Huntington Disease

What is Huntington Disease?

Huntington’s disease (HD) is a genetic disorder that results in the death of brain cells. This disease can be passed along by one or both parents and usually affects adult individuals between the ages of 30 and 50 years. HD causes uncontrollable movements, cognitive issues, and mood problems. The disease results from an unusual repetition of specific DNA components (Cytosine, Adenine, and Guanine- often referred to as CAG repeats) in a specific gene on chromosome 4. The more repetition in the gene, the earlier the symptoms may appear.

In fact, there’s a juvenile form of HD where symptoms start before the age of 20, which include learning difficulty and behavioral issues at school.

The diagnosis of HD can be confirmed if any movement, cognitive, or behavioral problems are detected in someone, whose parent(s) have been diagnosed with HD. Medical professionals can confirm the presence of the disease through genetic testing. Unfortunately, there’s no outright cure for Huntington’s disease. As the disease progresses, people with HD become entirely reliant on others for care.

The goal of managing the disease is to improve someone’s quality of life and reduce complications. Lung infection, or pneumonia, is a common cause of death amongst these patients, followed by suicide.

What Causes Huntington Disease?

Huntington’s disease is a genetic disorder inherited from one parent. This condition happens because of the expansion of a specific pattern of genes, known as CAG repeats, on the 4th chromosome in the HTT gene. This HTT gene plays a role in nerve cell communication and development after birth, believed to have some protective effects against a defective version of HTT protein. However, there is evidence that the defective form of this protein can lead to both new problems and the loss of its usual function. The disease gives rise to certain structures within nerve cells in the brain, whose role in causing the disease is not entirely clear. The disease is known for causing brain shrinkage, particularly in a region called the striatum, leading to significant loss of nerve cells.

Patients with Huntington’s disease often have an increased number of CAG repeats, usually between 36 to 55. However, those who suffer from the disease from an early age often have an even higher number of CAG repeats, exceeding 60. People with CAG repeats between 27 to 35 do not show signs of the disease, but they are likely to have unstable CAG repeats. There is a connection between the number of CAG repeats and the age at which the disease begins showing up; the more CAG repeats, the earlier the disease onset. Interestingly, this disease causes a ‘anticipation’ effect, where the child of an affected parent is likely to develop the condition at a younger age. This is due to the unstable nature of the CAG repeats during sperm formation.

Research has identified three main risk factors for the onset of the disease. These are the length of the CAG repeats in the HTT gene, instability of the CAG repeats, and modification by other genes. The most crucial among these is the length of the CAG repeats. The patterns of genes, particularly the length of the CAG sequence, play a significant role in the development and progression of the disease, particularly in cognitive, motor, and neurological disturbances.

Risk Factors and Frequency for Huntington Disease

Huntington’s disease (HD) is a rare brain disorder that affects about 2.7 out of every 100,000 people worldwide. The number of people affected can be over ten times higher or lower depending on where you are in the world. This is due to differences in how cases are identified and how the disease is diagnosed. Often, the disease develops in adulthood. Because of this, people may carry the genetic change that causes HD (expanded CAG repeats) without showing any signs of the disease. This means there might be more people with these genetic changes than what is currently known.

• Huntington’s disease is a rare condition affecting the brain.
• It impacts 2.7 out of every 100,000 people across the globe.
• The occurrence varies greatly depending on location due to differences in how it’s identified and diagnosed.
• The disease usually develops in adults.
• People can carry the genetic change causing the disease without showing symptoms.
• There might be more people with these genetic changes than we currently know.
• It’s less common in Asian populations but more common in Europe, North America, and Australia.

These differences in occurrence might be tied to specific variations in the HTT gene, which is involved in Huntington’s disease.

Signs and Symptoms of Huntington Disease

This disease generally affects people who are 30 to 50 years old. The main symptoms are categorized into three kinds: motor troubles, cognitive disturbances, and changes in mental health. Less common symptoms include weight loss, sleep issues, and problems with the autonomous nervous system.

