Vol. 17 • Issue 9 • Page 20
Geriatric Neurology CME
Editor's Note
ADVANCE for Physician Assistants and the Eugene Applebaum College of Pharmacy and Health Sciences, and Wayne State University School of Medicine, are pleased to offer this continuing education opportunity.
The Wayne State University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The Wayne State University School of Medicine designates this educational activity for a maximum of one AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
To receive 1 hour of AMA PRA Category 1 CME credit, read this article and follow the directions on the answer form at the end of the article.
Learning Objectives
1. Review the symptoms and clinical course of Huntington's disease.
2. Review the genetic transmission of Huntington's disease.
3. Discuss the role of genetic testing in Huntington's disease.
4. Describe possible future treatments for Huntington's disease.
Disclosure of Conflict of Interest
Karen Hemmer, MSBS, PA-C, and Karen Graham, MPAS, PA-C, indicate no relationships to disclose related to the contents of this article.
The CME coordinator for ADVANCE for Physician Assistants, John McGinnity, MS, PA-C, discloses receiving honoraria from Forest Laboratories and from Sanofi-Aventis and that he is on the speakers' bureau for Novartis.
Huntington's disease (HD) is a progressive, neurodegenerative genetic disorder without a cure that affects 4 million to 5 million people worldwide.1It is characterized by psychiatric, cognitive and motor disturbances resulting from progressive neurodegeneration in the cerebral cortex and basal ganglia.
As the disease progresses, a person becomes bedbound or wheelchair-bound; this functional decline is followed by death between 10 to 25 years after the onset of disease. Death has been known to result from malnutrition, aspiration pneumonia, cardiac complications and many others. It is increasingly important for primary care PAs to be aware of advances in genetic medicine. This article reviews the genetic transmission, genetic testing and possible future treatments for HD.
Genetic Transmission
HD symptoms (personality or mood changes, dementia and chorea) result from a mutation that is inherited in an autosomal dominant fashion. Figures 1, 2, 3 and 4 depict autosomal dominant transmission with Mendelian Punnett squares and pedigrees. In 2004, approximately one in 5,000 people were thought to be carrying the mutation that results in the development of HD.2HD has the highest prevalence among inherited neurodegenerative disorders.3Most people affected by the mutation have only one copy of the allele with a CAG expansion or are heterozygous (Figure 1). However, in rare instances a person can be homozygous for the mutation (Figure 2), resulting in two copies of the expanded allele.4In order to be homozygous, a person would have to inherit one allele with a CAG expansion from two affected parents; that person's offspring still would have a 100% chance of carrying the mutation and a 50% chance of transmitting it his or her children, even if the other parent is unaffected (Figure 4). Interestingly, the course of the disease is not worsened in people who are homozygous for the allele compared with heterozygous inheritance.5The inherited HD mutation causes a minimum of 36 glutamate trinucleotide repeats on a portion of chromosome 4p16.3. This results in a change in the huntingtin (htt) protein's structure that appears to be directly related to the change in its function.3(See sidebar for more information about the htt protein). The length of the trinucleotide repeat and age at the time of onset are inversely related.4As the mutation is passed from one generation to the next, alterations in the length of the trinucleotide repeat may occur.6 This may increase or decrease the age of onset observed for individuals in that generation.
The onset of most HD cases is in middle age. However, onset can occur much sooner in life, with an age range for HD onset from 2 to 85 years of age. While trinucleotide repeat length may influence the timing of onset, it seems to have very little if any impact on the timeline of symptom and disease progression.4In order to be diagnosed with juvenile Huntington's disease, symptom onset must begin before age 20.7A significant correlation has been established between onset of disease and paternal inheritance. If an allele is inherited from the father, age of onset typically is significantly younger.4This could be due in part to the fact that sperm undergo a greater number of cellular divisions than does the ovum, providing a greater opportunity for genetic mutations. This wide range of age at time of onset stresses the importance of a detailed family history at all ages in patients presenting with psychiatric, cognitive or motor complaints. Families with HD may not be aware of the condition in their family. HD still should be considered when symptoms of HD are present in the absence of a clear family history.
