The most striking feature of the Huntington’s disease is the bizarre and uncontrollable movement of various muscle groups. In fact, until recently the disease was more commonly referred to as Huntington’s chorea, since the choreatic, dance-like movements are a hallmark of the disease. While chorea as it is used in the word choreaography is usually rhythmic and graceful, chorea as a symptom is quite random and irregular. It is this disorder of movement that researchers in both the laboratory and the clinic have focused much of their efforts.

While chorea should be controlled if at all possible, there are other features of the disease that must also be recognized. George Huntington’s first description of the disease in 1872 included a comment about psychiatric illness as a cardinal feature of the disease [1]. He writes that the disease is invariably recognized by,

1. Its hereditary nature,
2. A tendency to insanity and suicide,
3. Its manifesting itself as a grave disease only in adult life.

In modern medicine we have mostly done away with the term “insanity,” yet the presence of psychiatric illness and suicide still exists in patients of Huntington’s disease today. Patients with Huntington’s disease suffer from psychological issues such as anxiety disorders, memory disturbances and depression. Estimates of the prevalence of neuropsychiatric symptoms in Huntington’s disease are between 33 to 76 percent of patients [2] although the true incidence and prevalence may be much higher. While we do not understand the precise neurobiological cause, it is clear that psychiatric symptoms occur much more frequently in patients of Huntington’s disease than in the general population. Further, neuropsychiatric symptoms are often the most distressing aspect of the disease for patients and their families and many times they necessitate hospitalization [3]. The most frequent psychiatric symptoms that occur with Huntington’s are depression, anxiety, irritability, obsession and compulsions and psychosis. Also, patients may have difficulty forming new memories and performing complex tasks.

Despite the fact that psychiatric illness was described in the earliest report on the disease, research as to how best to treat these conditions has been lacking. More than 218 papers have been published on the pharmacological treatment of Huntington’s disease and every one of them used chorea as the endpoint [4]. When it comes to treating psychiatric illness in Huntington’s disease, physicians do not have any clear guidelines or protocol. While limited anecdotal evidence exists for certain atypical antipsychotics and newer antidepressants, nothing even resembling a consensus exists for pharmacological treatment of these comorbid conditions.

Until there is a cure for Huntington’s disease, managing symptoms remains the primary focus of care. Psychiatric illnesses occur quite often in the disease — they should not go undiagnosed or untreated. While likely to contain few participants, properly controlled and blinded trials should be conducted that focus on psychiatric endpoints in Huntington’s disease such as anxiety, psychosis and depression. We have a growing armamentarium of treatments for psychiatric illness — exceedingly larger than what was known in George Huntington’s time. Physicians need to know which medicines are safe and which are most effective in patients that are already enduring so much. That knowledge will only come through the careful study of psychiatric illness as it occurs in Huntington’s disease.

References

1. Huntington G: On chorea. Med Surg Rep 1872; 26:317–32.

2. E. van Duijn, E.M. Kingma, R.C. van der Mast (2007). Psychopathology in Verified Huntington’s Disease Gene Carriers Journal of Neuropsychiatry, 19 (4), 441-448 DOI: 10.1176/appi.neuropsych.19.4.441

3. J M Hamilton (2003). Behavioural abnormalities contribute to functional decline in Huntington’s disease Journal of Neurology, Neurosurgery & Psychiatry, 74 (1), 120-122 DOI: 10.1136/jnnp.74.1.120

4. Raphael M. Bonelli, Gregor K. Wenning (2006). Pharmacological Management of Huntington’s Disease: An Evidence- Based Review Current Pharmaceutical Design, 12 (21), 2701-2720 DOI: 10.2174/138161206777698693

Symptoms of HD typically present in the third to fifth decade of life, but symptoms may appear as early as the first, or as late as the ninth, decade. The variation in age at onset is likely due to the number of defective trinucleotide repeats on the short arm of chromosome 4. Within the HD gene, more “CAG” repeats implies earlier onset of the disease. (Most juvenile HD patients have 60 or more repeat segments.) There is contradictory evidence about the rate of disease progression and clinical manifestations of HD related to the number of trinucleotide repeats.

While most adults with HD show symptoms of chorea — rapid, involuntary, jerky movements — juvenile HD presents a symptom profile different than adult-onset HD. The most common symptoms in juvenile HD include rigidity, stiffness, awkwardness in walking, and slurred speech. Seizures are also common in younger patients. Chorea is typically not present. Onset of the motor difficulties is usually used to define the age at onset.

