C l i n i c a l N e u ro g e n e t i c s Huntington Disease Yvette M. Bordelon,
MD, PhD
KEYWORDS Huntingtin CAG repeat disorder Striatum Presymptomatic genetic testing Preimplantation genetic diagnosis Tetrabenazine KEY POINTS Huntington disease (HD) is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene. HD is typically manifest in adulthood and characterized by progressive deterioration in motor, cognitive, and behavioral functions, with chorea as the primary motor manifestation of disease. The pathologic hallmark of HD is striatal atrophy, but widespread cell loss, gliosis, and huntingtin-positive neuronal inclusions are demonstrated in cortical and extrastriatal structures. HD serves as a model for presymptomatic genetic testing and preimplantation genetic diagnosis for multiple other disorders whose genetic causes are being identified. Current treatment approaches are symptomatic, but disease-modifying interventions including medications and gene-based and stem cell–based therapies are under investigation.
INTRODUCTION
Huntington disease (HD) results from an abnormal expansion of a CAG repeat in the huntingtin gene that is dominantly inherited. It is typically an adult-onset disorder that causes the following: Abnormal movements Chorea Dystonia Rigidity Bradykinesia
Disclosures: Member of Speakers Bureaus for Lundbeck, Inc, Teva Neuroscience and Medical Education Speakers Network. Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90210, USA E-mail address: [email protected] Neurol Clin 31 (2013) 1085–1094 http://dx.doi.org/10.1016/j.ncl.2013.05.004 neurologic.theclinics.com 0733-8619/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
1086
Bordelon
Behavioral manifestations Depression Anxiety Obsessive-compulsive symptoms Irritability/aggression Apathy Psychosis Cognitive impairment Impaired attention and concentration Poor organization and planning Memory loss Visuospatial dysfunction These symptoms appear gradually in any combination varying among individuals and families and progress inexorably leaving the person with HD ultimately mute and akinetic. CLINICAL FINDINGS
HD was first described by the physician George Huntington in 1872 in his paper entitled “On Chorea,” where he reported on the families living in Long Island, New York, affected by “that disorder” who were cared for by him as well as his grandfather and father before him.1 This paper described the core features of the illness including the typical adult onset, progressive nature of the disease, prominent chorea, and associated psychiatric illness with a tendency to suicide. He also characterized the inheritance pattern remarking that if a person in an affected family was spared the disease, no one descending from that individual would develop it; in other words, an autosomal dominant pattern. At present, the prevalence of HD is estimated to be 7 to 10 per 100,000 in the United States, and a similar range has also been reported in the United Kingdom, although a debate continues as to whether these are underestimates.2,3 The typical age of onset is in the fourth decade of life, and progression to death occurs over a 20- to 25-year period. In less than 10% of cases, the onset occurs before age 20 years and is accompanied by more severe motor symptoms of disease, sometimes accompanied by seizures and faster progression over a 10- to 15-year period (Westphal variant). The clinical hallmark of HD is chorea, defined as uncontrolled movements flowing from one muscle group to another. Additional abnormal movements that are part of HD include dystonia, gait and postural instability, myoclonus, rigidity, and bradykinesia. These motor symptoms are often quite subtle as they become manifest, and no clear definitions exist for the severity or types of motor symptoms that must be present to make a firm diagnosis of clinical onset. In addition, it has become clear from studies of gene-positive individuals that the cognitive and behavioral symptoms of HD often precede the movement disorder by several years.4–6 The cognitive impairment seen in HD is thought to arise from dysfunction of frontalsubcortical pathways, thus giving rise to deficits in executive tasks (attention, concentration, planning, and multitasking) and other frontal features such as impulsivity. Recent clinical research studies (PREDICT and TRACK-HD) have followed premotor manifest HD subjects over time to capture which tasks or functions may be affected earliest. These studies have demonstrated impairment in the domains of executive function, memory, and visuospatial tasks. As the disease progresses, cognitive impairment worsens and most eventually meet criteria for dementia, with multiple domains being affected and contributing to functional decline.7 However, even in
Huntington Disease
late-stage HD, patients may maintain alertness and cognitive processing skills that allow them to understand what is happening around them but without the motor function to communicate. Health care providers must be aware of this and try to develop creative methods for communicating. Behavioral symptoms of HD can present early and can be quite severe with significant impacts on interpersonal relationships and quality of life. The problems are diverse and vary among and within HD families. Depression is common in all stages of HD and has been estimated to occur in approximately 40% of patients.8 Anxiety as well as obsessive-compulsive traits may be present and can be quite severe. Irritability and emotional dyscontrol leading sometimes to violent outbursts can occur and are also difficult to treat. Impulsivity may be present. These symptoms in combination with the other behavioral manifestations of the disease contributes to the higher rate of suicide attempts and ideation seen in the population with HD.9 Patients with HD may also have various addiction problems including smoking, alcohol, and drugs. All behavioral manifestations are believed to result from disruption of frontal-subcortical circuits as well. The phenotypic expression of HD varies widely among and within families of HD. Often a pattern evolves whereby in one family the behavioral manifestations are the earliest and most debilitating and in another the motor features present initially and are the greatest source of impairment. In addition, although these symptoms emerge gradually over time, they generally only come to attention when they begin to interfere with an individual’s independent functioning. This functional impairment may be in the workplace or at home or in combination, and the threshold for “impairment” varies from person to person. Clinical studies have demonstrated that the first sign of diminished function in patients with HD is loss of employment.10 This change in function is more closely tied to the cognitive and behavioral features of HD rather than the motor. GENETICS AND DISEASE PATHOLOGY
