berg Balance Scale, and the Timed Up and Go Test. A Berg Balance Scale score of less than 40 or Timed Up and Go Test score of greater than 14 seconds indicate increased risk of falling in individuals with HD. However, more rigorous studies are needed for health authorities to endorse the usefulness of the rehabilitation professions. A multidisciplinary approach may be important to limit disability.
The families of individuals, who have inherited or are at risk of inheriting HD, have generations of experience of HD which may be outdated and lack knowledge of recent breakthroughs and improvements in genetic testing, family planning choices, care management, and other considerations. Genetic counseling benefits these individuals by updating their knowledge, dispelling any myths they may have and helping them consider their future options and plans.
5. Prognosis
The length of the trinucleotide repeat accounts for 60% of the variation in the age of onset and the rate of progression of symptoms. A longer repeat results in an earlier age of onset and a faster progression of symptoms. For example, individuals with a trinucleotide repeat greater than sixty repeats often develop the disease before twenty years of age, and those with less than forty repeats may not develop noticeable symptoms. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.
Life expectancy in HD is generally around 20 years following the onset of visible symptoms. Most of the complications that are life-threatening result from muscle coordination issues, or to a lesser extent from behavioral changes resulting from the decline in cognitive function. The largest risk is pneumonia, which is the cause of death of one-third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD. Suicide is the next greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by psychiatric symptoms, as they may be considered to be a response of an individual to retain a sense of control of their life or to avoid the later stages of the disease. Other associated risks include choking, physical injury from falls, and malnutrition.
6. Risk factors
Huntington’s disease is genetic disease, caused by mutation in a gene called IT15 located on chromosome 4 (4p16.3) that is inherited as an autosomal dominant trait. A child or an adult is at risk of inheriting or developing HD with 50% chance if one of his/her parent has the disease. In rare cases, one may develop the disease without a family history due to genetic mutation that could have happened during the father’s sperm development (7).
7. Research directions
Research into the mechanism of HD has focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces. Most research is conducted in animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Mice and monkeys, chemically induced to exhibit HD-like symptoms were initially used, but they did not mimic the progressive features of the disease. Since the Huntingtin gene was identified, transgenic animals (mice, Drosophila fruit flies, and more recently monkeys) exhibiting HD-like syndromes can be generated by inserting a CAG repeat expansion into the gene. Nematode worms also provide a valuable model when the gene is expressed.
Genetically engineered intracellular antibody fragments called have been shown to prevent mortality during the development stages of Drosophila models. Their mechanism of action was an inhibition of mHtt aggregation. As HD has been conclusively linked to a single gene, gene silencing is potentially possible and by using gene knockdown in mouse models, researchers have shown that when the influence of mHtt is reduced, symptoms improve. Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded some positive results using this technique in animal models and preliminary human clinical trials.
Numerous drugs have been reported to produce benefits in animals, including creatine, coenzyme Q10 and the antibiotic minocycline. Some of these have then been tested by humans in clinical trials, and as of 2009 several are at different stages of these trials. In 2010, minocycline was found to be ineffective for humans in a multi-center trial.
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