Huntington’s Disease
Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive loss of the physical and mental abilities of its victims. Huntington’s disease is caused by a mutation in the gene for a protein called huntingtin. The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more times than normal.
HD is an inherited disorder that causes degeneration of brain cells (neurons) primarily in motor control regions of the brain, but also affects the nerve cell clusters throughout the brain as well. 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. Today, there are approximately 30,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease. HD affects all gender, race and ethnic groups. Symptoms usually appear between the ages of 30 to 50, and worsen over a 10 to 25 year period.
Symptoms
HD was previously called Huntington’s chorea. The term chorea is derived from the Greek word meaning to dance, underscoring the common movement disorder seen in HD. Initially, mild chorea may pass for fidgetiness. Severe chorea may appear as uncontrollable flailing of the extremities (ballism). As the disease progresses, chorea coexists with and gradually is replaced by dystonia and parkinsonian features, such as bradykinesia (slowness in movement), rigidity, and postural instability. Other late features are spasticity, clonus, and extensor plantar responses.
Additional symptoms of the disease are:
abnormal body posture
changes in behavior, depression (early), dementia (late)
cognition and reasoning changes
functional decline seen with driving and problem solving
impaired coordination
slurred speech
difficulty feeding and swallowing
abnormal eye movement and excessive blinking
tics and myoclonic activity
aphasia
An earlier onset form called juvenile HD occurs under age 20. Approximately 10% of all HD cases are juvenile HD. Symptoms of juvenile HD differ somewhat from adult onset HD and include unsteadiness, clumsiness, rigidity, difficulty at school, and seizures.
Early stage HD usually includes subtle changes and perhaps some involuntary movements (chorea) and slight changes in mood or reasoning. Medications are often effective in treating depression or other emotional problems. The effects of the disease may make the person less able to function in their usual roles at home or work. As the disease processes, the movement disorder may intensify. 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. The person may have weight loss due to swallowing and worsening symptoms and nutritional needs must be addressed. Ordinary activities become harder to accomplish, putting additional strain on the person and family.
In the later stages, the person with HD is totally dependent and requires around the clock care. Choking and aspiration becomes a major concern. Injury from falls and spastic movements need to be addressed on an individual basis. Chorea may be severe or it may cease in late stages. HD patients can no longer walk and may be unable to speak. Severe dementia is also seen frequently with the inability to recognize loved ones.
Diagnosis
HD is an autosomal dominant disease that gives the offspring of a person known to have HD a 50/50 chance of inheriting the trait regardless of gender. A complete neurological exam and family history must be obtained. The mutated gene that causes HD was not identified until 1993. The gene for HD is located on the tip of chromosome 4, and is called the IT-15 gene. Everyone has a specific piece of DNA on chromosome 4 that makes up the HD gene. This segment of DNA repeats in units of three, and is called a CAG trinucleotide repeat. Positive test results in patients with HD show a repeat of 40 times or more.
Persons at risk for HD who request pre-symptomatic testing should undergo extensive genetic counseling and neurologic and psychiatric evaluation. Most testing centers follow strict protocols. People at-risk for the disease face a difficult choice about genetic testing for HD, given the current absence of an effective treatment or cure. Testing should be performed at a genetic testing center and results are usually not available for several weeks. Many people see no benefit in knowing that they will someday develop the disease while others want to make informed choices about the future. Patients can be tested and not given results unless requested at a further date. The decision is intensely personal and there is no “right” answer.
Genetic testing for children is typically prohibited prior to the age of 18 due to their vulnerability to pressure on life choices. However, a child under the age of 18 may be tested to confirm a diagnosis of juvenile onset HD after a thorough neurological exam.
Pre-genetic diagnostic (PGD) testing can be used with In Vitro Fertilization (IVF) to make sure that any fertilized egg implanted does not have the abnormal gene. This can be done without informing the at-risk patient whether or not they have the gene that causes HD. If a woman is already pregnant, she can receive testing for the fetus with a chorionic villus biopsy at 10-11 weeks or via amniocentesis at 14-18 weeks.