In the centennial celebration of George Huntington’s work, Dr Amerigo Negrette presented a paper describing a high prevalence of HD in people living in towns near Lake Maracaibo in Venezuela. Intrigued by this report, Dr Nancy Wexler of Columbia University organized the Venezuela Collaborative Huntington’s Disease project with the goal of finding the cause of HD. In 1981, the first of 22 annual trips to the region occurred where large pedigrees were established and data collected including motor and neuropsychological testing as well as blood samples. This massive effort resulted in identification of the marker on chromosome 4 in 1983 and discovery of the causative gene mutation, an expanded CAG repeat in the IT-15 gene (now called the huntingtin gene), in 1993.11 Since the identification of the HD gene mutation, there has been a wealth of research into the understanding of the role that this repeat expansion plays in the pathophysiology of the disease. The huntingtin gene is located on 4p16.3 and encodes the protein huntingtin. It belongs to a family of expanded CAG repeat disorders with spinal and bulbar muscular atrophy (Kennedy disease) being the first described.12 Diseasecausing mutations have a CAG repeat length of 40 and higher. There is an association with higher repeat lengths being associated with earlier age at onset but CAG repeat length only accounts for approximately 50% to 60% of predicted onset age.13,14 Other genetic modifiers and environmental influences that contribute to HD onset are being sought in ongoing research efforts. Huntingtin is a 348-kDa protein that is ubiquitously expressed, with the highest levels found in neurons. It is primarily cytoplasmic but also localizes to the nucleus and organelles.15 The N-terminus contains a polyproline region in addition to the
1087
1088
Bordelon
glutamine stretch resulting from the CAG expansion, which are both involved in the pathophysiology. The normal functions of huntingtin have not been completely elucidated, but it has thus far been found to play a role in a myriad of normal processes including axonal and vesicular transport, endocytosis, postsynaptic signaling, and cell survival pathways (reviewed in Ref.16). Mutant huntingtin undergoes N-terminal cleavage, resulting in polyglutamine fragments, which can oligomerize and form aggregates, both cytoplasmic and nuclear. The N-terminal fragments, oligomers of these fragments, and the fully formed inclusions have been implicated in the toxicity of HD. It has been demonstrated that mutant huntingtin adversely affects a multitude of intracellular processes and causes widespread disruption including mitochondrial dysfunction, transcriptional dysregulation of various genes, altered axonal transport of critical factors, disrupted calcium signaling, abnormal protein interactions, alterations in proteosomal function, and autophagy. These diverse mechanisms are well reviewed by Zuccato and colleagues.16 The overall effects of mutant huntingtin expression are cell loss and gliosis in the brain, with the striatum being most affected by the disease. Jean-Paul Vonsattel developed the pathologic grading scheme for HD using striatal atrophy as the hallmark by which to characterize disease severity.17 Grade 0 is defined by a normal gross appearance of the striatum but a 30% to 40% neuronal loss in the caudate nucleus, grade 1 exhibits atrophy of the tail of the caudate and 50% neuronal loss in the structure, grade 2 has mild-moderate gross atrophy of the caudate and even greater neuronal loss, grade 3 exhibits severe caudate atrophy with even greater neuronal loss, and grade 4 has severe atrophy with an obvious concave appearance of the caudate and greater than 95% neuronal loss (Fig. 1). In grades 3 and 4, there is notable cell loss of extrastriatal structures such as the cortex, globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum. Several elegant studies using magnetic resonance imaging have demonstrated progressive striatal atrophy first noted years before motor symptom onset in HD.18 Cortical atrophy is also apparent before motor symptoms, with posterior frontal regions affected the earliest
Fig. 1. Luxol fast blue with hematoxylin and eosin counterstained coronal sections of striatum from subjects with HD representative of each pathologic grade 0 to 4. (Courtesy of Jean-Paul Vonsattel, MD, Columbia University Medical Center.)
Huntington Disease
with progression to involve occipital, parietal, and other cortical regions eventually resulting in significant and widespread thinning.19,20 The medium-sized spiny gamma-aminobutyric acid (GABA) containing neurons of the striatum seem to be the most vulnerable to huntingtin toxicity. It has been proposed that the “indirect pathway” comprising GABAergic striatal projections to the external globus pallidus are affected earlier in the disease, thus resulting in loss of inhibition of this structure with resulting enhanced inhibition of GABAergic projections to the subthalamic nucleus. This in turn produces decreased excitation of the glutamatergic projections to the globus pallidus internus and overall diminished inhibitory GABAergic outflow to the thalamus. This disinhibition of the thalamus allows for enhanced excitatory outflow to the cortex resulting in hyperkinetic or uncontrolled movements, that is, chorea (Fig. 2). As the disease progresses into late stages the “direct pathway” also becomes profoundly affected, which results in loss of GABAergic inhibition of the internal globus pallidus and enhanced GABAergic inhibitory outflow to the thalamus. This thalamic inhibition of excitatory cortical connections produces a hypokinetic or akinetic state as seen in the last stages of HD (see Fig. 2).21 EVALUATION AND MANAGEMENT
The standard remains that symptomatic HD is diagnosed at the time of onset of the characteristic motor signs of the disease. However, since 1993, the genetic diagnosis of HD has been available, allowing for identification of individuals who carry the HD gene mutation but do not yet exhibit signs or symptoms of the disease. Titles for this population of gene-positive individuals have varied over time: presymptomatic, premanifest, premotor, and prodromal. All terms try to characterize a period of lack
Fig. 2. Early loss of indirect pathway neurons in HD causing hyperkinetic movements (chorea) followed by later involvement of direct pathway neurons (akinesia). D1, D2, dopamine receptors; GPe, globus pallidus externus; GPi, globus pallidus internus; STN, subthalamic nucleus; Thal, thalamus.
