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Predictive Testing for HD: 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 ethical concerns.
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.
Prenatal Testing
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 complications.
NEW TREATMENT STRATEGIES
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.
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February 15, 2008