• Motor disturbances: These are involuntary movements that begin in the arms or legs and can affect facial muscles as well. The issue starts small but can spread to larger muscles and get worse over time. Early on, the movements are hyperactive (choreic) but become slower and more rigid (hypokinetic, dystonic) as time goes on. Dysarthria and dysphagia, problems with speech and swallowing, emerge as the problem gets worse, leading to a high risk of pneumonia due to choking on food. Other issues include involuntary tics, problems with balance (ataxia), and a positive Babinski sign. Over time, the problem begins to disrupt daily activities and can lead to trouble with walking, standing, and a higher risk of falls.
• Behavioral and psychiatric symptoms: Some patients start showing mental health issues even before motor symptoms. Initial signs include having trouble paying attention, impulsivity, and irritability, which can lead to anger and aggression. Over time, patients may start to appear emotionally flat and lose their creativity and intuition. Apathy, or lack of interest, is a common issue and worsens alongside motor and cognitive problems. Patients can be depressed, but it is unclear whether depression is a result of the disease itself or underlying damage to the brain. Late-stage patients may exhibit psychosis and a lack of insight into their symptoms. This lack of insight can affect all aspects of their disease, so it’s important for family members to be involved in care decisions and symptom assessments.
• Cognitive disturbances: Cognitive problems can also start before motor issues, with the most notable being trouble with executive function tasks such as organizing, multitasking, and planning. As the disease progresses, patients experience more cognitive issues that can develop into dementia. This dementia is subcortical in nature, meaning that it doesn’t affect the outer layer of the brain (the cortex). Instead, it affects deeper structures, mainly the basal ganglia and related structures. Rather than having an issue with memory itself, patients have trouble retrieving memories. Additionally, psychomotor processes become markedly slowed.

Other secondary symptoms may include:

• Ataxia, or problems with balance and coordination (this is rare)
• Problems with walking
• Abnormal eye movements
• Seizures (these are most common in patients before the age of 10)

Patients tend to exhibit subtle motor and cognitive issues early on in the disease. Once symptoms interfere with quality of life, diseases modifying treatments can be initiated. The average age for developing symptoms is in the mid-40s. After the onset of symptoms, the usual survival period is 15 to 18 years. In some patients, onset is late, with symptoms starting after the age of 50 or even 70.

When this disease starts in childhood, before the age of 20, it’s called juvenile Huntington’s disease. The motor, cognitive, and psychiatric issues seen in adult patients also occur in children but present differently. The initial symptoms are usually learning difficulties and behavioral issues. Motor problems such as hypokinesia and bradykinesia with dystonic components are seen, but chorea is uncommon. Epileptic fits are more common in these patients. Severe cognitive deterioration, along with delays in motor, speech, and language progress, are characteristic of juvenile Huntington’s disease. In teenagers, the disease presents similarly to adults, with chorea and severe behavioral issues being common initial symptoms.

Testing for Huntington Disease

When doctors have to tell a patient they have Huntington’s disease (HD), it’s important to consider the person’s mental state. This disease can take a toll on someone’s emotional well-being and the shock of this news may have some significant negative effects. Every patient is different and thus doctors take their time to observe the patient and decide when best to break the news.

Huntington’s disease is usually diagnosed when a person shows certain symptoms and one of their parents is proven to have HD. Symptoms could include both physical movements and changes in behavior and thinking, and the order in which they appear can vary. Sometimes, this can make HD harder to diagnose or it can even lead to misdiagnosis.

Before performing a genetic test which is standard for HD diagnosis, doctors may ask for other lab tests. These can help to differentiate HD from other similar genetic syndromes. These tests may show increase in certain enzymes which could be signs of other conditions.