1089
1090
Bordelon
of measurable deficits before actual disease onset. This technology thus becomes “heavily loaded” with information for at-risk individuals that affects (1) the future of their own health, career, and family planning; (2) other family members’ risk status; and (3) their eligibility for obtaining life, long-term care, and possibly medical insurance in the future. (However, the federal Genetic Information Nondiscrimination Act passed in 2008 should prevent discrimination against persons with or at risk for genetic diseases by medical insurance providers and employers.) These special circumstances have led to the development of HD genetic testing procedures in the at-risk population. It is advised that all at-risk persons speak with genetic counselors to discuss the full implications of obtaining the test before having the testing performed. Many clinical sites will also arrange meetings with neurologists or psychologists before testing and recommend that a family member or friend accompany the person to all appointments. The results are always given in person rather than by phone or mail to provide the best supportive environment possible in dealing with reactions to the genetic diagnosis. It must be emphasized that many patients who receive a negative result for the HD gene test also have problems managing their negative diagnosis given the guilt that accompanies it. The gene test is reported as diagnostic for HD if the CAG repeat length in the huntingtin gene is 40 or greater and is normal if 26 or lower. Repeat lengths of 36 to 39 are “indeterminate,” meaning they may have reduced penetrance, whereas intermediate repeat lengths of 27 to 35 may be normal or potentially disease-causing. Juvenileonset HD typically occurs with repeat lengths of 50 and more. This condition occurs more commonly when the disease is inherited via the paternal line, as CAG repeat expansion may occur during spermatogenesis. There is a correlation between longer CAG repeat length and earlier onset of disease, but only approximately 50% to 60% of age of onset can be predicted by CAG repeat length.14 Other as yet unidentified genetic or environmental modifiers may influence onset age as well. Although the HD gene test has been available for some time, only a minority of at-risk people decide to obtain testing (estimated at 5% in the United States), as there are no known cures or treatments that delay the onset or progression of disease as yet.22 Family planning issues are some of the major driving forces when persons atrisk for HD do decide to obtain genetic testing, and studies have revealed that women more often than men seek predictive testing.23 Women who are at-risk for HD who are pregnant or are thinking about becoming pregnant can meet with genetic counselors to discuss testing options that are currently available. HD genetic testing can be obtained in utero through amniocentesis or chorionic villous sampling. Preimplantation genetic diagnosis (PGD) is performed utilizing in vitro fertilization technology.24 Embryos are formed in vitro and tested for the HD gene at the 8-cell stage. Only those embryos not carrying the HD gene are implanted. This offers the advantage of not having to reveal the HD gene status to the at-risk parent. The downside is cost of the procedure and the failure rate of pregnancy with in vitro fertilization techniques. Despite advances in testing options, there are few reports available documenting reproductive decision making in the population at risk for HD. Lesca and colleagues25 showed that in a group of 868 at-risk couples, 5% requested presymptomatic testing while pregnant. Most of the couples (73%) decided to continue their pregnancy, and only 9% decided to do prenatal testing on their current pregnancy. Decruyenaere and colleagues26 followed 89 subjects found to be carriers and 7 subjects with equivocal HD gene testing results for an average of 7 years after HD presymptomatic testing and reported on their reproductive decision making. They found that 48 subjects (46 gene positive and 2 equivocal) underwent gene testing for family planning reasons and 58% of them went on to have children with prenatal diagnosis or PGD. About 35% decided
Huntington Disease
not have children after receiving their results and 7% remained undecided or did not have children for other reasons. TREATMENT STRATEGIES
Despite the wealth of information learned during the past 2 decades on the function and dysfunction of mutant huntingtin, HD remains an incurable disease. However, symptomatic therapies are often used to provide some relief in the motor, behavioral, and cognitive symptoms. Motor Symptoms
There are several medications that may alleviate chorea, but few controlled trials demonstrate their efficacy.27,28 The American Academy of Neurology has published guidelines for chorea treatment in HD, but these are hampered by the paucity of randomized, placebo-controlled trials and comparisons among medications.29 Tetrabenazine is a vesicular monoamine transport-2 inhibitor that causes presynaptic dopamine depletion and serves to ameliorate the chorea seen in HD. In fact, it is currently the only US Food and Drug Administration–approved medication for the treatment of HD. A placebo-controlled trial of tetrabenazine in HD demonstrated a significant reduction in chorea compared with placebo, with a 5-point decrease in chorea severity compared with 1.5-point improvement with placebo.30 Amantadine has also been shown to provide improvement in chorea in HD presumably related to its antiglutamatergic action.31,32 Both tetrabenazine and amantadine have level B evidence for chorea control per the American Academy of Neurology guidelines.29 Dopamine receptor–blocking medications (neuroleptics) are also used to control chorea, although there are few studies to document whether any particular drug provides better symptom control than another. Both typical and atypical neuroleptics are used for chorea control, and selection depends on side-effect profile and availability. Benzodiazepines may also ameliorate chorea. If dystonia predominates the motor manifestations of the disease, which may often happen in the later stages of disease, treatment with trihexiphenidyl, baclofen, benzodiazepines, or botulinum toxin injections for focal dystonia may be considered. Often, physical and occupational therapies are useful interventions to help the gait and balance difficulties, as well as the diminished motor control that accompanies HD progression. Speech and swallow therapies should be considered for dysarthria and dysphagia. Behavioral Symptoms
The psychiatric manifestations of HD are wide ranging and include depression, anxiety, obsessive-compulsive symptoms, impulsivity, irritability, apathy, and psychosis. There is significant variability in the expression and severity of one or more of these symptoms in patients with HD, and evaluation and treatment of these symptoms must be individualized. There are few clinical trials that establish efficacy for any behavioral treatments in HD, but therapies are utilized alone or in combination in patients needing intervention. Selective serotonin reuptake inhibitors, serotoninnorepinephrine reuptake inhibitors, and other antidepressants are used in treatment of depression, anxiety, obsessive-compulsive symptoms, irritability, and impulsivity. A small study documented improvement in depression in subjects with HD with the use of venlafaxine XR.33 Mood-stabilizing agents such as valproic acid as well as benzodiazepines may also be considered for anxiety and irritability. Neuroleptics are often used as agents that will help manage multiple HD symptoms. In addition to antichorea
1091
1092
Bordelon
action, neuroleptics can also ameliorate irritability, psychosis, anxiety, and depression. Suicidal ideation is more common in the population with HD and must be addressed and risk factors (depression and impulsivity) treated aggressively. Concomitant psychotherapy including cognitive-behavioral therapy and counseling for patients and family members to handle these problems can provide significant improvement. Cognitive Symptoms
Medications utilized in the treatment of Alzheimer disease have been explored for efficacy in HD-related cognitive impairment. The cholinesterase inhibitors including donepezil and rivastigmine may be used, but there is no evidence for established efficacy in HD.27 Memantine may also be considered, but trials have not shown efficacy in cognitive symptomatology. Again, counseling patients and families may be of great benefit in managing these symptoms. Establishing routines, using novel communication strategies (centralized calendars), and close supervision are helpful. FUTURE DIRECTIONS IN THERAPY
There is no therapy or intervention available that is proved to delay the onset or slow the progression of disease. This remains the primary focus of multiple studies in neurodegenerative diseases. HD stands out among these disorders as an ideal disease for potential neuroprotective or disease-modifying trials, as an identifiable presymptomatic subject population exists and is the target for such interventions. Studies are underway to assess the potential benefit of coenzyme Q10 and creatine as potential disease-modifying therapies given their role in addressing the energetic dysfunction present in HD.27 Several other agents are being explored as well but have not yet moved into human clinical trials. The benefits of exercise are also being explored as an intervention that not only maintains mobility but may also serves to slow disease progression. Many other strategies are being explored to modify the disease at the genetic level with HD again serving as an ideal disorder to study. Antisense oligonucleotides and RNA interference strategies that reduce expression of mutant huntingtin have been shown to ameliorate disease pathology and progression in HD transgenic mice.34 These successes in animal models have spurred the design for human clinical trials using these interventions the start-ups of which are on the horizon. Another exciting avenue of potential treatments incorporates the use of stem cell therapies. Previous studies utilized human fetal transplants in patients with HD, but clinical outcomes showed only mild, transient improvement, and follow-up at autopsy documented huntingtin inclusions in the transplanted tissue demonstrating spread of the pathologic condition.35,36 However, many novel approaches are under development using a variety of stem cell sources including induced pluripotent stem cells, mesenchymal stem cells, neural stem cells, and embryonic stem cells. Such technologies are revealing further details of the pathophysiological mechanisms of disease in HD.37 In addition, these techniques alone or in combination with gene therapy are being developed for human clinical trials in patients with HD. SUMMARY
HD is an adult-onset, autosomal dominant, CAG repeat expansion disorder that results in progressive motor, behavioral, and cognitive decline related to striatal and cortical degeneration linked to pathologic inclusions of the huntingtin protein. HD serves as a model for genetic testing issues among dominantly inherited diseases.