Genetic Testing: Predictive
HD was the first late-onset autosomal-dominant neurologic disorder for which predictive testing in unaffected persons with a positive family history became available.8Several reasons explain why a person might choose to learn his or her predicted risk level through genetic testing. A 2002 study found that 81% of those who chose to undergo screening did so in order to alleviate the feeling of uncertainty.9 Other reasons include career or family planning, along with other long-term issues such as establishing advance care directives, living wills and durable power of attorney. Genetic testing also offers answers to individuals who previously might have been misdiagnosed or undiagnosed.8Of 626 diagnostic tests performed in 15 genetic centers throughout Canada, 31.5% of patients who displayed common HD symptoms were found to be negative for the mutation.8A person also may undergo genetic screening for the benefit of his or her children who may or may not have begun having children of their own. The parent may feel as though it is his or her duty to inform his or her children of the possibility that a mutation may be transmitted before they decide to start a family.
Linkage analysis and exclusion testing are the two available types of predictive genetic screening tools. Linkage analysis requires prior knowledge of other family members' status regarding the disease. Exclusion testing is more accurate and is most commonly used today; it does not require knowledge of parental status. Many genetic testing centers are located throughout the United States.
Because HD is a terminal disease with no cure, people in whom the HD diagnosis is suspected because of developing symptoms or family history should be referred to a genetic counselor. The counselor can serve as a guide in the decision-making process of whether to undergo testing. A variety of social and economic factors influence the HD testing decision. Reasons people decline genetic testing include the lack of available treatment options, the cost of the screening test, the fear of discovering that their children are at risk and the fear of coping with the reality of the result.8 However, a study conducted over a 10-year period found that the incidence of severe psychiatric disorders, including attempted suicide were very rare shortly after learning the diagnosis.10There is also a concern for any at-risk person about future employment or insurance coverage.9 Due to the inability to change the diagnosis, others simply prefer not to know and to go on with their lives.
It cannot be ignored that when results are disclosed, it not only divulges the status of the tested person but also may reveal the status of parents and grandparents, as well as the possible risk to the tested person's children. In a study in the United Kingdom, 56% of the family members of tested individuals felt that they had been given unsought information regarding their risk of HD. When asked, 35.7% of the parents did not want the person to undergo testing.11It becomes a conflict between the autonomous right of the individual being tested and the family members whose status it divulges.
The issue gets more ethically challenging when considering genetic testing in children who are not yet autonomous. A lack of consensus still exists among geneticists, hematologists and adoption agencies regarding the concept of childhood genetic testing.12The benefits of genetic testing in children include knowing how to plan for the future, opening the door for other family members to be tested and addressing parents' fears about whether they transmitted the mutation to their child. The shortcomings include violating the child's right to make his or her own decision, a change in how the parents and others will view the child as a result of the diagnosis, as well as self-esteem and life relationship issues. While there may never be agreement on the proper course of action, the rights of the child always should be taken into account. It may be best to forego testing until the child has reached the appropriate age and is able to understand not only the genetic aspects but also the possible social and emotional repercussions associated with testing.12
Genetic Testing: Prenatal
The decision about prenatal genetic testing occurs under a much more pressured timeframe than that of adult genetic testing.13The parent or parents whose fetus might be at risk for the genetic mutation must decide whether to go through with testing knowing that their future and that of their child may be greatly altered by that decision. People who are a part of a religious organization and people who already have other children are less likely to pursue testing. Many people refrain from prenatal testing because they are morally or ethically opposed to termination of pregnancy.14Even though prenatal testing has been available for years, the percentage of people deciding to use the available screening tests is not as high as had been expected.14Over a 13-year span in Canada, for example, only 18% of those eligible to receive prenatal genetic testing opted to do so.14Definitive testing requires information about the person's family in order to be accurate and offers a concrete answer about the status of a fetus. Testing can be performed through chorionic villus sampling or through amniocentesis. Either method offers a conclusive result, giving the fetus as low as a 3% risk or as high as a 96% risk of developing HD.14Preimplantation genetic diagnosis (PGD) is a newer alternative screening measure. In combination with in vitro fertilization, PGD allows for the transfer of only those embryos for which the mutation has been ruled out.2 The fate of the other embryos, even those with a 50-50 chance of being healthy, presents a moral dilemma for those who believe that life begins at conception. Another possible ethical issue with PGD is whether the discarded embryos should be used in research.
