Huntington’s disease

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances i.e. involuntary movement and intellectual, emotional and behavioural problems and dementia. It is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain.

Huntington’s disease was originally called Huntington’s chorea (“chorea” is the Greek word for dancing). This is because the involuntary movements associated with the condition can look like jerky dancing. However, “disease” is now the preferred term, because the condition involves a lot more than just abnormal movements.

HD causes cells in parts of the brain to die: specifically the caudate, the putamen and, as the disease progresses, the cerebral cortex. As the brain cells die, a person with Huntington’s becomes less able to control movements, recall events, make decisions and control emotions. The disease leads to incapacitation and, eventually, death (generally due to other health complications). Early features can include personality changes, mood swings, fidgety movements, irritability and altered behaviour, although these are often overlooked and attributed to something else.

HD is known as the quintessential family disease because every child of a parent with HD has a 50/50 chance of carrying the faulty gene. At present, there are approximately 30,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease. Males and females have the same risk of inheriting the disease. Huntington’s occurs in all races. Symptoms usually appear between the ages of 30 and 50, but the disease can appear in children or seniors.

Causes

• Genetic Disorder

HD is a genetic disorder, inherited in an auto-somal dominant pattern, which means that each child of an affected parent has a 50 percent chance of inheriting the disease-causing gene. Individuals who inherit the HD gene almost always develop the symptoms of HD, usually at the same age as their affected parent or earlier. In around 3% of cases of Huntington’s disease, there’s no obvious family history of the condition. This could be due to adoption or because relatives with the condition died early from other causes. In rare cases, it’s due to a new expansion in the gene.

• Gene Mutation

The gene responsible for HD is IT15, which is located on the short arm of chromosome 4. This gene produces a protein known as huntingtin, whose function remains unknown. The mutation that causes HD consists of an unstable enlargement of the gene’s CAG (cytosine-adenine-guanine) repeat sequence, which results in an abnormal elongation of the huntingtin protein. Normally, the number of CAG repeats is less than 29, while in persons with HD the gene usually contains more than 36 repeats. It is unclear whether individuals with between 29 and 36 CAG repeats, will develop symptoms of HD, but they may transmit HD to their children because the number of repeats grows over successive generations. The degree of repeat expansion over a generation is usually greater when the gene is inherited from one’s father. The number of repeats inversely correlates with the age at onset, such that children with HD may have 100 CAG repeats or more. Accordingly, young-onset patients usually inherit the disease from their father while older-onset patients are more likely to inherit the gene from their mother. There is no difference in the mean number of repeats between patients presenting with psychiatric symptoms and those with chorea and other motor disorders, though the rigid juvenile patients have the largest number of repeats.

• Environmental Triggers

Studies suggest that this same mechanism of gliadin binding to tissue transglutaminase (tTG) in Celiac’s Disease, is the environmental trigger in Huntington’s disease. It’s the gliadin-tTG complex that is influencing pathogenesis, or mechanism by which Huntington’s Disease is caused.

• Immune Activation: In another important set of studies, HLA-DR, a heterodimeric cell surface glycoprotein, expression was increased by gluten consumption. In active Huntington’s subjects, HLA-DR activity was so strong in their disease tissue, it was visible with the human eye after staining.
• In the same way that gluten breaks down the barrier of the gut, there is some evidence that gluten can open up the blood-brain barrier and allow the gliadin-tTG complex to enter protected neural regions and activate the Huntington aggregates.

Symptoms

Physical symptoms include:

• Mild twitching of the fingers and toes
• Lack of coordination and a tendency to knock things over
• Walking difficulties
• Dance-like or jerky movements of the arms or legs (chorea)
• Speech and swallowing difficulties.

Cognitive symptoms include:

• Short-term memory loss
• Difficulties in concentrating and making plans.
• Emotional symptoms include:
• Depression (around one third of people with Huntington’s disease experience depression)
• Insomnia
• Obsessive compulsive disorder
• Irritability
• Anxiety
• Mania
• Reduced sex drive
• Fatigue
• Feelings of worthlessness and guilt
• Suicidal thoughts

Behavioral problems

• Mood swings
• Apathy
• Aggression.

Although symptoms of HD vary from person to person, even within the same family, the progression of the disease can be roughly divided into three stages.

• Early stage – HD usually includes subtle changes in coordination, perhaps some involuntary movements (chorea), difficulty thinking through problems and often a depressed or irritable mood. Medications are often effective in treating depression or other emotional problems. The effects of the disease may make the person less able to work at their customary level and less functional in their regular activities at home.
• Middle stage – The movement disorder may become more of a problem. Medication for chorea may be considered to provide relief from involuntary movements. Occupational and physical therapists may be needed to help maintain control of voluntary movements and to deal with changes in thinking and reasoning abilities. Diminished speech and difficulty swallowing may require help from a speech language pathologist. Ordinary activities will become harder to do.
• Late stage – The person with HD is totally dependent on others for their care. Choking becomes a major concern. Chorea may be severe or it may cease. At this stage, the person with HD can no longer walk and will be unable to speak. However, he or she is generally still able to comprehend language and retains an awareness of family and friends. When a person with HD dies, it is typically from complications of the disease, such as choking or infection and not from the disease itself.

In all stages of HD, weight loss can be an important complication that can correspond with worsening symptoms and should be countered by adjusting the diet and maintaining appetite.