Magnetic resonance imaging (MRI), an imaging technique, can also be helpful in diagnosing HD. The MRI results could show changes in the brain’s structure and connectivity even before the symptoms start to appear. This imaging test could also be useful to distinguish HD from other neurological diseases. However, some other genetic syndromes could look similar on an MRI, making it non-conclusive.

The gold standard test, the one with the highest certainty, for diagnosing HD is a genetic test. This checks for repeats in a certain gene known as CAG repeat size. If there are 26 or fewer repeats, a person doesn’t typically have HD. But if there are 27 to 35 repeats, a person might not have HD but there is a risk of their child inheriting it. If there are 36 to 39 repeats, the person could get HD, but might not show symptoms, and if there are 40 or more repeats, this is usually associated with getting the disease.

Furthermore, there are ways to diagnose HD before a baby is born. One is through chorionic villi sampling, performed in the early stages of pregnancy, and the other is through amniocentesis, performed a few weeks later. Both allow for DNA testing of the baby. However, these are done only if the parents already know their own genetic status. Earlier detection using preimplantation diagnosis is also available in some countries, where an embryo’s genetic information is examined and only those without the CAG repeats are implanted for pregnancy.

Treatment Options for Huntington Disease

Huntington’s Disease, or HD, does not have a known cure. However, there are various treatments that aim to alleviate its symptoms and improve the patient’s quality of life. These treatments primarily involve medications and supportive care, with surgery playing a minimal role. Certain treatments have been assessed for their ability to control chorea, a movement disorder characterized by involuntary, irregular movements. These include dopamine antagonists, benzodiazepines, and more. These treatments primarily target the movement disorders associated with HD. Other treatments, like behavioral plans and cognitive interventions, may also be helpful.

Treatments recommended by the American Academy of Neurology for managing chorea include medications such as tetrabenazine (TBZ), amantadine, or riluzole. It is crucial to monitor patients taking TBZ for signs of depression or suicidal ideation since these can be side effects of the drug. Other frequently prescribed drugs include dopamine antagonists, benzodiazepines, and glutamate antagonists. Some medications containing L-Dopa might increase chorea, so their use must be carefully evaluated.

Medications like olanzapine, risperidone, quetiapine, and aripiprazole have been tested to manage motor symptoms. However, these drugs can also result in certain side effects, including restlessness and tardive dyskinesia, an involuntary movement disorder. At the same time, other drugs such as amantadine and riluzole have exhibited potential in reducing chorea.

For patients with the Westphal variant of HD, which involves slow movement and rigidity, Parkinson’s disease medications may be considered. Botulinum injections could be an option for treating focal dystonia, a localized form of muscle contractions.

Apart from medication, other treatments for HD include supportive care, diet, and special equipment. Patients and their families can also benefit from emotional support and counseling. New treatments such as gene therapy, which involves silencing the mutant genes causing the disease, are currently being explored and could hold promise for the future.

HD also comes with a range of behavioral and psychiatric issues. Although antidepressants are often used for depression, anxiety, and obsessive-compulsive disorders associated with HD, non-medical treatment should also be considered. Considering environmental modifications and therapy could be helpful.

The European Huntington Disease Network recommends different treatment approaches based on symptoms. These can include varied drugs, speech therapy, occupational therapy, and more. For instance, tetrabenazine (TBZ) is typically recommended for treating chorea unless the patient also experiences depression or suicidal thoughts. Physiotherapy can be beneficial for rigidity and gait abnormalities, and botulinum injections may be useful for treating dystonia, a disorder involving involunatry muscle contractions.

All in all, treatment of HD involves a multi-pronged approach. Medications, therapy, and lifestyle modifications can all work together to help manage symptoms and improve quality of life for individuals with this condition.

What else can Huntington Disease be?

Huntington’s disease is often considered when a patient presents symptoms like dementia, chorea (uncontrolled dance-like movements), and mental disturbances. However, similar symptoms can also suggest other conditions. These conditions can be both inherited or non-inherited.

