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INDEX Page
10 The Most Commonly Asked
Questions About Huntington's Disease
Steven M. Hersch, MD, PhD; H. Diana Rosas, MD
From the Department of Neurology, Emory University, Atlanta,
Georgia, USA (S.H.) and Department of Neurology, Massachusetts
General Hospital, Boston, Massachusettes, USA (H.D.R.).
THE NEUROLOGIST 2001;7:364-368
1. What causes Huntington's Disease?
Huntington's disease (HD) is a chronically progressive neuro-degenerative disorder with autosomal dominant inheritance and nearly complete penetrance. The genetic defect causing HD was discovered in 1993, affecting a gene on the short arm of chromosome 4 that codes for a protein that has been named huntingtin. The huntingtin protein normally contains a polymorphic stretch of repeated glutamine residues (coded by the DNA trinucleotide CAG) near its N-terminus. Huntington's disease occurs when this polyglutamine repeat sequence is expanded to more than approximately 37.
Once this mutation occurs in an individual, their offspring have a 50% chance of inheriting it. Because the HD gene is prone to developing this type of alteration, new mutations do occur occasionally, and thus many founders are responsible for HD worldwide. Rare individuals with polyglutamine repeat numbers falling in a range from 34 to 37 have an increased probability of developing the symptoms of HD and of passing it on to their offspring. Higher numbers of repeats correlate with an earlier age of onset.
Most cases of juvenile HD have more than 60 CAG repeats. Although the CAG number is a major determinant of onset, other factors contribute and it may have little effect on the rate of progression.
The CAG expansion occurs in the coding region of huntingtin, and, thus, abnormal huntingtin, is made containing an abnormally long polyglutamine stretch. Although huntingtin is normally found in most cells in the body, the toxic effects of mutant huntingtin are primarily realized in the brain in which there is selective neuronal toxicity and death.
Why some neurons are more effected than others is not yet understood. However, the pattern of selective vulnerability readily explains the symptoms and progression of HD clinically. The normal function of huntingtin is not well understood as yet, however, it may play a role in the intracellular transport of other proteins or of organelles. Loss of the normal function of huntingtin could play a role in neuronal toxicity.
There is also a great deal of evidence that a new function, caused by altered conformation, disturbed protein-protein interactions, or abnormal cleavage and aggregation could also be neurotoxic. The exact mechanisms and sequences of neurotoxicity continues to be studied and includes altered protein processing, protein aggregation, transcriptional dysregulation, excitotoxicity, oxidative injury, energy depletion, apoptotic cascades, and inflammatory mechanisms. The ongoing research into pathologic mechanisms is providing a wealth of potential neuroprotective approaches that are just beginning to be tested.
2. How is HD diagnosed?
In the setting of a known and confirmed family history, HD can be diagnosed clinically based on the presence of an otherwise unexplainable extrapyramidal movement disorder. Although chorea and eye movement abnormalities are typically prominent in HD, dystonia, bradykinesia, or rigidity can sometimes be the most prominent symptoms.
Depression, personality change, other psychiatric symptoms, and cognitive dysfunction can antedate the movement disorder; however, they do not provide the specificity necessary for an unequivocal diagnosis, and their own differential diagnoses should be considered even in individuals testing positive for the HD genetic mutation.
Neuroimaging and most laboratory studies are mostly useful to rule out other causes of the symptoms, particularly where there is no likely family history. Confirmatory genetic testing in symptomatic individuals can be very valuable, even when there is a suspected family history. Besides providing an unequivocal genetic diagnosis that provides certainty to family members and clinicians, it can help avoid performing unneeded studies.
3. How should presymptomatic genetic testing be performed?
Genetic testing in individuals who do not have diagnostic symptoms is termed pre-symptomatic genetic testing. Potential benefits of presymptomatic testing include family, social, and professional planning as well as removing the stress of uncertainty about the future.
Genetic testing also comes with many potential adverse consequences. For those who test positive, these consequences include the awful fate of waiting for an inescapable and horrible disease to start, increased genetic risk for existing offspring, real threats to health and life insurance coverage, and other forms of genetic discrimination. Even those testing negative can have poor psychological adjustments, such as survival guilt.
Adding to these complications, presymptomatic individuals often have a poor understanding of what they are asking for when they do seek genetic testing. For example, a common experience is for presymptomatic individuals to ask for genetic testing because they are worried about possible symptoms they are having, such as clumsiness or depression.
These individuals and their physicians may not realize that genetic testing is unlikely to be the best answer to a strictly clinical question. Because the perceived risks generally outweigh the benefits, less than 5% of individuals eligible for presymptomatic testing in the Untied States have had it done.
In the future, if preventive treatments are developed for use in presymptomatic individuals and if legislation lowers the risks of genetic discrimination, this low rate could change.
