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Huntington’s disease (HD) is the most common neurologic disorder in the developed world. It is a rare genetic disease with an increased prevalence in those of European descent (10 – 12 individuals affected per 100,000). Recent evidence suggests that the prevalence of Huntington’s disease in Maori population is 10 times more than the world average (1).
Huntington’s disease is characterised by a triad of symptoms involving motor, cognitive and neuro-psychiatric dysfunction. Most individuals with this condition would first present with neurologic symptoms such as changes in eye movements, minor chorea, difficulty in paying attention and recognising emotions, apathy and depression. As the disease progresses, motor disability becomes more severe and the affected individual would usually require complete care in the end stages of the disease. Approximately 5 – 10% of those with the condition experience symptoms before age 20 and are categorised as juvenile Huntington’s disease. These individuals present with severe mental deterioration, speech and language delay, and prominent motor and cerebellar symptoms. In addition, 30 – 50% of affected children below age 10 experience epileptic seizures (2). In recent years, researchers have divided the signs and symptoms of Huntington’s disease into three categories, pre-symptomatic, prodromal and manifest Huntington’s disease (3).
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The diagnosis of Huntington’s disease is based on clinical examination/history, family history and genetic testing. For patients with a family history of Huntington’s disease, diagnosis is generally straightforward. In individuals who are at risk or tested genetically positive, the diagnosis of motor onset of manifest Huntington’s disease is based on the unified Huntington’s disease rating scale (UHDRS) motor examination. It may be possible to diagnose Huntington’s disease prior to motor onset when an MRI or CT scan show symmetrical striatal atrophy in the absence of other changes (4). The disease is not curable and clinical care is centred on managing the symptoms that arises. From motor onset, the median survival time is 18 years (5). Due to the nature of the disease, most people with the disease would have seen how their loved one’s personality and cognition changes over time. This may cause emotional distress for them and their family members. If this is a new diagnosis in the family, siblings and children are now at risk as well. It could also potentially lead to family members being carers at a relatively young age, with the extra burden that they too would eventually lose their independence if tested positive (6).
Huntington’s disease is an autosomal dominant monogenic disorder caused by a trinucleotide (triplet) expansion of the Huntingtin (HTT) gene, located at chromosome 4p16.3 (7). The gene encodes for the HTT protein, however the normal function of this protein is not fully understood (4, 8, 9). It is a large complex protein with a range of support functions in embryonic development, transcriptional regulation of other genes, nucleocytoplasmic shuttling and synaptic vesicle transmission (10). Mutant HTT causes disease through a gain-of-function mechanism (11). There is no locus heterogeneity for the HTT gene (12). Huntington’s disease exhibit allelic heterogeneity. However, as it is a dominant genetic disease, only one copy of the mutant allele is needed to inherit the disease. Most patients are heterozygotes as it is very rare to have two copies of mutant alleles (13).
Mutations, Correlation between genotype and phenotype
The genetic mutation causing Huntington’s disease is a CAG repeat expansion in exon 1 of the HTT gene. This mutation is dynamic. On a single allele, the length of the expansion varies between cells within individuals and generally expands in subsequent generations (10). When translated to the HTT protein, the expansion leads to a corresponding poly-glutamine (polyQ) segment stretch near the amino terminus.
There is a significant inverse correlation between the length of CAG repeats and the onset of Huntington’s disease (4, 6, 8, 10, 14). However, the size of CAG only accounts for up to 70% of the variability in the age of onset, implying that disease onset is still not predictable (6, 15). In addition, it is the single largest expanded allele CAG repeat that contributes to disease onset, with no significant additive effects in homozygotes or protective effect in heterozygotes with shorter CAG repeats on the normal chromosome (16). Figure 1 gives a summary of the general relationship between the age of onset and the number of CAG repeats. Individuals with CAG repeat lengths between 36 and 39 may not develop the disease due to reduced penetrance; with those developing the disease having a later onset (6, 17, 18). The disease is fully penetrant with CAG repeat lengths greater than 40 (19). CAG repeats between 27 and 35 are termed intermediate alleles and do not give rise to the disease phenotype. However, due to the instability in the CAG repeats, individuals with intermediate allele (males in particular) are at risk of having a child with the disease (20, 21).
