What is Huntington’s Disease?
Huntington’s diseaseHuntington’s disease is a progressive disease that results in the slow loss of affected brain cells. It is an inherited condition that begins in adulthood. At present, typical Huntington’s disease is a lethal condition. Huntington’s disease is characterised by involuntary movements, dementia and psychological disturbances that worsen as the disease progresses.
Statistics on Huntington’s Disease
Huntington’s disease runs in families. It is an inheritable dominant disease, which means that receiving an abnormal gene from one parent will cause the disease, even if the matching gene from the other parent is normal. So, an affected parent has a 50% chance of passing the disease gene onto their children.
In some cases, a parent that carries the mutant gene but does not develop the disease can pass on the disease gene to a child and the child will develop Huntington’s disease, this is more common if passed down by the father.
Huntington’s disease occurs in 4 to 8 people per 100,000. Most of these people will have a previous family history of the disease. However, about 10% of people who develop the condition will not have it in their family history. De novo (meaning “new”) mutations can arise by chance in a person in which there is no previous family history. These “new” cases then also have a 50% chance of passing the disease gene onto their children.
Huntington’s disease is about 10 times more prevalent in Western European populations compared to African and Asian populations. Huntington’s occurs about twice as often in Tasmania compared to the rest of Australia due to an individual with Huntington’s settling in Tasmania many years ago and passing the mutation on. This local effect in Tasmania is known as a founder effect.
Risk Factors for Huntington’s Disease
Mutations in the huntingtin gene cause Huntington’s disease. These mutations in the gene result in the huntingtin protein being longer in length. This longer protein then accumulates abnormally in the brain cells and eventually leads to brain cell death. The age the disease begins in a person is heavily dependent on the length of the mutant protein, i.e. the longer the protein, the earlier the person will develop the disease.
In cases where a parent has the diseased huntingtin gene but does not develop Huntington’s disease, the length of the mutant protein in the parent is only slightly longer than normal. However, in their child who will get passed the diseased gene, the mutant protein is longer and the child will then develop the disease as an adult, a concept known as anticipation.
Progression of Huntington’s Disease
Huntington’s diseaseHuntington’s disease is a lethal disorder. Death usually occurs within 15 – 20 years of showing signs of the disease.
Due to the loss of brain cells involved with motor function, individuals have difficulty controlling their movement, swallowing and clearing their lungs. The most common cause of death is pneumonia due to the individual not being able to clear their lungs properly and having problems with swallowing, which results in food and liquid entering their lungs. The second most common cause of death is heart failure, followed by suicide.
Symptoms of Huntington’s Disease
Initially with Huntington’s disease, especially prior to diagnosis, family members often report that the individual becomes very difficult to live with, being aggressive and “out of sorts”. This can be very frustrating for the affected person and their family, and often subsequent diagnosis gives the family some much-needed relief since they now understand the reasons behind the personality and behavioural changes of their loved-one.
There are three different types of functions that are affected with Huntington’s disease, these include: motor function (movement), cognition (thought) and neuropsychiatric behavior (mental disease issues).
Often the first sign of Huntington’s disease is jerky, random and uncontrollable movements. This is a sign that the part of the brain controlling muscle control and coordination is affected. Other consequences of loss of muscle control are instability. This makes individuals more susceptible to loss of balance and falls, abnormal facial expressions and difficulties chewing, swallowing and speaking. Problems with eating often experience malnutrition and severe weight loss that may lead to the need for a feeding tube.
The effects of the disease on thought processes are progressive. Particular thought processes that are involved include executive functions, i.e. making plans and decisions, responding to situations in an appropriate manner rather than on impulse etc. Memory is also impaired; both short- and long-term memory-recall are affected. Cognitive impairment worsens as the disease develops and eventually leads to dementia.
Individuals also exhibit other psychological and behavioral disturbances including anxiety, depression, aggression, lack of emotion, irritability, denial, mania and compulsive tendencies. For many people with Huntington’s disease and their families these are the most distressing features of the disease, as they affect daily life for all involved. Suicide attempts and suicidal thoughts are also more common in Huntington’s.
Clinical Examination of Huntington’s Disease
A neurologist tests body movement, reflexes, eye movement, hearing and balance. Brain imaging scans may also be used to check for the characteristic changes in brain structure caused by HD. These clinical observations are combined with an extensive family medical history in order to yield the diagnosis. If an individual is found to be symptomatic, they can either continue with the genetic testing process to confirm the diagnosis, or withdraw from genetic testing.
How is Huntington’s Disease Diagnosed?
