What is Huntington's chorea (Huntington's disease)?

From the Guidelines

Huntington's chorea is a progressive, inherited neurodegenerative disorder that requires a comprehensive management approach, focusing on symptom control and quality of life, as there is currently no effective treatment to halt disease progression. The disease is characterized by involuntary jerking movements (chorea), cognitive decline, and psychiatric symptoms, caused by a genetic mutation in the HTT gene, which produces an abnormal version of the huntingtin protein that damages brain cells, particularly in the basal ganglia 1.

Key Considerations

• The disease is autosomal dominant, meaning a person needs only one copy of the mutated gene to develop the condition, and each child of an affected parent has a 50% chance of inheriting it.
• Symptoms typically begin between ages 30 and 50 and worsen over 10-30 years.
• Treatment focuses on managing symptoms rather than curing the disease, with medications like tetrabenazine, deutetrabenazine, or antipsychotics helping to control movement problems, while antidepressants, mood stabilizers, and cognitive behavioral therapy can address psychiatric symptoms 1.
• Physical therapy, occupational therapy, and speech therapy are important for maintaining function and quality of life.
• Genetic testing is available for those at risk, though this decision is complex and often involves genetic counseling, as noted in the American College of Medical Genetics and Genomics standards and guidelines for clinical genetics laboratories 1.

Diagnostic Approach

• The diagnostic workup for suspected Huntington's disease must consider other potential etiologies of chorea, including genetic and neurodegenerative disorders, as well as acquired conditions such as cerebrovascular, infectious, autoimmune, metabolic, and drug-induced syndromes 1.
• Genetic testing to determine the CAG repeat number for each allele is commercially available and the diagnostic test of choice, with patients undergoing genetic counseling and testing to exclude or confirm HD in concert with initial imaging 1.

Management and Prognosis

• As the disease progresses, patients eventually require full-time care due to severe physical and cognitive impairment, highlighting the importance of early intervention and comprehensive management to optimize quality of life.
• The incidence of Huntington's disease is approximately 10/100,000, with an average age of onset between 35 to 45 years and symptom progression until death within 15 to 20 years of onset 1.

From the FDA Drug Label

The efficacy of AUSTEDO as a treatment for chorea associated with Huntington's disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0. 0001).

Deutetrabenazine is effective in treating chorea associated with Huntington's disease, as demonstrated by a significant reduction in Total Maximal Chorea Scores compared to placebo 2.

• The study showed a statistically significant improvement in chorea symptoms, with a treatment effect of -2.5 units.
• Key findings include:
  • Total Maximal Chorea Scores improved by approximately 4.4 units from baseline to the maintenance period in patients receiving deutetrabenazine.
  • The treatment effect was statistically significant (p<0.0001).
• Clinical significance: Deutetrabenazine may be a useful treatment option for patients with Huntington's disease who experience chorea. However, it is essential to weigh the potential benefits against the risks of depression, suicidality, and other adverse effects associated with the medication.

From the Research

Overview of Huntington's Chorea

• Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized by progressive motor disturbances, including choreiform movements 3.
• Chorea is a hallmark feature of HD, causing unwanted contractions of the facial muscles, trunk, and extremities 3.

Current Pharmacological Approaches

• There are currently no effective pharmacological agents available to stop or prevent the progression of HD 3.
• Management of choreiform movements is usually advised if chorea interferes with daily functioning, causes social isolation, gait instability, falls, or physical injury 3.
• The current pharmacological treatment options to reduce chorea in HD include tetrabenazine, tiapride, olanzapine, and risperidone 3.
• Deutetrabenazine is a newly developed pharmacological agent similar to tetrabenazine, but with suggested less peak dose side effects 3, 4.

Deutetrabenazine as a Treatment Option

• Deutetrabenazine was recently approved for the treatment of chorea in HD and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use 4.
• Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor 4.
• In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians 4.
• Real-world data support current literature indicating that deutetrabenazine is an effective and well-tolerated treatment for HD-associated chorea 5.

Comparison with Tetrabenazine

• Tetrabenazine is a specific inhibitor of vesicular monoamine transporter, approved for chorea in HD patients 6.
• Deutetrabenazine has a unique pharmacokinetic profile that allows for a longer half-life, reduced plasma fluctuations, and less frequent dosing compared to tetrabenazine 5, 7.
• The tolerability profile of deutetrabenazine is similar to that of placebo, with most treatment-emergent adverse events of mild or moderate severity 7.
• Current evidence indicates that deutetrabenazine provides an effective and potentially better tolerated option than tetrabenazine for controlling chorea symptoms associated with HD 7.