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Huntington's Disease

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Description: Huntington's disease is a genetic disorder that causes progressive degeneration of nerve cells in the brain, affecting movement, cognition, and behavior.
Type: Huntington's disease is a neurodegenerative disorder. It is transmitted through an autosomal dominant inheritance pattern.
Signs And Symptoms: Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age and present as a triad of motor, cognitive, and psychiatric symptoms. When developed in an early stage, it is known as juvenile Huntington's disease. In 50% of cases, the psychiatric symptoms appear first. Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition and physical skills, irritability, and mood swings occur, all of which may go unnoticed, and these usually precede the motor symptoms. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Many people are not aware of their involuntary movements, or impeded by them. 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. When muscle control is affected such as rigidity or muscle contracture this is known as dystonia. Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble a tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing, and speaking. Sleep disturbances and weight loss are also associated symptoms. Eating difficulties commonly cause weight loss and may lead to malnutrition. Weight loss is common in people with Huntington's disease, and it progresses with the disease. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement, rigidity, and tremors is more typical in juvenile HD, as are seizures.Cognitive abilities are progressively impaired and tend to generally decline into dementia. Especially affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility, a lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. 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.Reported neuropsychiatric signs are anxiety, depression, a reduced display of emotions, egocentrism, aggression, and compulsive behavior and hallucination and delusion. Other common psychiatric disorders could include obsessive–compulsive disorder, mania, insomnia and bipolar disorder. 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 with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization. Early behavioral changes in HD result in an increased risk of suicide. Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.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.
Prognosis: The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms. Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic. 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 10 to 30 years following the onset of visible symptoms. Juvenile Huntington's disease has a life expectancy rate of 10 years after onset of visible symptoms. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in 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 third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease. Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, physical injury from falls, and malnutrition.
Onset: Huntington's disease typically has an onset between the ages of 30 and 50, although it can occur earlier or later.
Prevalence: Huntington's disease has a prevalence of approximately 5-10 cases per 100,000 people in Western countries. The prevalence may be lower in other parts of the world.
Epidemiology: The late onset of Huntington's disease means it does not usually affect reproduction. 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 seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000. Additionally, some localized areas have a much higher prevalence than their regional average. One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden. Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation. Some of these carriers have been traced back hundreds of years using genealogical studies. Genetic haplotypes can also give clues for the geographic variations of prevalence. Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended from the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century. Finland, as well, has a low incidence of only 2.2 per 100,000 people.Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.
Intractability: Huntington's disease is currently considered intractable. There is no cure for the disease, and treatments primarily focus on managing symptoms and improving quality of life. Research is ongoing to find effective therapies, but as of now, Huntington's disease remains a progressive and ultimately fatal condition.
Disease Severity: Huntington's disease severity can vary widely among individuals and tends to worsen over time. It generally progresses through stages, including:

1. **Early Stage:** Subtle changes in coordination, mild chorea (involuntary jerking or twitching movements), and cognitive difficulties.
2. **Middle Stage:** Worsening chorea, more pronounced motor symptoms, and cognitive decline. Daily activities become more challenging.
3. **Late Stage:** Severe motor impairment, significant cognitive decline, difficulty in communication, and complete dependency on caregivers.

The progression rate can vary, but symptoms typically begin between ages 30 and 50 and worsen over 10 to 25 years.
Healthcare Professionals: Disease Ontology ID - DOID:12858
Pathophysiology: Huntington's disease is a progressive neurodegenerative disorder caused by a genetic mutation. Pathophysiologically, it is characterized by the expansion of CAG trinucleotide repeats in the HTT gene on chromosome 4. This mutation leads to the production of an abnormal huntingtin protein that aggregates and causes neuronal cell death, particularly in the striatum and cortex. The degeneration of these brain regions results in motor dysfunction, cognitive decline, and psychiatric symptoms. The number of CAG repeats typically correlates with the age of onset and severity of the disease.
Carrier Status: Huntington's disease is an autosomal dominant genetic disorder. This means that if a person inherits one copy of the mutated gene from an affected parent, they will develop the disease. There is no carrier status as seen in autosomal recessive disorders because even one copy of the mutated gene will result in the disease. Therefore, an individual with the mutation will exhibit symptoms, while those without it will not.
Mechanism: Huntington's disease (HD) is a neurodegenerative disorder caused by a genetic mutation.