Huntington Disease
In addition, it is ideal for investigating novel disease-modifying interventions including medications, gene silencing, gene therapy, and stem cell transplantation techniques. REFERENCES
1. Huntington G. On chorea. The Medical and Surgical Reporter 1872;789:317–21. 2. Biglan KM, Shoulson I. Huntington’s disease. In: Hallett M, Poewe W, editors. Therapeutics of Parkinson’s disease and other movement disorders. Chicester (United Kingdom): John Wiley and Sons; 2008. p. 295–315. 3. Sackley C, Hoppitt TJ, Calvert M, et al. Huntington’s disease: current epidemiology and pharmacological management in UK primary care. Neuroepidemiology 2011;37:216–21. 4. Stout JC, Paulsen JS, Queller S, et al. Neurocognitive signs in prodromal Huntington disease. Neuropsychology 2011;25:1–14. 5. Duff K, Paulsen JS, Beglinger LJ, et al. “Frontal” behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci 2010;22:196–207. 6. Tabrizi SJ, Scahill RJ, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011;10:31–42. 7. Peavy GM, Jacobson MW, Goldstein JL, et al. Cognitive and functional decline in Huntington’s disease: dementia criteria revisited. Mov Disord 2010;25:1163–9. 8. Paulsen JS, Nehl C, Hoth KF, et al. Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 2005;17:496–502. 9. Paulsen JS, Hoth KF, Nehl C, et al. Critical periods of suicide risk in Huntington’s disease. Am J Psychiatry 2005;162:725–31. 10. Paulsen JS, Wang C, Duff K, et al. Challenges assessing clinical end points in early Huntington disease. Mov Disord 2010;25:2595–603. 11. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971–83. 12. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. 13. Brinkman RR, Mezel MM, Theilmann J, et al. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997;60:1202–10. 14. Wexler NS, Lorimer J, Porter J, 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;101:3498–503. 15. DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995;14:1075–81. 16. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 2010;90:905–81. 17. Vonsattel JP, Myers RH, Stevens TJ, et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985;44:559–77. 18. Aylward EH, Liu D, Nopoulos PC, et al. Striatal volume contributes to the prediction of onset of Huntington disease in incident cases. Biol Psychiatry 2011;71(9): 822–8. 19. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8:791–801.
1093
1094
Bordelon
20. Rosas HD, Salat DH, Lee SY, et al. Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 2008;131:1057–68. 21. Deng YP, Albin RL, Penney JB, et al. Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study. J Chem Neuroanat 2004;27:143–64. 22. Hayden MR. Predictive testing for Huntington’s disease: a universal model? Lancet Neurol 2003;2:141–2. 23. Goizet C, Lesca G, Durr A. Presymptomatic testing in Huntington’s disease and autosomal dominant cerebellar ataxias. Neurology 2002;59:1330–6. 24. 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: 1007–14. 25. Lesca G, Goizet C, Durr A. Predictive testing in the context of pregnancy: experience in Huntington’s disease and autosomal dominant cerebellar ataxia. J Med Genet 2002;39:522–5. 26. Decruyenaere M, Evers-Kiebooms G, Boogaerts A, et al. The complexity of reproductive decision-making in asymptomatic carriers of the Huntington mutation. Eur J Hum Genet 2007;15:453–62. 27. Venuto CS, McGarry A, Ma Q, et al. Pharmacologic approaches to the treatment of Huntington’s disease. Mov Disord 2012;27:31–42. 28. Killoran A, Biglan KM. Therapeutics in Huntington’s disease. Curr Treat Options Neurol 2012;14:137–49. 29. Armstrong MJ, Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease. Neurology 2012;79:597–603. 30. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized control trial. Neurology 2006;66:366–72. 31. Verhagen Metman L, Morris MJ, Farmer C, et al. Huntington’s disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002;59: 694–9. 32. O’Suilleabhain P, Dewey RB Jr. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60:996–8. 33. Holl AK, Wilkinson I, Painold A, et al. Combating depression in Huntington disease: effective antidepressive treatment with venlafaxine XR. Int Clin Psychopharmacol 2010;25:46–50. 34. Harper SQ. Progress and challenges in RNA interference therapy for Huntington disease. Arch Neurol 2009;66:933–8. 35. Bachoud-Levi AC, Gaura V, Brugieres P, et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 2006;5:303–9. 36. Cicchetti F, Saporta S, Hauser RA, et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc Natl Acad Sci U S A 2009;106:12483–8. 37. Kaye JA, Finkbeiner S. Modeling Huntington’s disease with induced pluripotent stem cells. Mol Cell Neurosci 2013;56C:50–64.