Huntington’s diseaseThe diagnosis of Huntington’s disease is usually made after an individual has presented with the physical features of the disease, namely involuntary movements. If they are thought to have Huntington’s disease, a blood sample is collected and a genetic test conducted to determine the length of the expansion in the huntingtin gene. Normal huntingtin is defined as having
< 26 repeats, and >
40 repeats as Huntington’s disease. People who have repeats between 27 – 39 may develop the disease in rare cases and they usually only show features of the disease much later in life, in their 60s and 70s. However, these people do have a high chance of passing on Huntington’s disease to their children.
For affected individuals, family planning becomes increasing important since there is a 50% chance of passing Huntington’s onto their children. If a couple becomes pregnant prenatal diagnosis is available so the couple can test whether the embryo carries the mutation. Prenatal screening is a very private and personal matter and is always done along with genetic counselling. It is strongly advised against seeking a prenatal genetic test if the parents will not terminate the affected foetus. At-risk individuals who do not wish to know whether they will develop Huntington’s disease or not may choose to have pre-implantation genetic testing so that only unaffected embryos are implanted without knowing their own status. This requires some level of secrecy between the individuals being tested and medical staff, so that medical staff whom know the status of the at-risk parent do not tell them what their status is.
Prognosis of Huntington’s Disease
Huntington’s diseaseHuntington’s disease is a lethal disease, with death usually occurring within 15 – 20 years after an individual shows signs of the disease. The age of onset is heavily dependent on the length of the expansion and other factors including environmental factors and other genes that act to modify the age that the signs of the disease first occur. Currently, there are no treatments available to cure or slow the pace of the disease.
How is Huntington’s Disease Treated?
Huntington’s diseaseAt present, there are no drug treatments available that are able to cure or slow the progression of the Huntington’s disease or are there treatments to slow the disease progression. However, there are a number of treatments and therapies that can help to reduce the symptoms of Huntington’s.
Treatment of involuntary movements
Tetrabenazine (Xenazine) was developed specifically to reduce the severity of the jerky/involuntary movements occurring in Huntington’s disease. Other drugs are also used to help reduce involuntary movements – these include neuroleptics and benzodiazepines. The rigidity experienced by some patients can be treated with antiparkinsonian drugs.
Treatment of psychological effects
Selective serotonin reuptake inhibitors and the serotonin receptor antagonist mirtazapine can be used to treat depression, while atypical antipsychotic drugs can be taken to manage psychosis and behavioural problems. Involvement with Huntington’s disease and other disease support groups and communities can also very helpful in managing the psychological effects of Huntington’s for both the affected individual and their family. There is a National Huntington’s Disease Association and also various State-based networks. Links to the State-based Huntington’s Disease Associations can be found on the National website. A website has also been established which specifically handles Juvenile Huntington’s.
Weight loss and eating difficulties due to swallowing difficulties and lack of other muscle coordination make management of nutrition important. Thickening agents can be added to liquids to make the fluids easier and safer to swallow and reduce the chance of fluids entering the lungs. If eating becomes too dangerous or uncomfortable, a feeding tube can be used.
In combination with adding thickening agents to liquids, nutrition can be managed by feeding individuals soups and purees of fruits, vegetables and meats. There are a number of recipe books available that are specifically tailored to individuals with feeding difficulties. For tips, guidelines regarding fluid and calorie requirements and recipe ideas for maintaining adequate nutrition in individuals with swallowing diffculties, visit the following website: http://www.gicare.com/Diets/Dysphagia.aspx.
Often the behavioural changes that occur in Huntington’s individuals are the most worrying for the patient and their families. These include lack of concentration, memory lapses, depression, mood swings and aggression. These behavioural changes together with the progressive loss of mobility and independence place a lot of pressure and stresses on the individual’s family. In the late stages of the disease, full-time nursing care is required. Most often the individual’s spouse provides the nursing care. The primary carers can often feel or become isolated due to having less contact with friends and society in general. Since people more peripheral to the disease do not understand the behavioural changes that occur in Huntington’s, the carer is often embarrassed or reluctant to socialise with their affected spouse. It is very important that the individuals responsible for care-giving receive breaks from their care-giving duties and manage the psychological burden the disease places on them. Tapping into support networks to ease the psychological burden and isolation, and specific equipment that can be used to ease the physical burden can help individuals cope with their care-giving role.
Physical and speech therapy
Huntington’s diseasePhysical and speech therapy can be very useful in the management of Huntington’s disease and has been shown to maintain cognitive and motor function. Physical therapy is particularly important in helping the patient to adjust to their reducing motor control and instability. These include making postural changes, balance transfer, preventing falls, learning how to use walking aids and other assistance devices.
