Huntington’s disease (HD) is one of the most devastating diseases of mankind. It incapacitates patients by affecting their ability to move, think, and behave normally. It causes uncontrollable and disabling movements of the face, neck, trunk and
limbs, loss of balance, and uncoordinated movements. In addition to these motor dysfunctions, memory, thinking, and judgment become progressively impaired. Furthermore, patients with HD exhibit a wide variety of psychiatric problems. At the beginning
of the disease, the patient’s job-related capacity is frequently overestimated because they can perform isolated tasks reasonably well for a short period of time. In a real job environment, this is not the case.
This deceptively mild disability on a casual neurological examination frequently delays qualification of the patient for the disability status and income.
Physical disability and intellectual loss are already devastating to HD patients and their families. However, severe psychiatric problems are the ones that often render the entire family dysfunctional. The disease can change the sweetest persons intoangry, aggressive, irrational individuals. To make matters worse, the caregivers are frequently the main targets of HD patients’ aggression. HD is an eventually fatal disease although the lifespan considerably varies from patient to patient. There have been no medications proven to slow down, halt, or reverse the progression of the disease. However, many medications can alleviate many symptoms of HD, particularly involuntary movements and psychiatric problems. As the disease progresses, it overcomes the therapeutic effects of these medications. It is important to note, however, that cautious optimism exists for the future. Many scientists and clinical investigators believe that recent advances in research are about to change this dismal prognosis of HD.
HD patients and their caregivers need psychological, financial, social, and legal supports. It is also very important to proactively address a number of problems expected to occur in HD. Advance directives and durable power of attorney play important
roles in deciding the treatment options in the later stages of this disease. Protection of patients’ dignity often becomes a challenging task as the disease advances. Educating patients themselves, caregivers, family members, physicians, nurses,
and other healthcare professionals about the complex medical and non-medical problems of this disease is essential for optimum care. A multidisciplinary approach involving a wide variety of healthcare professionals is an effective way to optimize
the care of HD patients. The HD Clinic at UTMB is established to answer the complex needs by HD patients, caregivers, and family members.
It is extremely important to let HD patients know that there are teams of physicians and scientists all over the world challenging the dismal outcome of this disease. Research is the best hope for developing effective treatments to change the course of
HD. The hope has become increasingly promising. In 1993, the genetic mutation causing HD was discovered. Before then, we had no clue how the disease process was started. Since the discovery of the HD gene, scientists have been accumulating an increasing
amount of data that are important for understanding the disease-causing mechanism. Furthermore, the genetic mutation of HD was experimentally introduced into animals. These “transgenic” animals show a disease similar to human HD, and have
become an important experimental system to study the disease-causing mechanisms. Transgenic HD animals are also used to screen drugs to find new treatments for HD. These efforts are paying off. New drugs that show promising results in animals are
expected to come to human therapeutic trials in the near future under the auspice of the Huntington Study Group (HSG). As a member of the HSG, the Department of Neurology at UTMB is preparing for participation in such studies.
HISTORY OF HUNTINGTON’S DISEASE
In 1872, George Huntington (1850-1916) in Middleport , Ohio wrote a paper entitled "On Chorea." A short time later the medical community adopted the eponym "Huntington's Chorea." The word “chorea” is derived from the Latin word 'choreus',
which means dance and the Greek word 'choros' which means chorus. Chorea has become the hallmark of the movement aspect of this neurodegenerative disorder. Although this was George Huntington’s only original contribution to the medical literature,
he beautifully described all the cardinal features of this disease, including the adult onset, progressive course and eventually fatal outcome, the choreic movements combined with mental disorders, and some features of inheritance.