Also significant in juvenile HD patients are severe cognitive and psychiatric disturbances. Since these are often the first disease symptoms to appear in young patients, HD is often not diagnosed until later in the disease process. This is particularly important in cases in which family history is either unknown or negative for HD. The cognitive dysfunction and loss of motor abilities is more severe in patients with juvenile HD.

Depression is common in juvenile HD patients, as well as aggression and impulsiveness. Adolescents with HD are particularly vulnerable to impulsiveness related to sexuality. Seizures occur in approximately 25% of juvenile HD patients. Some medication therapies can be implemented to treat some of these symptoms, but may have unwanted side effects in adolescents. The only FDA-approved drug for management of HD is not appropriate for use in children.

As HD progresses, children with the disease will lose the ability to walk, talk, dress themselves, and perform activities of daily living. They will require constant care and supervision. There is no cure for HD, and care is focused on symptom management. The team of medical professionals involved in the care of juvenile HD patients often includes a pediatrician, neurologist, psychiatrist, social worker or genetic counselor, and speech, occupational, and physical therapists.

Children diagnosed with HD will gradually lose the ability to attend school, perform routine tasks, or care for themselves. Families need immense amounts of emotional support from medical professionals, family members, and friends. The average life expectancy after diagnosis for a juvenile HD patient is less than 10 years.

Juvenile HD is a devastating disease, not just for the individual affected with the disease, but also for the entire family. With such a small number of people affected by HD, and an even smaller number affected by juvenile HD, researchers and drug and medical treatment manufacturers are reluctant to invest too much time and money into HD. But, there is hope, and advocacy groups are gaining in strength and voice, and new treatment options are currently under development.

References

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

E. Gomez-Tortosa (1998). Severity of Cognitive Impairment in Juvenile and Late-Onset Huntington Disease Archives of Neurology, 55 (6), 835-843 DOI: 10.1001/archneur.55.6.835

P. Ribai, K. Nguyen, V. Hahn-Barma, I. Gourfinkel-An, M. Vidailhet, A. Legout, C. Dode, A. Brice, A. Durr (2007). Psychiatric and Cognitive Difficulties as Indicators of Juvenile Huntington Disease Onset in 29 Patients Archives of Neurology, 64 (6), 813-819 DOI: 10.1001/archneur.64.6.813

Shihui Xing, Ling Chen, Xi Chen, Zhong Pei, Jinsheng Zeng, Jinru Li (2008). Excessive blinking as an initial manifestation of juvenile Huntington’s disease Neurological Sciences, 29 (4), 275-277 DOI: 10.1007/s10072-008-0981-7

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

At the age of 22, the year following his graduation from medical school at Columbia, George Huntington (1850-1916) made his contribution to medical research, publishing his report on a hereditary form of chorea in The Medical and Surgical Reporter in the April 13, 1872 issue. His publication became one of the classical descriptions of neurological disease.

Huntington dealt with hereditary chorea as a reminiscence of his childhood spent on the eastern extremity of Long Island (New York), where, as the son and grandson of physicians, he recalled patients from his father’s practice. The hereditary chorea, as he called it, was a rare but terrible disease. Its essential features, tersely noted by Dr. Huntington in three short paragraphs, included a “hereditary nature,” a “tendency toward insanity” and “its manifestation as a grave disease in adult life.” He also commented on the grotesque nature of associated abnormal movements and the lack of knowledge of both the cause and cure of the disorder.

Huntington noted that the disorder was confined to “a few families, and has been transmitted to them, an heirloom from generations away back in the dim past.” He also noted that in unaffected offspring, “the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.” Huntington in his description states that the first symptoms usually occur at an adult age, and he delineates the development of the chorea:

The movements gradually increase when muscles hitherto unaffected take on the spasmodic action, until every muscle in the body becomes affected (excepting the involuntary ones)…

On mental symptoms he writes:

As the disease progresses the mind becomes more or less impaired, in many accounting to insanity, while in others mind and body gradually fail until death relieves them of their suffering.

Huntington’s disease is of tremendous interest to neuropsychiatry because it has a known cause and manifests in changes in behavior, cognition, and affect. It is known to be caused by a mutation resulting in trinucleotide CAG repeats (polyglutamine) on the Huntington protein encoded on the short arm of chromosome 4. Neuropsychiatric studies of Huntington’s disease may lead to breakthroughs in understanding the neuropathological correlates of psychiatric disorders.

Reference

Neylan, T.C. (2003). Neurodegenerative Disorders: George Huntington’s Description of Hereditary Chorea. Journal of Neuropsychiatry, 15(1), 108-108. DOI: 10.1176/appi.neuropsych.15.1.108