Speech therapists can assist with maintaining breathing capacity and control of swallowing and eating muscles. These can all help to maintain quality of life.
Potential therapies for the future and getting involved with clinical trials
A number of compounds that have shown promise in animal studies and in pilot clinical trials are currently under investigation for the treatment of Huntington’s disease. To keep up to date with the latest developments with clinical trials, these websites might be useful:
* European Huntington’s Disease Network
* Huntington Study Group
* Huntington’s Disease Society of America
Gene therapies to reduce the amount of mutant huntingtin protein in the brain have shown great promise in the laboratory setting. However, it is likely to take sometime before clinical trials of gene therapies are underway.
Source: Neurological Rehabilitation and Movement Disorders.
1. Falush D, Almqvist EW, Brinkmann RR, Iwasa Y, Hayden MR. Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases. Am J Hum Genet. 2001;68(2):373-85.
2. Warby SC, Montpetit A, Hayden AR, Carroll JB, Butland SL, Visscher H, et al. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet. 2009;84(3):351-66.
3. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A. 2004;101(10):3498-503.
4. Pridmore SA. The prevalence of Huntington’s disease in Tasmania. Med J Aust. 1990;153(3):133-4.
5. Morell V. Huntington’s gene finally found. Science. 1993;260(5104):28-30.
6. ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. The American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Am J Hum Genet. 1998;62(5):1243-7.
7. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994;330(20):1401-6.
8. Rosenblatt A, Brinkman RR, Liang KY, Almqvist EW, Margolis RL, Huang CY, et al. Familial influence on age of onset among siblings with Huntington disease. Am J Med Genet. 2001;105(5):399-403.
9. Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, et al. Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nat Genet. 1993;5(2):174-9.
10. Carter RJ, Hunt MJ, Morton AJ. Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington’s disease gene. Mov Disord. 2000;15(5):925-37.
11. van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington’s in mice. Nature. 2000;404(6779):721-2.
12. Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, et al. Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J Neurosci. 2004;24(9):2270-6.
13. Altschuler EL. Strenuous, intensive, long-term exercise does not prevent or delay the onset of Huntington’s disease. Med Hypotheses. 2006;67(6):1429-30.
14. Graveland GA, Williams RS, DiFiglia M. Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science. 1985;227(4688):770-3.
15. Estrada Sanchez AM, Mejia-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington’s disease. Arch Med Res. 2008;39(3):265-76.
16. Henley SM, Wild EJ, Hobbs NZ, Scahill RI, Ridgway GR, Macmanus DG, et al. Relationship between CAG repeat length and brain volume in premanifest and early Huntington’s disease. J Neurol. 2009;256(2):203-12.
17. Ruocco HH, Bonilha L, Li LM, Lopes-Cendes I, Cendes F. Longitudinal analysis of regional grey matter loss in Huntington disease: effects of the length of the expanded CAG repeat. J Neurol Neurosurg Psychiatry. 2008;79(2):130-5.
18. Kremer B. Clinical neurology of Huntington’s disease. In: Bates G, Harper P, Jones L (eds). Huntington’s Disease (Third Edition). Oxford: Oxford University Press; 2002, p. 28-53.
19. Beste C, Willemssen R, Saft C, Falkenstein M. Error processing in normal aging and in basal ganglia disorders. Neuroscience. 2009;159(1):143-9.
20. Walker FO. Huntington’s disease. Lancet. 2007;369(9557):218-28.
21. van der Burg JM, Bjorkqvist M, Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol. 2009;8(8):765-74.
22. Xing S, Chen L, Chen X, Pei Z, Zeng J, Li J. Excessive blinking as an initial manifestation of juvenile Huntington’s disease. Neurol Sci. 2008;29(4):275-7.
23. Groen JL, de Bie RM, Foncke EM, Roos RA, Leenders KL, Tijssen MA. Late-onset Huntington disease with intermediate CAG repeats: true or false? J Neurol Neurosurg Psychiatry. 2010;81(2):228-30.
24. Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM. Suicide risk in Huntington’s disease. J Med Genet. 1993;30(4):293-5.
25. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996;11(2):136-42.
26. Siesling S, van Vugt JP, Zwinderman KA, Kieburtz K, Roos RA. Unified Huntington’s disease rating scale: a follow up. Mov Disord. 1998;13(6):915-9.
27. Hines KA, Veach PM, LeRoy BS. Genetic counselors’ perceived responsibilities regarding reproductive issues for patients at risk for Huntington disease. J Genet Couns. 2010;19(2):131-47.
28. Asscher E, Koops BJ. The right not to know and preimplantation genetic diagnosis for Huntington’s disease. J Med Ethics. 2010;36(1):30-3.