Although Charles Oscar Waters and George Huntington had recognized the hereditary nature of HD, it was not until 1908 when the mendelian dominant inheritance was established in HD. In 1930s and 1940s, the eugenic movement in Nazi Germany launched an HD
eradication program by sterilizing individuals with this disease. It should be noted, however, that this approach was not only inhumane, but also ineffective. New cases of HD pop up in the general population as results of new mutation events (See
the section of the Genetics of Huntington’s Disease). The next major breakthrough came with the mapping of the HD locus to the short arm of chromosome 4 in 1983. (See the section on Pathogenic Process of Huntington’s Disease). However,
in spite of vigorous search of the gene in this chromosomal region, it took another 10 years to find the gene. In 1993, the HD-causing mutation was finally identified in the gene then known as IT15 (“intriguing transcript 15”), which is
now officially registered as HD in the Genome Database. Starting in 1993, the progress in research has been remarkable and rapid enough to raise a cautious optimism for the development of effective treatments for this devastating disease in the near
SYMPTOMS AND SIGNS OF HUNTINGTON’S DISEASE
Chorea consists of involuntary, continuous, rapid, abrupt, brief, unsustained, irregular movements that flow randomly from one body part to another. Patients are able to partially and temporarily suppress the chorea with efforts for a limited time period.
Many patients "camouflage" some of the movements by incorporating them into semipurposeful activities. This is called parakinesia. Patients also exhibit the inability to maintain voluntary contractions, which is known as “motor impersistance”
and is exemplified by an inability to protrude the tongue for an extended period or failure to make continuous tight manual grip (milk-maid grip). Affected individuals typically have a peculiar, irregular, and dance-like gait. Other motor disorders
include dysarthria (slurred speech), dysphagia (swallowing difficulties), postural instability, ataxia (loss of motor coordination), dystonia (sustained involuntary postures and/or movements, myoclonus (lightening-like jerky movements), and tics.
Besides these involuntary movements, there are two other major components of the disease, i.e., cognitive decline and psychiatric symptoms. The neurobehavioral symptoms vary but are usually expressed as personality changes, apathy, social withdrawal,
agitation, impulsiveness, depression, mania, paranoia, delusions, hostility, hallucinations or psychosis. Cognitive changes are manifested chiefly by loss of recent memory, poor judgment, impaired concentration and acquisition. These changes occur
in nearly all patients with HD; but some patients with late-onset chorea never develop a significant loss of their intellectual abilities. Cognitive impairments in HD differ from the severe general loss of intellectual abilities” seen in Alzheimer’s
disease. For example, most HD patients recognize their family members until very late stage of the disease. In HD, tasks requiring psychomotor or visuospatial processing are affected early on and get worse a lot faster than memory loss. Because of
this unique pattern, the cognitive loss in HD often appears deceivingly mild, and is missed on a casual neurological examination of the patient by disability-assessing doctors.
About 10% of HD cases start having symptoms or signs of the disease before age 20, but the usually HD starts at 40 - 50 years of age. Juvenile-onset patients usually inherit the disease from their father. Juvenile HD (onset of symptoms before 20 years)
typically starts with the combination of progressive parkinsonism (manifestations similar to those seen in Parkinson’s disease), loss of intellectual ability, ataxia (loss of coordination and balance), and seizures. In contrast, the clinical
diagnosis of adult HD is usually established when patients have the insidious onset of clumsiness and involuntary restless movements, which may be wrongly attributed to simple nervousness. Slowness of movement (bradykinesia) usually occurs in patients
with the rigid form of HD, but it often coexists with chorea in adult cases. When this happens it may not be fully appreciated on a routine examination. Bradykinesia in HD may be caused by a mechanism different from true Parkinson’s disease,
and this possibly explains why a reduction in chorea with anti-dopaminergic drugs rarely improves overall motor functioning and indeed may cause an exacerbation of the motor impairment.