The central dilemma in prenatal testing for HD is the issue of personal feelings regarding pregnancy termination upon receiving a positive result. Unwillingness to terminate a pregnancy is one of the main reasons that people choose not to undergo genetic testing.8 In one study, 80% of individuals who chose to refrain from prenatal testing stated that they were hoping for a cure.9
Treatment Options
The only available treatment options for HD attempt to control the symptoms, but most of these therapies have limited efficacy.15Only one medication, tetrabenazine, is FDA-approved for symptomatic treatment of HD. Treatment options that are being researched include gene therapy, aggregation inhibitors, proteolysis inhibitors, excitotoxicity inhibitors, mitochondrial enhancers and transplantation of embryonic stem cells.
Gene therapy is thought to be one way in which the defective allele in HD might be corrected. A gene unaffected by the mutation could be placed inside (e.g., delivered by a vector such as an inactivated virus) the genome in an attempt to replace the defective gene. A different technique, homologous recombination, uses one of the natural processes of a cell to modify a specific gene without interrupting the rest of the genome, but with limited success.16Other researchers have utilized the same mechanism to repair DNA in rodent models with a known genetic disorder. After the cells have been inserted with the modified DNA sequence, they are allowed to differentiate and are then transplanted into the host organism.17The hope is that there also may be a way to alter the regulation of the gene involved in HD. One challenge related to gene therapy is how to safely introduce progenitor cells into the central nervous system. The use of various viruses, such as adenoviruses or retroviruses, may prove to be a useful method of delivering normal genetic information into a cell affected by HD. Another growing area of research is the transplantation of embryonic stem cells in an attempt to replace degenerated neurons.18
Genes, PAs & Awareness
Because HD is an autosomal-dominant disease, affected individuals have a 50% chance of passing it to their offspring. The decision to undergo genetic testing or not involves consideration of more than just the person being tested. That no effective therapies exist for HD makes the decision more difficult. While new areas of research such as gene therapy and neural stem cell transplantation are being explored, there is still much to learn about this incurable disorder.
PAs need to be familiar enough with genetics to be able to communicate with patients about genetic transmission and testing for HD.
References
1. Degenerative diseases of the nervous system. In: Ropper AH, Brown RH. Adams and Victor's Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005:895-958.
2. Moutou C, Gardes N, Viville S. New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications. Eur J Hum Genet. 2004;12(12):1007-1014.
3. Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep. 2004;5(10):958-963.
4. Gusella JF, MacDonald ME. Huntington's disease: seeing the pathogenic process through a genetic lens. Trends Biochem Sci. 2006;31(9):533-540.
5. Kremer B, Goldberg P, Andrew SE, 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):1401-1406.
6. Gusella JF, MacDonald ME. Huntington's disease and repeating trinucleotides. N Engl J Med. 1994;330(20):1450-1451.
7. Ribaï P, Nguyen K, Hahn-Barma V, et al. Psychiatric and cognitive difficulties as indicators of juvenile Huntington disease onset in 29 patients. Arch Neurol. 2007;64(6):813-819.
8. Creighton S, Almqvist EW, MacGregor D, et al. Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000. Clin Genet. 2003;63(6):462-475.
9. Evers-Kiebooms G, Nys K, Harper P, et al. Predictive DNA-testing for Huntington's disease and reproductive decision making: a European collaborative study. Eur J Hum Genet. 2002;10(3):167-176.
10. Harper PS, Lim C, Craufurd D. Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium. J Med Genet. 2000;37(8):567-571.
11. Benjamin CM, Lashwood A. United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington's disease. Clin Genet. 2000;58(1):41-49.
12. Clarke A. The genetic testing of children. Working Party of the Clinical Genetics Society. J Med Genet. 1994;31(10):785-797.
13. Scully JL, Porz R, Rehmann-Sutter C. 'You don't make genetic test decisions from one day to the next'-using time to preserve moral space. Bioethics. 2007;21(4):208-217.
14. Adam S, Wiggins S, Whyte P, et al. Five year study of prenatal testing for Huntington's disease: demand, attitudes, and psychological assessment. J Med Genet. 1993;30(7):549-556.
15. Bonelli RM, Wenning GK, Kapfhammer HP. Huntington's disease: present treatments and future therapeutic modalities. Int Clin Psychopharmacol. 2004;19(2):51-62.
16. Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature. 1985;317(6034):230-234.
17. Rideout WM III, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell. 2002;109(1):17-27.
18. McBride JL, Behrstock SP, Chen EY, et al. Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. J Comp Neurol. 2004;475(2):211-219.
Karen Hemmer is PA in Bellevue, Ohio. Karen Graham is a PA at the University of Toledo Center for Neurological Disorders and an assistant professor at the University of Toledo PA program in Toledo, Ohio.
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