Treatment

Medications

Following drugs are used in the treatment of HD –

• Dopamine-modifying Drugs – Dopamine is an important chemical in the brain. It is needed for nerve cells to communicate with areas of the body. Drugs that affect dopamine levels in the brain have been studied for treating HD. Studies suggest that the drug tetrabenazine (TBZ) can be helpful. TBZ appears to have a powerful effect on HD. However, be aware that TBZ can have the following serious side effects:
  • Parkinsonism (slowness in movement)
  • Depression; thoughts or plans of suicide
  • Neuroleptic malignant syndrome (a serious nervous system disorder)
  • Falls
  • Extreme restlessness

Neuroleptics are drugs used for psychosis, a mental disorder. These include – Clozapine, Olanzapine, Quetiapine, Risperidone

• Glutamatergic-modifying Drugs – Glutamate is another important brain chemical. Like dopamine, glutamate helps nerve cells communicate with parts of the body. Drugs that affect glutamate levels in the brain have been studied for treating HD these include, amantadine and riluzole.
  • Blood Problems
  • Hypersensitivity Reaction
  • Neuroleptic malignant syndrome
  • Fluid buildup in the lungs
  • Lung failure
  • Thoughts or plans of suicide
  • Heart Problems

• Energy Metabolites – Metabolism is the way in which the body breaks down certain chemicals for energy. These are known as energy metabolites. Some occur naturally in the body. Others come from foods or supplements such as vitamins. There is moderate evidence that ethyl-EPA may not have a strong effect on treating chorea. Weak evidence shows creatine may not have a strong effect.
• Antipsychotic drugs – Drugs such as haloperidol (Haldol) and chlorpromazine, have a side effect of suppressing movements. Therefore, they may be beneficial in treating chorea. These drugs may, however, worsen involuntary contractions (dystonia) and muscle rigidity. Newer drugs, such as risperidone (Risperdal) and quetiapine (Seroquel), may have fewer side effects but still should be used with caution, as they may also worsen symptoms.

• Other Drugs – Several other drugs have been studied for use in HD chorea. One such drug, nabilone, typically is used to treat nausea (upset stomach) and vomiting from chemotherapy in some cancers. Nabilone also has been used to treat pain. Weak evidence shows nabilone may have a slight effect in treating HD . There is not enough evidence to know if nabilone should be used long-term. This drug may be habit forming and may cause psychosis. Donepezil is another drug studied for treating HD. This drug was developed to treat thinking problems in dementia. There is not enough evidence to know if donepezil helps treat HD chorea. Two additional drugs have been studied in treating HD chorea. One, the antibiotic minocycline, is used to treat infections. Moderate evidence shows minocycline does not have a strong effect in treating HD chorea. The drug coenzyme Q10 is a supplement used to treat a number of conditions. There is evidence that coenzyme Q10 does not have a moderate effect in treating HD.

• Psychotherapy – A psychotherapist — a psychiatrist, psychologist or clinical social worker — can provide talk therapy to help a person manage behavioral problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.
  

• Speech therapy – Huntington’s disease can significantly impair control of muscles of the mouth and throat that are essential for speech, eating and swallowing. A speech therapist can help improve the ability to speak clearly or teach the use communication devices — such as a board covered with pictures of everyday items and activities. Speech therapists can also address difficulties with muscles used in eating and swallowing.
• Physical therapy – A physical therapist can teach appropriate and safe exercises that enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls.

Stem cell transplantation – Experimental studies for the treatment of HD include transplantation of human (stem cells) or pig fetal cells. Stem cell research is investigational and the side effects are not known.

Alternative Medicine –

• Vitamin E – Vitamin E can fight damage in the brain caused by free radicals, and has been suggested to lower the risk of HD. Vitamin E supplements can increase the risk of bleeding, especially if you also take blood thinners, such as warfarin (Coumadin), clopidogrel (Plavix), or aspirin. Selenium is an antioxidant that works with vitamin E. It also helps to increase circulation and tissue oxygenation, thereby limiting damage to nerve cells.
• Gamma-aminobutyric acid (GABA) is an amino acid that acts as a neurotransmitter. It helps both to strengthen and relax the nervous system.
• Acidophilus and bifidobacteria are friendly bacteria that ensure a healthy gastrointestinal tract. Probiotics are especially helpful for preventing Gut issues which is often a problem for people with HD
• Alpha-lipoic acid is an antioxidant that also helps to “recharge” other antioxidants in the body.
• Calcium and magnesium are imperative for maintaining a healthy nervous system.
• Coenzyme Q10 is an oxygenating antioxidant that helps prevent free-radical damage and important for cell renewal.
• Evening primrose oil and flaxseed oil contain valuable essential fatty acids (EFAs), which are often deficient in people with HD.
• Creatine – Some studies suggest that taking creatine, an amino acid that helps supply energy to muscles, may help slow progression of HD among people who are in the early stages, and who do not need medication to control symptoms
• Bacopa monnieri (Brahmi) Supplements – It is used for the treatment of epilepsy, insomnia, anxiety, and as memory enhancer.
• Turmeric – Studies suggest that the improved 3-NP-induced motor and cognitive impairment along with a strong antioxidant property indicates that turmeric could be useful and can act as a lead molecule in the treatment of HD.
• Flavonoids – Flavonoids exhibit several biological effects such as anti-inflammatory, anti-hepatotoxic, anti-ulcer, anti-allergic, and antiviral actions. They are potent antioxidants and have free radical scavenging abilities by virtue of their aromatic hydroxyl groups.
• DHA – DHA (docosahexaenoic acid) is probably the most important of the omega 3 fatty acids for Huntington’s. Recent research shows that EPA, (eicosapentaenoate), and GLA (gamma linoleic acid) are probably far inferior.