THE GENETICS OF HUNTINGTON’S DISEASE
HD was long known to be a genetic condition. The disease would run in families and appeared to be passed directly from parent to child, without skipping generations or showing a preference for affecting one sex more than the other. This pattern of inheritance
is known as autosomal dominant. All genes (except for those found on X chromosome of males) occur in two copies within cells, i.e., one copy inherited from the father and the other copy from the mother. To cause an autosomal dominant disorder, only
one of the two copies have to be mutated, and the mutated gene must have come from one of the parents. The chance of an affected parent passing the mutant gene to each child is 50%. Either females or males can inherit the gene from their mother or
father. If a child inherits the normal copy of the gene from the affected parent (also a 50% chance), then the child should not develop the disorder, and will also not pass on the condition to his or her children. If a child inherits the mutated copy
from the affected parent, then the child can pass on the mutated gene to each of his or her child with 50% chance.
Generally, all individuals who inherit a mutant HD gene will develop signs and symptoms of the condition, if they live long enough. There are rare exceptional cases, in which the mutant gene may not manifest clinical or histological findings of HD (see
mutation in the “reduced penetrance range” in the next paragraph). The age at onset can vary widely among individuals, even within the same family. When an affected father passes the diseases to his children, the age of onset tends to
be earlier in the children. This phenomenon is called "anticipation."
The mutation that causes HD is an expansion of a part of the HD gene. The expanded part consists of tandemly repeated CAGs, which is a genetic code for amino acid glutamine. In normal individuals, the repeat contains less than 29 CAGs in both genes (i.e.,
one inherited from the father and the other from mother). However, HD patients have one gene with a normal number of CAGs (<29), and the other with an expanded number (>35) of CAGs. Occasionally, the CAG repeat length exceeds 70 and it could
expand beyond 100 in some cases. Individuals with 36 to 39 CAG repeats do not always develop HD during their expected life span. Thus, this range is considered as the "reduced penetrance range". Individuals with 29 to 35 CAG repeats have never been
documented with HD. However, some of these individuals may produce children with the disease. Expanded CAG repeats generally show repeat size instability when they are passed on from one generation to the next. In some normal individuals who have
the CAG repeat in the range of 29-35, the CAG repeat occasionally expand to the range >39 CAGs in the children, who would develop HD. Therefore, 29 to 35 CAG repeats are considered "mutable normal" range. The CAG repeat of this range can be found
in a small fraction of the normal population, and appears to play a role of reservoir for the new cases of HD. The large mutant repeats with the number of CAG s >70 are mostly found in children with juvenile HD who had received the mutant HD gene
from the affected father. Since the CAG repeat size shows an inverse correlation with the age of onset, this intergenerational expansion of the CAG repeat size provides the molecular basis of anticipation. The CAG repeats within the mutable normal
range expand to >39 repeat only when the father is the transmitting parent. Thus, the gender of transmitting parent is an important determinant for the stability of the CAG repeat in HD.
With the identification of the HD gene, there has been a major advance in predictive testing for HD. Direct testing for the CAG repeat length can not only identify individuals who will develop the disorder, but it also can identify those who have not
inherited the mutant gene from a parent. In addition, direct mutation analysis of the CAG repeat length can be used for prenatal testing for Huntington's disease, if parents choose this as an option.
MECHANISMS THAT CAUSE BRAIN CELL DAMAGE IN HD
Involuntary movements, such as chorea, result from abnormalities in the structures called basal ganglia, which are located deep in the brain and regulate motor movements. One of these structures called striatum shows a decreased volume in HD. The atrophy
is due to degeneration of a particular subpopulation of the neurons (brain cells with electrical activities) called medium-size spiny neurons located within the striatum. Dementia and psychiatric abnormalities are due to degeneration of neurons outside
the basal ganglia. A loss of neurons in the cerebral cortex (the surface layers of the brain) is particularly prominent in HD.
