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Healthcare: Neurology

Huntington's Disease

Master
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What Is Huntington's Disease?

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the gene called huntingtin on chromosome 4. HD is inherited in an autosomal dominant fashion, so that each child of an affected parent has a 50 percent chance of inheriting the mutated gene and developing the disease. Most people with HD develop the symptoms in their 40's and 50's. About 10 percent of patients have the symptom onset before age 20, which is known as juvenile HD, and about 10 percent have onset after age 60.

HD typically manifests as a triad of motor, cognitive, and psychiatric symptoms which begin gradually and progress over many years. The movement disorder is characterized by involuntary movements known as chorea, and by the impairment of voluntary movements. The latter often presents the greatest disability resulting in reduced manual dexterity, slurred speech, swallowing difficulties, balance problems and falls. Both chorea and impairment of voluntary movements progress in the middle stages of the disease, but later, chorea may gradually subside as rigidity and stiffness progress. Cognitive changes are initially characterized by forgetfulness and impaired judgment. These mental changes may gradually progress to confusion and true dementia. The most frequent psychiatric symptoms include irritability, depression, paranoia, and erratic behavior. Patients may also exhibit manic and obsessive-compulsive states. Other symptoms may include anxiety, agitation, impulsivity, apathy, and social withdrawal.

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Diagnosis

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Before the advent of a genetic blood test, the diagnosis of HD was based upon the typical clinical presentation and a positive family history of HD, supported by the findings of atrophy (shrinkage) of the caudate nucleus on brain imaging. Today, DNA testing can reliably diagnose HD and differentiate the disease from other disorders that cause similar symptoms. DNA testing is also available for family members of patients with HD who may not have symptoms but are at risk for the disease. However, because of potential psychological and legal implications of identifying a HD gene mutation in an asymptomatic, at-risk individual, predictive testing should be performed by a team of clinicians and geneticists who are knowledgeable about the disease and genetic techniques and who are sensitive to the psychosocial and ethical issues associated with such testing.

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Cause

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HD is a genetic disorder, inherited in an autosomal 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.

The gene responsible for HD is HTT, which is located on the short arm of chromosome 4 (4p16.3). This gene produces a protein known as huntingtin, whose function remains unclear. The mutation that causes HD consists of an unstable enlargement of the gene, which results in an abnormal elongation of the huntingtin protein. The abnormal huntingtin is toxic generates death of neurons with though various mechanisms. The part of the gene that is enlarged contains a repeats of three nucleotides (cytosine-adenine-guanine, or CAG). Normally, the number of CAG repeats is less than 26, while in persons with HD the gene usually contains more than 40 repeats. Individuals with repeats ranging from 27 to 39 CAG repeats may rarely 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.

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Treatment

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There is no cure for HD. There are current studies in laboratory evaluating potential treatments targeting the DNA and RNA, such as the antisense strategy. However, those are not studied in humans yet. Among available medications, coenzyme Q10 was recently evaluated in a placebo-controlled study, and it did not slow the disease progression. Currently, the focus of the treatment is to improve the symptoms.

The treatment of chorea relays on drugs called dopaminergic depleters. They block the release of dopamine in the neuron terminals and modulate the control of movements. The advantage of these drugs is that they do not to cause late involuntary movements, called tardive dyskinesia. Tetrabenazine (Xenazine) was the first FDA approved medication for HD. Tetrabenazine might cause drowsiness, slowness of movement, and restlessness. Drowsiness is a common side effect and a common reason for patients to discontinue the medication. In addition, tetrabenazine requires a three times a day dosing due to its variable metabolism and short half-life. Prior to the drug's general FDA approval, Dr. Jankovic received special permission from the FDA (via an investigation new drug permit) to prescribe tetrabenazine in 1979 and has used the drug has since that time in well over a thousand patients, including those with HD.

More recently, deutetrabenazine (AUSTEDO®) was FDA-approved as an alternative for the treatment of chorea in HD. It contains a molecule called deuterium, which affects the drug metabolism and allows more prolonged medication duration and more stable blood levels. Deutetrabenazine requires twice a day dosing and the side effects were comparable with the placebo. Both tetrabenazine and deutetrabenazine had a warning of increased risk of depression and suicidality.

Psychosis may improve with neuroleptics (drugs that block dopamine receptors), such as haloperidol, pimozide, fluphenazine and thioridazine. These drugs, however, can induce tardive dyskinesia and should only be used if absolutely needed to control symptoms. The atypical antipsychotics are preferred due to the lower risk of tardive dyskinesia. Clozapine, an atypical antipsychotic, may be a useful alternative to the typical neuroleptics, but the risk of agranulocytosis (a very low white cell count) complicates its use. Other atypical neuroleptics such as olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon) do not need close monitoring and may be easier to use, but are less effective in controlling chorea. Other medications for memory loss, depression and anxiety also may be useful in some HD patients.

The Movement Disorders Clinic at Baylor Medicine was designated as a Center of Excellence by the Huntington's Disease Society of America. It is also a member of the Huntington Study Group, a consortium of academic clinicians and researchers interested in finding the cause of neurodegeneration in HD and designing therapeutic trials of new medications.

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©2021 Joseph Jankovic, M.D.