Non-inherited conditions that show similar symptoms can include:

• Tardive dyskinesia: uncontrolled movements due to long-term use of certain medications.
• Thyrotoxicosis: an overactive thyroid.
• Cerebral lupus: brain inflammation caused by Lupus, an autoimmune disease.
• Levodopa-induced dyskinesia: uncontrolled body movements caused by long-term use of a Parkinson’s disease treatment.
• Group A beta-hemolytic streptococcus: a bacterial infection that can cause movement disorders and other symptoms.

Additionally, there are several inherited conditions to consider:

• Chorea-acanthocytosis: This is caused by mutations in the VPS13A gene and can result in aggressive neck spasms and cognitive and behavioural changes.
• McLeod syndrome: This disorder impacts the brain and muscle groups, causing cognitive disturbances and other symptoms similar to Huntington’s disease but can be differentiated by certain blood-based factors.
• Pantothenate kinase-associated neurodegeneration: This specific condition is known to result from mutations in the PANK2 gene. It manifests early in childhood with a range of movement disorders and cognitive issues.
• Wilson disease: This results in dystonia (abnormal muscular movements) and parkinsonism.
• Huntington disease-like 1: As the name implies, this is similar to Huntington’s disease but tends to progress more slowly.
• Huntington disease-like 2: This is virtually indistinguishable from Huntington’s disease and is seen largely in patients of African descent.
• Spinocerebellar ataxia type 17: Presents symptoms such as chorea, dementia, and mental disturbances – similar to Huntington’s disease, but also features significant cerebellar ataxia (incoordination).
• Dentatorubral-pallidoluysian atrophy: It displays progressive movement disorders and mental disturbance as well, yet features more prominent ataxia and myoclonus (involuntary twitching).

These conditions present various challenges to physicians, and a correct diagnosis requires careful examination of symptoms and patient history.

What to expect with Huntington Disease

Huntington’s disease is a brain disorder for which there is currently no cure. People diagnosed with this disease typically live for about 15 to 20 years. Certain genetic markers, known as CAG repeats, can help predict when symptoms will begin and also when death might occur. The larger the number of these markers, the quicker the person’s motor skills, cognitive abilities, or routine functions tend to deteriorate.

However, these genetic markers do not determine the progression of behavioral symptoms. People who have a double dose (two copies) of the gene for Huntington’s disease (homozygotes) tend to show symptoms at the same age as those with one copy (heterozygotes), but their condition could progress more quickly.

As the disease progresses, individuals become entirely dependent on others for their daily activities, eventually needing full-time care. The most common cause of death for people with Huntington’s disease is pneumonia, with suicide being the second most common cause.

Possible Complications When Diagnosed with Huntington Disease

Huntington’s disease can lead to many complications which can negatively impact a patient’s life.

• Patients suffering from dystonia and difficulties swallowing may experience an increased rate of complications, leading to a shorter lifespan.
• Chorea, or involuntary movement, of a large magnitude can result in injuries, poor posture, fractures, and head trauma.
• Death is often due to issues related to lack of mobility, such as pneumonia, heart disease, or infections.
• It’s worth noting that about 25% of patients try to commit suicide.
• Behavioral problems caused by the disease can be extremely disabling, causing distress to not only the patient but also their family and caregivers.

Preventing Huntington Disease

Adults who are potentially at risk of developing Huntington’s Disease (HD), but aren’t showing symptoms, can get genetic counseling and testing. This helps patients understand their situation better and make choices about future caregiving, finances, and the possibility of having children. Also, this enables them to be part of clinical trials, where new treatments are tested.

The best time to understand the genetic risk and talk about testing before having a baby is before one gets pregnant. DNA banking, or the saving of one’s DNA, can also be done for potential future use. This is like keeping a sample of your genetic code that could be used in future medical procedures or studies.

Living with HD can be stressful, so getting mental health support, like psychiatry or psychology services, is recommended. These professionals can help patients manage stress and other emotional challenges that may come with having HD.