The mechanism of the degeneration is not fully understood. However, the final process of brain cell death appears to be mediated by a class of amino acids (called excitatory amino acids) released from other neurons in which excessive excitation of neurons
causes "exhaustion" of the neurons and eventually leads to cell death, especially when the neurons already suffer from a disease process. This phenomenon is called "excitotoxic cell death." Injecting chemical compounds that activate the excitotoxic
receptors into animals produces a selective loss of neurons closely resembling HD. Biochemical changes and behavioral changes in these animals are also very similar to HD. These studies suggest that excitotoxic cell death may play an important role
The energy metabolism appears to be affected in the medium-size spiny neurons in the striatum in HD patients. The abnormal energy metabolism quickly "exhausts" the neurons, making them susceptible to excitotoxicity. Mitochondria are the power house of
cells and produce energy by a chain of chemical reactions called oxidative phosphorylation. Inhibitors of oxidative phosphorylation such as 3-nitropropionic acid (3NP) cause a disease with similar clinical signs and increased lactate levels similar
to those seen in HD. Interestingly, 3NP causes damage specifically in the medium size spiny neurons and, consequently, in the cortical neurons. Thus, abnormal energy metabolism may contribute to the disease-causing mechanisms in HD.
The key question is how the genetic abnormality in HD can lead to these changes in the brain? In HD, the expanded CAG repeat tract should be translated into an expanded glutamine repeat tract. In fact, enlarged huntingtin protein molecules were found
in HD patients and they appeared to contain expanded glutamine repeats. Since, in addition to this mutant gene, HD patients have the other HD gene that has normal size CAG repeat. This is the gene the patient inherited from the normal parent. Therefore,
they have the huntingtin protein with a normal glutamine tract in an amount of 50% of normal individuals. For most proteins, cells can function normally if there is 50% of the normal amount, and this is true for huntingtin. Patients in whom a piece
of DNA containing the entire HD gene is deleted from one of the chromosomes 4 do not have any signs of HD. Mice in which one of the two HD genes has been "knocked out" also fail to show signs of HD. Thus, an idea that the abnormal huntingtin with
an expanded tract of glutamine repeat gains new toxic function was introduced to explain these observations. If this gain-of-function theory is right, what is the new function? The amino acid sequence of huntingtin has no resemblance to any known
human protein. As a result, what the normal and mutant huntingtin do in cells is unknown. Furthermore, this gain of function must significantly affect only certain cells in the brain (for example, medium-sized spiny neurons in the area of the brain
called striatum), since no other tissues appear to be abnormal in HD despite the widespread presence of huntingtin protein among various tissues.
Experimental data suggested that the normal huntingtin protein does interact with other cellular proteins. The mutant huntingtin protein with a long polyglutamine repeat appears to interact a different set of proteins although it may still interact with
the proteins that interact with the normal huntingtin. Since all these proteins that interact with normal and mutant huntingtin proteins are expressed not only in the striatum but also in other parts of the brain, regional distributions of these proteins
are an unlikely cause of the selective neuronal death in HD.
However, by postulating another tissue-specific variable, we may be able to explain why the medium-sized spiny neurons are more vulnerable. Interesting hypotheses have been proposed for each huntingtin-interacting protein. Whether any of these proteins
actually play a significant role in the disease mechanisms of HD remains to be further investigated.
Transgenic mice, which have multiple and random integrations of a transgene containing a part or whole HD gene with an expanded CAG repeat in variety of size, exhibited clinical and pathological features similar to HD. In other experimental mouse models,
an expanded CAG repeat was introduced into the mice’s own gene that codes for a protein, which closely resembles the human huntingtin protein. They, too, exhibited clinical and pathological features similar to HD. It is expected that these animal
models reflect the disease mechanisms of human HD. Such animal models have provided important insights into understanding the disease mechanisms in HD, and are being used to test promising drugs for treatment of HD before human trials.