MD, PhD
KEYWORDS Huntingtin CAG repeat disorder Striatum Presymptomatic genetic testing Preimplantation genetic diagnosis Tetrabenazine KEY POINTS Huntington disease (HD) is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene. HD is typically manifest in adulthood and characterized by progressive deterioration in motor, cognitive, and behavioral functions, with chorea as the primary motor manifestation of disease. The pathologic hallmark of HD is striatal atrophy, but widespread cell loss, gliosis, and huntingtin-positive neuronal inclusions are demonstrated in cortical and extrastriatal structures. HD serves as a model for presymptomatic genetic testing and preimplantation genetic diagnosis for multiple other disorders whose genetic causes are being identified. Current treatment approaches are symptomatic, but disease-modifying interventions including medications and gene-based and stem cell–based therapies are under investigation.
INTRODUCTION
Huntington disease (HD) results from an abnormal expansion of a CAG repeat in the huntingtin gene that is dominantly inherited. It is typically an adult-onset disorder that causes the following: Abnormal movements Chorea Dystonia Rigidity Bradykinesia
Disclosures: Member of Speakers Bureaus for Lundbeck, Inc, Teva Neuroscience and Medical Education Speakers Network. Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90210, USA E-mail address: [email protected] Neurol Clin 31 (2013) 1085–1094 http://dx.doi.org/10.1016/j.ncl.2013.05.004 neurologic.theclinics.com 0733-8619/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
1086
Bordelon
Behavioral manifestations Depression Anxiety Obsessive-compulsive symptoms Irritability/aggression Apathy Psychosis Cognitive impairment Impaired attention and concentration Poor organization and planning Memory loss Visuospatial dysfunction These symptoms appear gradually in any combination varying among individuals and families and progress inexorably leaving the person with HD ultimately mute and akinetic. CLINICAL FINDINGS
HD was first described by the physician George Huntington in 1872 in his paper entitled “On Chorea,” where he reported on the families living in Long Island, New York, affected by “that disorder” who were cared for by him as well as his grandfather and father before him.1 This paper described the core features of the illness including the typical adult onset, progressive nature of the disease, prominent chorea, and associated psychiatric illness with a tendency to suicide. He also characterized the inheritance pattern remarking that if a person in an affected family was spared the disease, no one descending from that individual would develop it; in other words, an autosomal dominant pattern. At present, the prevalence of HD is estimated to be 7 to 10 per 100,000 in the United States, and a similar range has also been reported in the United Kingdom, although a debate continues as to whether these are underestimates.2,3 The typical age of onset is in the fourth decade of life, and progression to death occurs over a 20- to 25-year period. In less than 10% of cases, the onset occurs before age 20 years and is accompanied by more severe motor symptoms of disease, sometimes accompanied by seizures and faster progression over a 10- to 15-year period (Westphal variant). The clinical hallmark of HD is chorea, defined as uncontrolled movements flowing from one muscle group to another. Additional abnormal movements that are part of HD include dystonia, gait and postural instability, myoclonus, rigidity, and bradykinesia. These motor symptoms are often quite subtle as they become manifest, and no clear definitions exist for the severity or types of motor symptoms that must be present to make a firm diagnosis of clinical onset. In addition, it has become clear from studies of gene-positive individuals that the cognitive and behavioral symptoms of HD often precede the movement disorder by several years.4–6 The cognitive impairment seen in HD is thought to arise from dysfunction of frontalsubcortical pathways, thus giving rise to deficits in executive tasks (attention, concentration, planning, and multitasking) and other frontal features such as impulsivity. Recent clinical research studies (PREDICT and TRACK-HD) have followed premotor manifest HD subjects over time to capture which tasks or functions may be affected earliest. These studies have demonstrated impairment in the domains of executive function, memory, and visuospatial tasks. As the disease progresses, cognitive impairment worsens and most eventually meet criteria for dementia, with multiple domains being affected and contributing to functional decline.7 However, even in
Huntington Disease
late-stage HD, patients may maintain alertness and cognitive processing skills that allow them to understand what is happening around them but without the motor function to communicate. Health care providers must be aware of this and try to develop creative methods for communicating. Behavioral symptoms of HD can present early and can be quite severe with significant impacts on interpersonal relationships and quality of life. The problems are diverse and vary among and within HD families. Depression is common in all stages of HD and has been estimated to occur in approximately 40% of patients.8 Anxiety as well as obsessive-compulsive traits may be present and can be quite severe. Irritability and emotional dyscontrol leading sometimes to violent outbursts can occur and are also difficult to treat. Impulsivity may be present. These symptoms in combination with the other behavioral manifestations of the disease contributes to the higher rate of suicide attempts and ideation seen in the population with HD.9 Patients with HD may also have various addiction problems including smoking, alcohol, and drugs. All behavioral manifestations are believed to result from disruption of frontal-subcortical circuits as well. The phenotypic expression of HD varies widely among and within families of HD. Often a pattern evolves whereby in one family the behavioral manifestations are the earliest and most debilitating and in another the motor features present initially and are the greatest source of impairment. In addition, although these symptoms emerge gradually over time, they generally only come to attention when they begin to interfere with an individual’s independent functioning. This functional impairment may be in the workplace or at home or in combination, and the threshold for “impairment” varies from person to person. Clinical studies have demonstrated that the first sign of diminished function in patients with HD is loss of employment.10 This change in function is more closely tied to the cognitive and behavioral features of HD rather than the motor. GENETICS AND DISEASE PATHOLOGY