Because presymptomatic genetic testing brings up many complicated issues and the results are so far-reaching, it should not be seen as a standard office test. Rather it should be performed with great deliberation in the setting of genetic counseling, psychological assessment, a neurological examination, and enough time taken to ensure that the risks and benefits are well understood, fully considered, and managed before proceeding.
There is a network of genetic testing centers available to most individuals that are well equipped for handling this process and available by inquiry to the Huntington's Disease Society of America.
4. How should the movement disorder be treated?
First think about whether the movement disorder really needs to be treated pharmacologically. Chorea can be more cosmetic than disabling. Patients with HD are often unaware and untroubled by much of their chorea and often do not give it the importance observers do.
Disordered motor control and sequencing and cognitive slowing often cause more of the motor disability than chorea. Medications that suppress chorea may not help these aspects of motor dysfunction and can make them worse. Minorities of the patients we care for are thus on antichorea medications.
Nevertheless, for targeted symptoms in selected patients, typical and newer atypical dopamine-blocking agents, dopamine-depleting agents, and benzodiazepines can all suppress involuntary movements.
When using many of these agents, mental slowing, rigidity, depression, apathy, increased swallowing dysfunction, and tardive dyskinesia are among the complications to be aware of, even at low doses.
It is also important to intermittently review the need for these medications and to reduce or discontinue them when possible.
5. What nonpharmacologic interventions help in managing HD?
The movement disorder may interfere with an individuals ability to function independently. Assessments by a trained physical therapist, occupational therapist, and speech and language pathologist are increasingly valuable as HD progresses. These modalities, as well as general physical conditioning through moderate exercise, are important to helping the individual with HD remain independent.
A physical therapist can recommend an appropriate home exercise program, including heel stretches and shoulder strengthening exercises, which may help with balance.
As the disease advances, individuals can be fitted for assistive devices, such as a walker, Rollaider, or wheelchair. It is important that training in the use of these devices be started early, because it may be more difficult to train individuals to use them later in the course of disease. Additionally, devices may need to be modified on a periodic basis as symptoms evolve.
Individuals with HD often lose tremendous amounts of weight, even in the absence
of much chorea. A higher body weight has been associated with slowing of the progression of disease, and it is recommended that individuals with HD maintain a
body weight of at least 10% above ideal body weight.
If the chorea is interfering with food intake, an occupational therapist may recommend aids such as weighted utensils, nonslip dishes, or covered cups. Dysphagia develops as HD progresses and poses a risk of choking and aspiration pneumonia. Caregivers should be able to perform the Heimlich maneuver.
Speech pathology and clinical nutrition consultants can recommend modifications in environment, posture, and food composition and consistency. In some cases, individuals will need to be evaluated with a modified barium swallow study, and gastric tube placement and should be considered in cases of frank aspiration.
In HD transgenic mouse studies, an enriched environment has been associated with a slowing of progression. Participation in an adult day program should be considered, even for individuals who have difficulty communicating.
Language boards may be helpful for communicating with these individuals and for limiting the frustration they frequently feel about not being understood.
6. What can be done about behavioral and psychiatric symptoms?
Behavioral and psychiatric symptoms generally cause more morbidity and occasion many more calls for help and intervention than do motor symptoms, especially in the early and middle years of the disorder.
Among common problems are personality change, depression, emotional hyper-reactivity, anger outbursts, impulsiveness, obsessive thinking, apathy, altered sexuality, and irritability. Delusions and frank psychosis are uncommon but difficult to manage when present.
Psychiatric symptoms such as depression, psychosis, and obsessive thinking are treated much like they would be in individuals who don't have HD and generally respond similarly. For episodic behavioral problems, such as anger and irritability, the first principal is to analyze potential triggers.
Addressable problems such as hunger, disordered sleep, inconsistent routine, and specific environmental stresses, should always be considered before resorting to or in concert with pharmacotherapy.
When medications are necessary, serotonin reuptake inhibitors, mood stabilizing anticonvulsant medications, and antipsychotic medications alone or in combination can be effective.
7. What are the experimental drugs for slowing the progression
of HD that patients are asking about?
A variety of medications aimed at slowing progression in symptomatic patients are being actively tested in transgenic mice with an HD phenotype as well as in phase II and phase III clinical trials. These trials are often well publicized and patients not participating in the trials frequently ask about taking the medications.
Categories of medications being tested include glutamate antagonists, antioxidant medications, energy enhancers, and antiapoptotic agents, among others. Although there is an experimental basis for these trials, they are in early phases of testing and none have yet come all the way through phase III testing and shown demonstrable efficacy. A phase III trial of the glutamate blocker Remacemide alone or in combination with coenzyme Q10 is being completed currently by the Huntington Study Group (HSG). Results should be known in 2001.