DNA TESTING FOR HUNTINGTON’S DISEASE
Prior to the discovery of the HD mutation, some HD family members underwent a less accurate and more complex DNA analysis, termed linkage analysis. Linkage analysis examines the inheritance of DNA markers that are in close proximity to the huntingtin
gene and requires the participation of several affected family members and certain unaffected family members. The inaccuracy of the analysis comes from the fact that the analysis indirectly look at the HD gene status via nearby genetic markers that
are likely to be passed on to the next generation when the HD gene is passed on. Thus, direct mutation detection was a major improvement in the molecular evaluation of HD.
The direct gene test is now widely used for confirmation of clinical diagnosis in adult patients who have symptoms and signs compatible with HD. While all testing requires informed consent, predictive testing follows a special protocol. Predictive testing
is available to individuals ages 18 and older at 50% risk and requires that all subjects be enrolled in a center with a written protocol for predictive testing. While molecular analysis of the clinically affected relative is recommended, it is not
Molecular analysis uses polymerase chain reaction (PCR) analysis with or without Southern analysis of the DNA from an individual todetermine the size of the CAG repeat in the HD gene. As already mentioned in the section of Genetics of Huntington’s
Disease, the normal range is considered to be up to 28 copies of the repeat. The range of 29 through 39 CAG repeats are inconclusive and often called intermediate alleles. The intermediate range consists of the HD range with reduced penetrance (36
through 39 CAG repeats) and the mutable normal range (28 through 35 CAG repeats). The robust HD (full HD expansion) range is 40 repeats and greater. Individuals who have a fully expanded CAG repeat will eventually develop HD in their expected life
spans. The probability of future generations for the mutable normal allele to expand into full expansion range cannot be reliably determined. The factors that influence the penetrance of the 36-39 CAG repeat range are also unknown. Additional information
about the intergenerational stability of these intermediate alleles is necessary in order to provide useful information to such families. While age of onset generally shows an inverse correlation with the length of the expanded CAG repeat, genotype/phenotype
correlations are not precise enough to be used clinically and may sometimes give a misleading impression to the test subjects.
GENETIC COUNSELING IN THE DNA TESTING OF HUNTINGTON’S DISEASE
While the long awaited discovery of the HD gene has led to improved diagnostic and predictive testing for this disease, this new technology has raised a number of challenging counseling, clinical and ethical dilemmas. This section will address the benefits
and limitations of currently available molecular analyses for HD.
Confirmation of Suspected Diagnosis of HD
Direct gene testing can be extremely helpful in determining the differential diagnosis for a patient with a movement disorder. While most individuals are aware when they have a family history of HD, some are unclear or unaware of the existence of HD in
the family. With the direct gene testing, it became possible to diagnose HD regardless of family history.
We recommend genetic counseling for every subject who has DNA testing. Understanding the genetic issues of HD is beneficial to the subjects and their family members. Psychological counseling should also be made available for symptomatic individual, especially
those who are having difficulty accepting their diagnosis. We strongly recommend psychological counseling for patients who have signs of depression and other psychiatric problems, even if the patients already carry the clinical diagnosis of HD. For
adult individuals with "soft signs" of HD and a positive family history, extreme caution should be taken to order a mutation analysis as a ''confirmatory'' test. It should be noted that a positive result does not necessarily confirm that the "symptoms"
represent the onset of HD and such information has significant psychological impacts. These individuals would benefit from a predictive testing protocol.
PREDICTIVE TESTING FOR HUNTINGTON'S: NEW CHALLENGES
Advantage of the direct DNA test.
Predictive and prenatal testing for HD has been available using linkage analysis since shortly after the mapping of the gene in 1983. Linkage analysis is a probability-based analysis and requires testing of multiple family members including affected relatives
and thus, for those individuals whose affected relatives or other key family members were deceased or not willing to be tested, predictive testing was impossible. With the direct gene test, the HD gene status of at-risk individuals could be determined
by a simple blood test of the subject without involving the family members. However, predictive testing is offered in the context of an interdisciplinary program with a well defined protocol, because of the regarding psychological, social, legal and
Who can have the predictive testing?