In the centennial celebration of George Huntington’s work, Dr Amerigo Negrette presented a paper describing a high prevalence of HD in people living in towns near Lake Maracaibo in Venezuela. Intrigued by this report, Dr Nancy Wexler of Columbia University organized the Venezuela Collaborative Huntington’s Disease project with the goal of finding the cause of HD. In 1981, the first of 22 annual trips to the region occurred where large pedigrees were established and data collected including motor and neuropsychological testing as well as blood samples. This massive effort resulted in identification of the marker on chromosome 4 in 1983 and discovery of the causative gene mutation, an expanded CAG repeat in the IT-15 gene (now called the huntingtin gene), in 1993.11 Since the identification of the HD gene mutation, there has been a wealth of research into the understanding of the role that this repeat expansion plays in the pathophysiology of the disease. The huntingtin gene is located on 4p16.3 and encodes the protein huntingtin. It belongs to a family of expanded CAG repeat disorders with spinal and bulbar muscular atrophy (Kennedy disease) being the first described.12 Diseasecausing mutations have a CAG repeat length of 40 and higher. There is an association with higher repeat lengths being associated with earlier age at onset but CAG repeat length only accounts for approximately 50% to 60% of predicted onset age.13,14 Other genetic modifiers and environmental influences that contribute to HD onset are being sought in ongoing research efforts. Huntingtin is a 348-kDa protein that is ubiquitously expressed, with the highest levels found in neurons. It is primarily cytoplasmic but also localizes to the nucleus and organelles.15 The N-terminus contains a polyproline region in addition to the
1087
1088
Bordelon
glutamine stretch resulting from the CAG expansion, which are both involved in the pathophysiology. The normal functions of huntingtin have not been completely elucidated, but it has thus far been found to play a role in a myriad of normal processes including axonal and vesicular transport, endocytosis, postsynaptic signaling, and cell survival pathways (reviewed in Ref.16). Mutant huntingtin undergoes N-terminal cleavage, resulting in polyglutamine fragments, which can oligomerize and form aggregates, both cytoplasmic and nuclear. The N-terminal fragments, oligomers of these fragments, and the fully formed inclusions have been implicated in the toxicity of HD. It has been demonstrated that mutant huntingtin adversely affects a multitude of intracellular processes and causes widespread disruption including mitochondrial dysfunction, transcriptional dysregulation of various genes, altered axonal transport of critical factors, disrupted calcium signaling, abnormal protein interactions, alterations in proteosomal function, and autophagy. These diverse mechanisms are well reviewed by Zuccato and colleagues.16 The overall effects of mutant huntingtin expression are cell loss and gliosis in the brain, with the striatum being most affected by the disease. Jean-Paul Vonsattel developed the pathologic grading scheme for HD using striatal atrophy as the hallmark by which to characterize disease severity.17 Grade 0 is defined by a normal gross appearance of the striatum but a 30% to 40% neuronal loss in the caudate nucleus, grade 1 exhibits atrophy of the tail of the caudate and 50% neuronal loss in the structure, grade 2 has mild-moderate gross atrophy of the caudate and even greater neuronal loss, grade 3 exhibits severe caudate atrophy with even greater neuronal loss, and grade 4 has severe atrophy with an obvious concave appearance of the caudate and greater than 95% neuronal loss (Fig. 1). In grades 3 and 4, there is notable cell loss of extrastriatal structures such as the cortex, globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum. Several elegant studies using magnetic resonance imaging have demonstrated progressive striatal atrophy first noted years before motor symptom onset in HD.18 Cortical atrophy is also apparent before motor symptoms, with posterior frontal regions affected the earliest
Fig. 1. Luxol fast blue with hematoxylin and eosin counterstained coronal sections of striatum from subjects with HD representative of each pathologic grade 0 to 4. (Courtesy of Jean-Paul Vonsattel, MD, Columbia University Medical Center.)
Huntington Disease
with progression to involve occipital, parietal, and other cortical regions eventually resulting in significant and widespread thinning.19,20 The medium-sized spiny gamma-aminobutyric acid (GABA) containing neurons of the striatum seem to be the most vulnerable to huntingtin toxicity. It has been proposed that the “indirect pathway” comprising GABAergic striatal projections to the external globus pallidus are affected earlier in the disease, thus resulting in loss of inhibition of this structure with resulting enhanced inhibition of GABAergic projections to the subthalamic nucleus. This in turn produces decreased excitation of the glutamatergic projections to the globus pallidus internus and overall diminished inhibitory GABAergic outflow to the thalamus. This disinhibition of the thalamus allows for enhanced excitatory outflow to the cortex resulting in hyperkinetic or uncontrolled movements, that is, chorea (Fig. 2). As the disease progresses into late stages the “direct pathway” also becomes profoundly affected, which results in loss of GABAergic inhibition of the internal globus pallidus and enhanced GABAergic inhibitory outflow to the thalamus. This thalamic inhibition of excitatory cortical connections produces a hypokinetic or akinetic state as seen in the last stages of HD (see Fig. 2).21 EVALUATION AND MANAGEMENT
The standard remains that symptomatic HD is diagnosed at the time of onset of the characteristic motor signs of the disease. However, since 1993, the genetic diagnosis of HD has been available, allowing for identification of individuals who carry the HD gene mutation but do not yet exhibit signs or symptoms of the disease. Titles for this population of gene-positive individuals have varied over time: presymptomatic, premanifest, premotor, and prodromal. All terms try to characterize a period of lack
Fig. 2. Early loss of indirect pathway neurons in HD causing hyperkinetic movements (chorea) followed by later involvement of direct pathway neurons (akinesia). D1, D2, dopamine receptors; GPe, globus pallidus externus; GPi, globus pallidus internus; STN, subthalamic nucleus; Thal, thalamus.