An industry-sponsored phase III trial of eicosapentanoate (a phospholipid isolated from fish oil) is ongoing. Ongoing or planned phase II trials, unlikely to have the power to test efficacy, include creatine (energy enhancer), riluzole (glutamate antagonist), and minocycline (antiapoptotic).
These human trials, as well as promising results from mouse trials, indicate potential progress in neuroprotection but dont yet provide a firm basis for prescribing. As always, when considering using some of these agents, risks must be balanced against unknown benefits. Increasing attention is being given to finding treatments for individuals who are at risk for HD, but not symptomatic, that could delay or prevent onset.
HSG is sponsoring two ground-breaking clinical studies in the HD at-risk population called PHAROS and PREDICT.
PHAROS is designed to determine, in at-risk individuals not undergoing genetic testing, the rate and predictors of becoming symptomatic as well as to study the feasibility and ethical issues of performing studies in this subject population.
PREDICT is a study of gene-positive individuals who do not yet have symptoms with the goal of determining how a variety of clinical, neuropsychological,imaging, or laboratory studies correlate with the development of symptoms. These studies will provide a wealth of information for designing medication trials for at-risk, pre-symptomatic individuals in the future.
8. Are there replacement, genetic, or functional surgical
treatments with promise for HD?
A variety of trials of striatal neurotransplantation have been completed, are underway, or are in planning stages. These trials have raised some ethical and safety questions while demonstrating feasibility, but have not yet demonstrated efficacy. The aggregate experience of these trials does not support the use of these procedures outside of well-designed controlled clinical trials. Nevertheless, neurotransplantation remains an important and promising experimental approach.
Stem cell technology and gene therapy approaches are undergoing rapid progress, foreseeably leading to experimental clinical trials for HD within the next several years. There has been limited experience with functional neurosurgery, such as pallidotomy or deep brain stimulation, for HD and significant complications have occurred. These approaches should also be considered experimental.
9. What support can be provided to families with HD?
Because HD usually occurs during an individuals years of parenting and wage earning, it can have devastating effects on entire families. Thus, counseling, assistance, and referrals in regards to vital family issues are extremely important.
Areas of major concern early on include financial planning, health, life, and long-term care insurance, and obtaining assistance through employment disability. As the disease progresses, additional Medicare and Medicaid eligibility, caregiver support, planning for possible long-term care, and providing for eventual financial and health care supervision through advanced directives or custody proceedings become increasingly important.
Proactively dealing with such issues are an important part of caring for HD families and extend from the physicians awareness of them, often to involve social workers or other counselors, community resources, health care attorneys, and support groups for HD families. Regional HD clinics, Huntington's Disease Society of America (HDSA) chapters, Huntington Study Group sites, and the HDSA national office are good sources for counseling, referrals, and support groups.
Family issues should begin to be addressed when individuals are at risk for HD. For example, an individual considering presymptomatic genetic testing might want to address life, health, and long-term care insurance before a positive test result forever effects eligibility. The same consideration applies to individuals at risk for HD who are being followed through the time during which symptoms may be beginning but are not yet definitively diagnostic.
Individuals who are gene positive but presymptomatic, or their spouses, might be well advised to work for larger employers with insurance plans that do not scrutinize individual risks.
10, Where can I refer families to for information about HD,
subspecialty care, and about participating in clinical trials?
The Huntington's Disease Society of America publishes extensively on every aspect of HD, including information useful for affected families as well as for health care professionals. HDSA periodicals inform about current clinical and research issues.
In addition, the HDSA maintains an information line (800-345-HDSA) and is able to make referrals to local HDSA chapters, genetic testing centers, and HD clinics. The HDSA also supports a growing network of regional HD specialty clinics through its Center of Excellence Program and funds basic and clinical research through several funding mechanisms. Their web site is www.hdsa.org and has links to many related web sites and chat rooms. Regional HDSA chapters are local sources for referrals, educational materials, family services, support groups, and advocacy.
The Hereditary Disease Foundation (HDF) stimulates and supports research aimed at basic mechanisms and treatment discovery and maintains an extensive web site www.hdfoundation.org especially focused on basic and preclinical research.
HSG is an international collaboration of clinicians and scientists that conceive and conducts clinical research and clinical trials related to HD. The HSG is based in the University of Rochester, has open and democratic governance, and includes more than 55 centers in North America, Europe, and Australia that have a particular interest in HD. Because of this interest, these sites represent locations patients can often be referred to for subspecialty care, as well as for study participation. The phone number for the HSG is 800-942-0424 and its web address is
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Send reprint requests to Steven Hersch, MD, PhD, Center for Aging Genetics and
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