In most instances, the individual seeking predictive HD testing is an adult with a 50% risk for HD. The current DNA testing guidelines recommend against testing juvenile (below the legal age of 18) at-risk subjects who do not have clinical diagnosis of
HD. It should be noted that “soft” signs of HD, such as learning disability, depression, and uncomplicated seizures, should not be considered sufficient to establish the clinical diagnosis of HD unless characteristic movement disorders
and/or progressive cognitive dysfunction accompany these conditions. Predictive testing of individuals at 25% risk is problematic when the at-risk parent is living and unwilling to be tested. The positive result in the 25% at-risk individuals discloses
that the 50% at-risk parent is a gene carrier. Confidentiality of the test result must be strictly maintained in such cases.
Procedures for the predictive DNA testing.
The predictive DNA testing for HD requires at least three visits. One is scheduled a few weeks prior to the blood drawing. Psychological testing, genetic counseling, and a neurological examination will be obtained during the first visit. During the pre-test
counseling, the reasons for taking the test, and the potentially severe negative psychological impact, as well as the social and legal implications of the test, are discussed. Many patients decide not to take the predictive DNA testing after the first
counseling, and some others learn how to prepare for the complicated consequences of the DNA diagnosis. This confirms the necessity of the pre-testing visit.
During the second visit a blood sample is drawn from the subject for the DNA test. The subjects will be briefly counseled to make sure he/she is well prepared for testing. At the third visit, which takes place about three weeks later, the result is disclosed
to the subject. Subjects are encouraged to call or visit the clinic whenever questions or concerns arise. All patients are made aware that post-test counseling/evaluation by any of the team members is available at any time.
Patients are encouraged to have a person significant in their lives such as, a spouse, close friend or relative, attend all visits with them. This companion should not be someone who has HD or is at risk for having HD. We also suggest the patient have
a trained support person in their community such as, a psychiatrist, psychologist, social worker or clergy to whom they can turn for immediate psychological support during and after the testing process.
If at all possible, testing of an affected relative prior to the subject’s testing, is often required to ensure a correct diagnosis. If an affected relative has already been tested, medical records of the affected individual should be obtained.
If no individuals with HD are alive, medical records confirming the diagnosis should be submitted.
We encourage patients who desire testing but cannot afford it to call and discuss their situation. An individual's insurance may or may not cover these expenses. Insurance payment may interfere with confidentiality. Some individuals have been denied insurance
after testing positive for HD or even being at risk for HD. Discrimination of subjects with a positive HD DNA test at the workplace is a concern. Many individuals have taken the predictive DNA test by paying out of their own pocket because of these
concerns. Some patients have even used a different name and social security number to conceal their identities. Of course, this can only be done if they are paying cash for the test.
The direct gene test allows for highly accurate prenatal diagnosis. The sample must be obtained by an amniocenthesis or a chorionic villus biopsy, which are minor but invasive procedure routinely done at an outpatient clinic. Prenatal testing should not
be performed unless abortion is planned if the fetus has a positive result. Otherwise, the mother and fetus would be exposed to small but unnecessary risk associated with the procedure. Furthermore, the fetus would have to grow up with the genetic
information, and this violates the guidelines of no testing of asymptomatic juveniles. The number of CAGs in the fetus should not be used to predict the age of onset or the prognosis of HD.
CURRENT MEDICAL TREATMENT OF HUNTINGTON’S DISEASE
The first step in the management of patients with Huntington s disease (HD) is education of the patient and the family about the nature of the disease and the prognosis. This must be coupled with skilled genetic and psychological counseling. Because of
the complexity and high variability of the symptoms in HD, medical therapy must be individualized and tailored to specific needs of the patient. The medications are targeted to control the most troublesome symptoms.