1089
1090
Bordelon
of measurable deficits before actual disease onset. This technology thus becomes “heavily loaded” with information for at-risk individuals that affects (1) the future of their own health, career, and family planning; (2) other family members’ risk status; and (3) their eligibility for obtaining life, long-term care, and possibly medical insurance in the future. (However, the federal Genetic Information Nondiscrimination Act passed in 2008 should prevent discrimination against persons with or at risk for genetic diseases by medical insurance providers and employers.) These special circumstances have led to the development of HD genetic testing procedures in the at-risk population. It is advised that all at-risk persons speak with genetic counselors to discuss the full implications of obtaining the test before having the testing performed. Many clinical sites will also arrange meetings with neurologists or psychologists before testing and recommend that a family member or friend accompany the person to all appointments. The results are always given in person rather than by phone or mail to provide the best supportive environment possible in dealing with reactions to the genetic diagnosis. It must be emphasized that many patients who receive a negative result for the HD gene test also have problems managing their negative diagnosis given the guilt that accompanies it. The gene test is reported as diagnostic for HD if the CAG repeat length in the huntingtin gene is 40 or greater and is normal if 26 or lower. Repeat lengths of 36 to 39 are “indeterminate,” meaning they may have reduced penetrance, whereas intermediate repeat lengths of 27 to 35 may be normal or potentially disease-causing. Juvenileonset HD typically occurs with repeat lengths of 50 and more. This condition occurs more commonly when the disease is inherited via the paternal line, as CAG repeat expansion may occur during spermatogenesis. There is a correlation between longer CAG repeat length and earlier onset of disease, but only approximately 50% to 60% of age of onset can be predicted by CAG repeat length.14 Other as yet unidentified genetic or environmental modifiers may influence onset age as well. Although the HD gene test has been available for some time, only a minority of at-risk people decide to obtain testing (estimated at 5% in the United States), as there are no known cures or treatments that delay the onset or progression of disease as yet.22 Family planning issues are some of the major driving forces when persons atrisk for HD do decide to obtain genetic testing, and studies have revealed that women more often than men seek predictive testing.23 Women who are at-risk for HD who are pregnant or are thinking about becoming pregnant can meet with genetic counselors to discuss testing options that are currently available. HD genetic testing can be obtained in utero through amniocentesis or chorionic villous sampling. Preimplantation genetic diagnosis (PGD) is performed utilizing in vitro fertilization technology.24 Embryos are formed in vitro and tested for the HD gene at the 8-cell stage. Only those embryos not carrying the HD gene are implanted. This offers the advantage of not having to reveal the HD gene status to the at-risk parent. The downside is cost of the procedure and the failure rate of pregnancy with in vitro fertilization techniques. Despite advances in testing options, there are few reports available documenting reproductive decision making in the population at risk for HD. Lesca and colleagues25 showed that in a group of 868 at-risk couples, 5% requested presymptomatic testing while pregnant. Most of the couples (73%) decided to continue their pregnancy, and only 9% decided to do prenatal testing on their current pregnancy. Decruyenaere and colleagues26 followed 89 subjects found to be carriers and 7 subjects with equivocal HD gene testing results for an average of 7 years after HD presymptomatic testing and reported on their reproductive decision making. They found that 48 subjects (46 gene positive and 2 equivocal) underwent gene testing for family planning reasons and 58% of them went on to have children with prenatal diagnosis or PGD. About 35% decided
Huntington Disease
not have children after receiving their results and 7% remained undecided or did not have children for other reasons. TREATMENT STRATEGIES
Despite the wealth of information learned during the past 2 decades on the function and dysfunction of mutant huntingtin, HD remains an incurable disease. However, symptomatic therapies are often used to provide some relief in the motor, behavioral, and cognitive symptoms. Motor Symptoms
There are several medications that may alleviate chorea, but few controlled trials demonstrate their efficacy.27,28 The American Academy of Neurology has published guidelines for chorea treatment in HD, but these are hampered by the paucity of randomized, placebo-controlled trials and comparisons among medications.29 Tetrabenazine is a vesicular monoamine transport-2 inhibitor that causes presynaptic dopamine depletion and serves to ameliorate the chorea seen in HD. In fact, it is currently the only US Food and Drug Administration–approved medication for the treatment of HD. A placebo-controlled trial of tetrabenazine in HD demonstrated a significant reduction in chorea compared with placebo, with a 5-point decrease in chorea severity compared with 1.5-point improvement with placebo.30 Amantadine has also been shown to provide improvement in chorea in HD presumably related to its antiglutamatergic action.31,32 Both tetrabenazine and amantadine have level B evidence for chorea control per the American Academy of Neurology guidelines.29 Dopamine receptor–blocking medications (neuroleptics) are also used to control chorea, although there are few studies to document whether any particular drug provides better symptom control than another. Both typical and atypical neuroleptics are used for chorea control, and selection depends on side-effect profile and availability. Benzodiazepines may also ameliorate chorea. If dystonia predominates the motor manifestations of the disease, which may often happen in the later stages of disease, treatment with trihexiphenidyl, baclofen, benzodiazepines, or botulinum toxin injections for focal dystonia may be considered. Often, physical and occupational therapies are useful interventions to help the gait and balance difficulties, as well as the diminished motor control that accompanies HD progression. Speech and swallow therapies should be considered for dysarthria and dysphagia. Behavioral Symptoms
The psychiatric manifestations of HD are wide ranging and include depression, anxiety, obsessive-compulsive symptoms, impulsivity, irritability, apathy, and psychosis. There is significant variability in the expression and severity of one or more of these symptoms in patients with HD, and evaluation and treatment of these symptoms must be individualized. There are few clinical trials that establish efficacy for any behavioral treatments in HD, but therapies are utilized alone or in combination in patients needing intervention. Selective serotonin reuptake inhibitors, serotoninnorepinephrine reuptake inhibitors, and other antidepressants are used in treatment of depression, anxiety, obsessive-compulsive symptoms, irritability, and impulsivity. A small study documented improvement in depression in subjects with HD with the use of venlafaxine XR.33 Mood-stabilizing agents such as valproic acid as well as benzodiazepines may also be considered for anxiety and irritability. Neuroleptics are often used as agents that will help manage multiple HD symptoms. In addition to antichorea
1091
1092
Bordelon
action, neuroleptics can also ameliorate irritability, psychosis, anxiety, and depression. Suicidal ideation is more common in the population with HD and must be addressed and risk factors (depression and impulsivity) treated aggressively. Concomitant psychotherapy including cognitive-behavioral therapy and counseling for patients and family members to handle these problems can provide significant improvement. Cognitive Symptoms
Medications utilized in the treatment of Alzheimer disease have been explored for efficacy in HD-related cognitive impairment. The cholinesterase inhibitors including donepezil and rivastigmine may be used, but there is no evidence for established efficacy in HD.27 Memantine may also be considered, but trials have not shown efficacy in cognitive symptomatology. Again, counseling patients and families may be of great benefit in managing these symptoms. Establishing routines, using novel communication strategies (centralized calendars), and close supervision are helpful. FUTURE DIRECTIONS IN THERAPY
There is no therapy or intervention available that is proved to delay the onset or slow the progression of disease. This remains the primary focus of multiple studies in neurodegenerative diseases. HD stands out among these disorders as an ideal disease for potential neuroprotective or disease-modifying trials, as an identifiable presymptomatic subject population exists and is the target for such interventions. Studies are underway to assess the potential benefit of coenzyme Q10 and creatine as potential disease-modifying therapies given their role in addressing the energetic dysfunction present in HD.27 Several other agents are being explored as well but have not yet moved into human clinical trials. The benefits of exercise are also being explored as an intervention that not only maintains mobility but may also serves to slow disease progression. Many other strategies are being explored to modify the disease at the genetic level with HD again serving as an ideal disorder to study. Antisense oligonucleotides and RNA interference strategies that reduce expression of mutant huntingtin have been shown to ameliorate disease pathology and progression in HD transgenic mice.34 These successes in animal models have spurred the design for human clinical trials using these interventions the start-ups of which are on the horizon. Another exciting avenue of potential treatments incorporates the use of stem cell therapies. Previous studies utilized human fetal transplants in patients with HD, but clinical outcomes showed only mild, transient improvement, and follow-up at autopsy documented huntingtin inclusions in the transplanted tissue demonstrating spread of the pathologic condition.35,36 However, many novel approaches are under development using a variety of stem cell sources including induced pluripotent stem cells, mesenchymal stem cells, neural stem cells, and embryonic stem cells. Such technologies are revealing further details of the pathophysiological mechanisms of disease in HD.37 In addition, these techniques alone or in combination with gene therapy are being developed for human clinical trials in patients with HD. SUMMARY
HD is an adult-onset, autosomal dominant, CAG repeat expansion disorder that results in progressive motor, behavioral, and cognitive decline related to striatal and cortical degeneration linked to pathologic inclusions of the huntingtin protein. HD serves as a model for genetic testing issues among dominantly inherited diseases.