**Mechanism:**
HD is primarily caused by an autosomal dominant mutation in the huntingtin (HTT) gene, which is located on chromosome 4. This mutation results in an expanded polyglutamine (CAG) repeat sequence in the HTT gene. Normal individuals typically have 10-35 CAG repeats, while individuals with HD have 36 or more repeats. The longer the repeat sequence, the earlier the onset and more severe the symptoms of the disease.

**Molecular mechanisms:**
1. **Protein Aggregation:** The expanded polyglutamine tract leads to the production of an abnormal huntingtin protein (mHTT). This mutant protein misfolds and aggregates, forming intranuclear and cytoplasmic inclusions.

2. **Proteolytic Cleavage:** mHTT is susceptible to proteolytic cleavage, producing toxic N-terminal fragments that further contribute to cellular dysfunction.

3. **Transcriptional Dysregulation:** mHTT interacts abnormally with various transcription factors, leading to altered gene expression that disrupts normal cellular functions.

4. **Mitochondrial Dysfunction:** mHTT impairs mitochondrial function, resulting in reduced ATP production, increased oxidative stress, and eventual neuronal cell death.

5. **Impaired Protein Degradation:** The ubiquitin-proteasome system and autophagy, both essential for protein degradation, are disrupted by mHTT, leading to accumulation of toxic proteins.

6. **Excitotoxicity:** Altered glutamate signaling and impaired calcium homeostasis contribute to neuronal excitotoxicity, further promoting neuronal damage and death.

These molecular abnormalities predominantly affect neurons, especially in the striatum and cortex, leading to the progressive motor, cognitive, and psychiatric symptoms characteristic of Huntington's disease.
Treatment: Currently, there is no cure for Huntington's disease, but treatment focuses on managing symptoms and improving quality of life. These treatments may include:

1. Medications:
- Tetrabenazine and deutetrabenazine to reduce chorea (involuntary movements).
- Antipsychotic drugs to manage mood swings, irritability, and hallucinations.
- Antidepressants for depression and anxiety.
- Mood-stabilizing drugs for significant mood changes.

2. Therapies:
- Physical therapy to improve strength, balance, and flexibility.
- Occupational therapy to help with daily tasks.
- Speech therapy to address speech and swallowing difficulties.

3. Supportive Care:
- Nutritional support to manage weight loss and dietary needs.
- Counseling and psychiatric support for mental health issues.
- Social support and community resources for families and caregivers.
Compassionate Use Treatment: Compassionate use treatment and off-label or experimental treatments for Huntington's disease (HD) focus on addressing the symptoms and, in some cases, attempting to slow disease progression. These treatment options can include:

1. **Tetrabenazine and deutetrabenazine:** Although primarily used for managing chorea, these drugs are sometimes explored for broader symptom control.
2. **Antidepressants and antipsychotics:** Drugs such as selective serotonin reuptake inhibitors (SSRIs) and dopamine antagonists, typically used off-label, can help manage psychiatric symptoms like depression and psychosis.
3. **Antioxidants and mitochondrial enhancers:** Creatine, coenzyme Q10, and other compounds are being studied for their potential neuroprotective effects.
4. **Gene silencing therapies:** Experimental treatments such as antisense oligonucleotides (ASOs) aim to reduce the production of the mutant huntingtin protein. Trials for drugs like tominersen are ongoing.
5. **Stem cell therapy:** Research is investigating the potential of stem cells to replace or repair damaged neurons in HD.