Depression, commonly seen even in early stages of the disease, is partly biological and partly situational arising from the realization of impending progressive functional impairment. Even with a plenty of support from family and friends, most patients
will eventually require medical therapy. The serotonergic drugs such as fluoxetine and sertraline are helpful in patients who, in addition to depression, exhibit obsessive compulsive disorder. Tricyclic antidepressants, such as amitriptyline, imipramine
and nortriptyline, are also effective, and have the advantage of alleviating insomnia and fighting weight loss by stimulating appetite. Both insomnia and weight loss are frequent problems in HD. Anxiolytics, such as diazepam, alpralozam, and clonazepam,
may be helpful to control agitation. We also sometimes use carbamazepine, valproate, and lithium to help control manic behavior. Impulse control problems may respond to a trial with clonidine or propranolol. Rarely, electroconvulsive therapy is required
in patients with medically intractable depression.
Psychosis may be treated with dopamine receptor blocking drugs (neuroleptics), such as haloperidol, pimozide, fluphenazine and thioridazine. However, these drugs can induce tardive dyskinesia (drug induced involuntary movements) and should be used only
if absolutely needed to control symptoms. A new generation of atypical antipsychotic drug that does not cause tardive dyskinesia, may be a useful alternative to the typical neuroleptics.
Neuroleptics are the most effective drugs in the treatment of chorea, although they may cause tardive dyskinesia. Monoamine depleting drugs, such as reserpine and tetrabenazine, have the advantage that they do not cause tardive dyskinesia. In our experience,
tetrabenazine is the most effective suppressant of chorea, but this drug is categorized as investigational and not readily available in the U.S. . Both classes of neuroleptics may cause or exacerbate depression, sedation, akathisia and parkinsonism.
Supportive therapies such as nursing care, psychological adjustments, physical therapy, speech therapy, diet modifications, etc. become essential as the disease progresses. Patients with advanced HD require prevention and treatments of various medical
NEW TREATMENT STRATEGIES (Top)
Treatment of Huntington's disease (HD) has been limited to symptomatic and supportive therapies. A number of medications have been introduced to treat chorea, depression, anxiety and psychosis as described in the previous section. While some of them are
quite effective for alleviating the symptoms and play essential roles in management of HD, they do not stop the disease process itself. Simply, they mask the symptoms. Since 1993, the research has been providing increasing understanding of the disease
mechanisms, allowing for discussions on new therapeutic strategies. Some of them are becoming available for clinical trials, while others require further development as clinically feasible therapies.
There is substantial evidence that the final pathway of cell death in the brain of HD patients involves excitotoxicity. The excitotoxic loss of neurons is mediated by binding of excitatory amino acids to their receptors. Among these excitatory amino acids,
glutamate appears to produce excitotoxicity by binding to one type of glutamatergic receptor called N-methyl-D-aspartate (NMDA) receptor in HD. Drugs that inhibit the glutamatergic transmission may be useful for treating HD patients. These include
blockers of a glutamate receptor, such as remacemide, and drugs that inhibit a release or synthesis of glutamate, such as riluzole (Rilutek), lamotrigine (Lamictal) and gabapentin (Neurontin). One of these medications, Riluzole, has a slight (10%)
benefit on the life-spans of patients with Lou Gehrig's disease (another neurological disease known as ALS or amyotrophic lateral sclerosis, in which excitotoxicity appears to contribute to disease). Riluzole is currently being studied by the Huntington
Study Group. Lamotrigine and remacemide has failed to show efficacy in treatment of patients with HD, although remacemide may suppress chorea.
Since energy metabolism abnormalities may play an important role in excitotoxic cell death in HD, drugs that improve the energy metabolism, such as coenzyme Q10 (CoQ10), idebenone and nicotinamide, may be of interest in treatment of HD. CoQ10 has shown
a trend of efficacy in slowing down the progression of HD in a recent study, although the efficacy did not reach the statistical significance. Antioxidants such as alpha-tocopherol (vitamin E) and thioctic acid may also be studied. Excitotoxicity
increases the concentration of calcium in the cells. Various calcium channel blockers, inhibitors of calcium binding proteins and inhibitors of calcium- activated enzymes such as nitric oxide synthetase (NOS) may be included in the strategies for
prevention of cell death in HD. NOS produces a tissue-damaging free radicals and its neuronal isoform (nNOS) is involved in neurotoxicity.