Huntington Disease
In addition, it is ideal for investigating novel disease-modifying interventions including medications, gene silencing, gene therapy, and stem cell transplantation techniques. REFERENCES
1. Huntington G. On chorea. The Medical and Surgical Reporter 1872;789:317–21. 2. Biglan KM, Shoulson I. Huntington’s disease. In: Hallett M, Poewe W, editors. Therapeutics of Parkinson’s disease and other movement disorders. Chicester (United Kingdom): John Wiley and Sons; 2008. p. 295–315. 3. Sackley C, Hoppitt TJ, Calvert M, et al. Huntington’s disease: current epidemiology and pharmacological management in UK primary care. Neuroepidemiology 2011;37:216–21. 4. Stout JC, Paulsen JS, Queller S, et al. Neurocognitive signs in prodromal Huntington disease. Neuropsychology 2011;25:1–14. 5. Duff K, Paulsen JS, Beglinger LJ, et al. “Frontal” behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci 2010;22:196–207. 6. Tabrizi SJ, Scahill RJ, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011;10:31–42. 7. Peavy GM, Jacobson MW, Goldstein JL, et al. Cognitive and functional decline in Huntington’s disease: dementia criteria revisited. Mov Disord 2010;25:1163–9. 8. Paulsen JS, Nehl C, Hoth KF, et al. Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 2005;17:496–502. 9. Paulsen JS, Hoth KF, Nehl C, et al. Critical periods of suicide risk in Huntington’s disease. Am J Psychiatry 2005;162:725–31. 10. Paulsen JS, Wang C, Duff K, et al. Challenges assessing clinical end points in early Huntington disease. Mov Disord 2010;25:2595–603. 11. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971–83. 12. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. 13. Brinkman RR, Mezel MM, Theilmann J, et al. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997;60:1202–10. 14. Wexler NS, Lorimer J, Porter J, 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;101:3498–503. 15. DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995;14:1075–81. 16. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 2010;90:905–81. 17. Vonsattel JP, Myers RH, Stevens TJ, et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985;44:559–77. 18. Aylward EH, Liu D, Nopoulos PC, et al. Striatal volume contributes to the prediction of onset of Huntington disease in incident cases. Biol Psychiatry 2011;71(9): 822–8. 19. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8:791–801.
1093
1094
Bordelon
20. Rosas HD, Salat DH, Lee SY, et al. Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 2008;131:1057–68. 21. Deng YP, Albin RL, Penney JB, et al. Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study. J Chem Neuroanat 2004;27:143–64. 22. Hayden MR. Predictive testing for Huntington’s disease: a universal model? Lancet Neurol 2003;2:141–2. 23. Goizet C, Lesca G, Durr A. Presymptomatic testing in Huntington’s disease and autosomal dominant cerebellar ataxias. Neurology 2002;59:1330–6. 24. 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: 1007–14. 25. Lesca G, Goizet C, Durr A. Predictive testing in the context of pregnancy: experience in Huntington’s disease and autosomal dominant cerebellar ataxia. J Med Genet 2002;39:522–5. 26. Decruyenaere M, Evers-Kiebooms G, Boogaerts A, et al. The complexity of reproductive decision-making in asymptomatic carriers of the Huntington mutation. Eur J Hum Genet 2007;15:453–62. 27. Venuto CS, McGarry A, Ma Q, et al. Pharmacologic approaches to the treatment of Huntington’s disease. Mov Disord 2012;27:31–42. 28. Killoran A, Biglan KM. Therapeutics in Huntington’s disease. Curr Treat Options Neurol 2012;14:137–49. 29. Armstrong MJ, Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease. Neurology 2012;79:597–603. 30. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized control trial. Neurology 2006;66:366–72. 31. Verhagen Metman L, Morris MJ, Farmer C, et al. Huntington’s disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002;59: 694–9. 32. O’Suilleabhain P, Dewey RB Jr. A randomized trial of amantadine in Huntington disease. Arch Neurol 2003;60:996–8. 33. Holl AK, Wilkinson I, Painold A, et al. Combating depression in Huntington disease: effective antidepressive treatment with venlafaxine XR. Int Clin Psychopharmacol 2010;25:46–50. 34. Harper SQ. Progress and challenges in RNA interference therapy for Huntington disease. Arch Neurol 2009;66:933–8. 35. Bachoud-Levi AC, Gaura V, Brugieres P, et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 2006;5:303–9. 36. Cicchetti F, Saporta S, Hauser RA, et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc Natl Acad Sci U S A 2009;106:12483–8. 37. Kaye JA, Finkbeiner S. Modeling Huntington’s disease with induced pluripotent stem cells. Mol Cell Neurosci 2013;56C:50–64.
