Huntington’s Disease (HD) is a fatal, inherited neurodegenerative disease. It affects approximately 30,000 people in the United States, with another 200,000 at risk of developing the disease. There is currently no cure.

Hope is on the horizon, however, with the FDA’s approval of the first drug to treat HD in August of 2008. The drug, Xenazine (tetrabenazine) was developed in the 1950’s to treat psychosis, but had limited success. Now, it is available in the United States, as well as Europe, Canada, and Australia, to treat one of the hallmark symptoms of HD — chorea.

HD is inherited — each child of a parent with HD has a 50% chance of developing the disease – and is caused by an abnormal repeat of CAG basepairs on the short arm of chromosome 4. Symptoms of HD usually appear in people aged 30 to 50 years, and include chorea, or involuntary, jerky movements, dystonia, and dementia. The disease is characterized by a build up of malformed proteins in brain cells, primarily in the basal ganglia and the cerebral cortex. Usually, cells destroy waste products, such as malformed proteins, through a process called autophagy, or “self-eating”, but this process is incomplete in HD. This gradual build-up of protein, and the lack of autophagy, leads to the death of millions of neurons, which leads to cognitive difficulties, personality changes, and psychiatric symptoms.

Since there is no cure for HD, treatments are focused on symptom management and supportive care. Many adults with HD take neuroleptics or antipsychotic medications, such as haloperidol, or muscle relaxants to reduce chorea, but these drugs can severely impair alertness and learning ability. Newer antipsychotic drugs are associated with fewer side effects, but none — other than tetrabenazine — are approved for use in HD. Antidepressants are sometimes useful in adults with HD, and reduce sleep disturbances, but may aggravate seizures and trembling. Several high blood pressure and migraine medications are under investigation to stimulate autophagy, but have not yet been tested in humans.

Xenazine works in the brain to reduce the amount of dopamine available in the brain. Dopamine normally functions to communicate between brain cells, but in HD, dopamine is overactive and leads to the abnormal, involuntary movements called chorea. In clinical trials, patients with HD experienced at least a 25% improvement in chorea, leading to a dramatic improvement in quality of life. Patients with HD are often not able to complete daily activities, including eating at restaurants or attending church, and patients taking Xenazine were able to reclaim part of their daily life lost to HD.

Xanazine does present significant side effects, but many patients, and their physicians, feel that the benefits of improved symptoms outweigh the risks. The most common side effects seen in clinical trials were insomnia, depression, drowsiness, restlessness, and nausea. Most importantly, depression and thoughts of suicide were associated with Xenazine. Many HD patients are already at increased risk for suicidal behavior and close monitoring by family members and caregivers is critical.

Xenazine does not stop the disease process involved in HD, or delay its progression. But, its approval as an orphan drug is symbolic, as HD is increasingly becoming the focus of drug research and development.

Most HD patients die within 15 to 20 years after symptom onset, usually not from the disease itself, but from medical complications resulting from immobility. While this new drug cannot stop, or even delay, HD progression, it may offer patients and families suffering from HD improved quality of life.

References

Huntington Study Group (2006). Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial Neurology, 66 (3), 366-372 DOI: 10.1212/01.wnl.0000198586.85250.13

Aubeeluck A, Brewer H (2008). Huntington’s disease. Part 2: treatment and management issues in juvenile HD. Br J Nurs, 17 (4), 260-263 PMID: 18414272

Andrea Williams, Sovan Sarkar, Paul Cuddon, Evangelia K Ttofi, Shinji Saiki, Farah H Siddiqi, Luca Jahreiss, Angeleen Fleming, Dean Pask, Paul Goldsmith, Cahir J O’Kane, Rodrigo Andres Floto, David C Rubinsztein (2008). Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway Nature Chemical Biology, 4 (5), 295-305 DOI: 10.1038/nchembio.79

Heitz F, La Rosa S, Gonzalez-Couto E, Gaviraghi G, Terstappen GC (2008). Drug discovery and development for Huntington’s disease – an orphan indication with high medical need. IDrugs, 11 (9), 653-660 PMID: 18763216

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