Neurosurgical procedures have shown promising results in the treatment of Parkinson's disease (PD). These procedures include pallidotomy, thalamotomy and deep brain stimulation. Because of the development of CT-guided stereotactic neurosurgical technique,
these procedures have become much less invasive. Whether these procedures are effective in HD is yet to be seen, premiminary data have suggested that some of the abrasive procedures (i.e., deliverate removal of tissue for treatment purposes) have
no benefits in HD. The deep brain stimulation has not been tried on HD patients. Researchers also know that these procedures treat the symptoms of HD but they are not expected to stop the disease process. We should also be aware that the movement
disorder is only a part of problems in HD, and loss of intellectual functions and psychiatric manifestations are unlikely to improve with these procedures. Nevertheless, if effective, these stereotactic neurosurgical procedures may offer a new treatment
modality for HD patients.
In PD, fetal brain tissue transplantation has shown some success in restoring the functions of the lost neurons. Similar approaches may work in HD. A research team in Phoenix used fetal cell transplants to treat over eleven patients with HD. Although
they reported that the transplantation halted the progression and reversed some deterioration, the study is still too preliminary to assess the true therapeutic value of the procedure. Nevertheless, investigators at the University of South Florida
also demonstrated that the transplantation of fetal brain tissue is feasible, and French investigators found encouraging preliminary results. Alternative tissue sources may also be considered. In Massachusetts , fetal pig striatal tissues have been
transplanted in some HD patients. Recent advances in research on neuronal stem cells may have significant impact on this line of research. If we can identify neurotrophic factors that support the survival of degenerating cells in the striatum, transplantation
of genetically engineered cell lines producing the neurotrophic factors may be another interesting approach.
The understanding of how HD molecules affect the brain give hope to new approaches that may be able to attack HD at an earlier stage. This earlier intervention may be more effective since it may prevent neurons from injury instead of trying to rescue
them after the fact. The mutant huntingtin protein with an elongated glutamine repeat tract causes toxic effects to the brain cells. Thus, supplementing the normal huntingtin protein by conventional gene therapy is unlikely to solve the problem in
HD. The rational approach would be alleviating the toxicity by (1) to eliminate the mutant huntingtin protein or (2) to prevent the mutant huntingtin protein from producing the gain-of-function effects. In HD, the expanded CAG repeat in the gene is
transcribed into an expanded CAG repeat in the mRNA, which is then translated into an expanded glutamine repeat in the huntingtin protein. At present, selective inhibition of the mutant HD gene transcription and translation is not feasible. More promising
is the second approach. We now know that the huntingtin protein interacts to other proteins. Thus, modulators of such interactions may decrease the gain of function effect, leading to a therapeutic effect. Transgenic mouse and fruit fly models of
HD can be effectively used to screen drugs with such actions. Research efforts to find such modulators is underway, and some promising drugs have already found. For example, minocycline, which is a widely used antibiotics, was found to block caspase
activities, and administration of minocycline has shown improvement of HD-like disease in transgenic mice. Efficacy of roal minocycline administration for treatment of HD is currently being tested in human. Highly unsaturated fatty acids such as ethyl
ester of eicosapentanoic acid (LAX101) have shown promising results in double-blind randomized control studies. Cystamine (transglutaminase inhibitor), tauroursodeoxycholic acid (hydrophilic bile acid), inhibitors of glycogen synthase kinase 3 beta,
dichloracetate (pyruvate dehydrogenase stimulator), and histon deacetylase inhibitors (transcription modulator) have also been found to alleviate the disease in HD transgenic mice, and some of these will come to human trial. We are expecting to have
a growing number of medications that need to be tested in human trials.