Always consult healthcare providers for the most current treatment options and clinical trials.
Lifestyle Recommendations: For managing Huntington's disease, lifestyle recommendations may include the following:

1. **Physical Activity**: Engage in regular physical exercise to maintain muscle strength and coordination. Walking, swimming, and other low-impact activities can be beneficial.

2. **Nutrition**: Maintain a balanced diet rich in fruits, vegetables, whole grains, and lean protein. High-calorie foods may be necessary to compensate for increased energy expenditure due to involuntary movements.

3. **Mental Stimulation**: Keep the brain active with puzzles, reading, or learning new skills. Cognitive exercises can help slow mental decline.

4. **Social Support**: Surround yourself with a strong support system of family, friends, and support groups to manage emotional and psychological challenges.

5. **Routine Medical Care**: Regular appointments with healthcare providers to monitor disease progression and manage symptoms.

6. **Safety Modifications**: Make home modifications to reduce the risk of falls and injuries, such as installing grab bars and removing tripping hazards.

7. **Stress Management**: Practice stress-reducing techniques like meditation, yoga, or deep-breathing exercises.

8. **Speech and Occupational Therapy**: Engage in therapy programs for maintaining communication abilities and daily living skills.

These recommendations aim to improve quality of life and manage symptoms effectively.
Medication: Tetrabenazine was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US. Although other drugs had been used "off label", tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is amantadine but there is limited evidence for its safety and efficacy.Other drugs that help to reduce chorea include antipsychotics and benzodiazepines. Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid. Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year. In 2017, deutetrabenazine, a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA. This is marketed as Austedo.
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 antipsychotics are recommended for psychosis and behavioral problems. Specialist neuropsychiatric input is recommended since people may require long-term treatment with multiple medications in combination.
Repurposable Drugs: Currently, there are no established disease-modifying treatments for Huntington's disease, but some repurposable drugs have shown potential in research settings. These include:

1. **Tetrabenazine and Deutetrabenazine** - Approved for managing chorea in Huntington's disease.
2. **Riluzole** - Primarily used for ALS, has been explored for neuroprotective effects.
3. **Memantine** - Used for Alzheimer's disease; studied for cognitive symptoms in Huntington's.
4. **SSRIs (Selective Serotonin Reuptake Inhibitors)** - Often prescribed for psychiatric symptoms such as depression and anxiety associated with Huntington's.

Ongoing clinical trials and research are further exploring these and other existing drugs for potential benefits in managing Huntington's disease symptoms or slowing its progression.
Metabolites: Huntington's disease is characterized by several metabolic abnormalities, including alterations in energy metabolism, neurotransmitter imbalances, and mitochondrial dysfunction. Specific metabolites affected can include decreased levels of ATP, changes in amino acids like glutamate and GABA, and altered lipid metabolism. These metabolic disturbances contribute to the neuronal damage and clinical symptoms seen in the disease.
Nutraceuticals: Nutraceuticals refer to food products that provide medical or health benefits, including the prevention and treatment of disease. For Huntington's disease, some nutraceuticals under investigation include:

1. **Omega-3 Fatty Acids**: These are thought to have neuroprotective properties.
2. **Coenzyme Q10**: An antioxidant that may help in slowing down disease progression.
3. **Creatine**: Believed to support cellular energy production and show potential in clinical trials.
4. **Antioxidants (e.g., Vitamins E and C)**: These might reduce oxidative stress in neural cells.

It is important to note that while some studies suggest potential benefits, more research is necessary to conclusively determine the efficacy and safety of these nutraceuticals in managing Huntington's disease. Always consult a healthcare professional before starting any new treatment.
Peptides: Huntington's disease is a neurodegenerative disorder caused by a mutation in the HTT gene, which leads to the production of abnormal huntingtin protein. Peptides are short chains of amino acids that can influence cellular processes. In the context of Huntington's disease, research is ongoing to develop peptide-based therapeutics that can modulate protein interactions, inhibit aggregation of mutant huntingtin, or enhance cellular protective mechanisms. As of now, no peptide-based treatments have been approved for Huntington's disease, but they remain a promising area of study.