Available treatments
Clinical and observational trials are an important way to further treatment. Due to the relatively small number of cases of HD when compared to more common ones such as heart disease, pharmaceutical companies tend to not invest in this research. The common drugs used to treat the symptoms of HD were developed to treat other conditions and their effectiveness varies from patient to patient. There is no treatment that can stop or reverse the course of HD, so treatment revolves around managing the patient’s symptoms. The major classification of drugs are listed below:
Monoamine Inhibitors
The anti-chorea effect of central monoamine depleting agents is believed to be related to its effect on reversible depletion of monoamines (e.g., dopamine, serotonin, and norepinephrine) from nerve terminals.
The drug tetrabenazine is a central acting vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is a dopamine-depleting agent and was approved by the FDA in August 2008. It may be more effective than reserpine in the treatment of chorea and less likely to cause hypotension. A second VMAT2 inhibitor, deutetrabenazine, was approved by the FDA in April 2017. Tetrabenazine and deutetrabenazine are prescribed for treating the chorea associated with HD.
Anticonvulsants
These agents are used to manage muscle spasms in chorea. Most commonly, valproic acid is used due to its mild side effects but clonazepam, a benzodiazepine, can also be used.
Antidepressants and antipsychotics
Depression is relatively common in patients with HD and should be treated pharmacologically as soon as diagnosis of depression is made. Depression in patients with HD can be treated with the same agents used for treatment of depression of any other cause. SSRIs may be used as first-line therapy because of their low adverse-effect profile, convenient dosing, and safety in the event of overdose. Electroconvulsive therapy can be effective when used on an individual in crisis and in patients who do not respond to repeated trials of medication. As the disease progresses, lithium and reserpine may help to alleviate chorea and may also be used to help control hallucinations, delusions, and violent outbursts.
Antiviral
Amantadine is an antiviral drug that has been used to treat a variety of illnesses including Parkinson’s disease. Amantadine works by attaching to special sites called NMDA (N-methyl-D-aspartate) receptors and blocking the normal activity of glutamate there. Glutamate is an amino acid released by brain cells and has been associated with the symptoms of Parkinson’s disease.
On the horizon
Gene silencing appears to be the most promising treatment on the horizon. Since Huntington’s results from inheriting a defect in a specific gene, gene silencing tricks cells into shutting off the HD gene. The first human clinical trials involving a drug that kills crucial messenger molecules to the HD gene are underway in England and Canada. Fetal neural transplantation, stem cell transplantation, ablative surgical procedures and deep brain stimulation are all being researched as potential cures or remissions. Unfortunately insurance companies are reticent to cover costs of “experimental” treatments so most patients usually need to be accepted into a research study to gain access to these treatments.
Staging and Progression
Multiple scoring methods have been used to predict and assess the progression of HD. The Unified Huntington Disease Rating Scale (UHDRS), The Beck Depression Inventory, the Total Functional Capacity Scale can all be used to assess minor deteriorations in the patient’s condition. These scales rate cognitive, motor skills, depression and daily functional activities as predictors to the onset and progression of the disease and may be useful for prodromal patients and their families.
A multidisciplinary approach to the diagnosis and treatment of HD includes the collaboration of experts in the fields of nursing, neurology, psychiatry, genetics, speech, and social work. Support groups and educational programs are often small but can be held online to encompass the needs of patients and families who may have no local support. The Huntington’s Disease Society of America (HDSA) has developed a nationwide network of chapters and centers to support patients and their caregivers. Awareness of ongoing research to find an effective cure for HD must be a part of the care plan of an individual patient and the patient’s family.
References:
Huntington’s Disease Information Page. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-In…
Paulsen, Jane S. et. al. (2011). Challenges assessing clinical endpoints in early Huntington disease. Mov Discord., 25 (15), 2595-2603. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978744/.
Treatment of Huntington’s Chorea with Amantadine. Retrieved from https://clinicaltrials.gov/show/NCT00001930.
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