Figure 1. The relationship between the length of CAG repeat and the approximate age of onset. JHD, juvenile Huntington’s disease (14).
Huntington’s disease is the first adult-onset, autosomal-dominant disorder for which predictive testing is an option (22, 23). Prenatal diagnosis (PND) is available and is usually only done if the parent at risk had been tested. If the parent does not want to know his/her genetic status, exclusion PND is an option (24). However, if the foetus tested positive for the genetic mutation, the parent at risk may still know his/her genetic status. PND involves either chorionic villus sampling or amniocentesis, both entailing a risk of miscarriage. Recent researches have looked at non-invasive prenatal diagnosis (NIPD) using cell-free foetal DNA (ccffDNA) in maternal blood to reduce the risk of miscarriages, however there were problems with removing maternal DNA and in detecting longer CAG expansions (25, 26). Another option is preimplantation genetic diagnosis (PGD). For asymptotic individuals with greater than 36 CAG repeats, it is recommended to offer this as an option (22, 24).
Genetic testing can be diagnostic or predictive. For individuals presenting with clinical symptoms, CAG-repeat testing is the most useful confirmatory test. In New Zealand, predictive testing (PT) is only available to those over age 18 in accordance with the updated recommendations of European Huntington Disease Network (EHDN) (24). Prior to predictive testing being available, up to 80% of individuals expressed their interest in taking such a test. However, actual uptake of the test for individuals at risk when it was available was only between 5-25% (22, 23, 27). This could be attributed to the fact that there is no treatment or cure. The main motives for taking a test are planning for children, planning for individuals’ own future and informing children of their risk (28). A disadvantage of predictive testing is the psychological impact as they anticipate the onset of the disease. Those who tested positive but are asymptomatic have been found to have higher levels of anxiety (29). However, individuals have also reported that knowing their genetic status has encouraged them to make financial plans and try new things. A negative test may cause individuals to have “survivor guilt” as they have been spared while other family members have to live with the disease (30). Getting predictive testing is a difficult process, hence it is recommended that individuals undergo genetic counselling before the test (24).
Current research and research paper
Current research investigate ways of modifying the path of disease by targeting the DNA using CRISPR/Cas9 (31-33) or zinc-finger transcription factor (34-36). Studies are currently in the preclinical phase and involves regulating gene-transcription or by changing the HTT gene directly. If successful, a single treatment is all it needs to treat Huntington’s disease. An example of therapies targeting the RNA involves the use of antisense oligonucleotides (ASOs), which are delivered intrathecally. ASOs inhibits the translation of the mutant HTT protein by degrading HTT mRNA using RNAase H (37). A recent review paper gives further details on advances in both DNA and RNA therapies for Huntington’s disease (38). The development of therapies targeting HTT expression is promising, with a number of clinical trials underway or in the midst of recruiting participants. Although success in gene therapy is still not guaranteed, the research community is active and continuously working towards treatment and cure of the disease.
The chosen research paper investigated the use of paired Cas9 nickase strategy to inactivate the HTT gene by targeting the area around the CAG repeat tract and removing the tract. Four small guide RNA (sgRNA) were designed, and along with Cas9 nickases, the most active pair was electroplated into Huntington’s disease fibroblasts with different lengths of CAG repeat. HTT protein level reduces by 68 – 82% regardless of tract length. The nickase version of Cas9 is safer and more specific than wild-type Cas9. The study also found that the new method is resistant to nonsense-mediated decay (NMD) as the concentration of the shortened HTT transcript remained constant (39).
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8. Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nature Reviews Neuroscience. 2005;6(12):919.
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10. De Souza RA, Leavitt BR. Neurobiology of Huntington’s disease. Behavioral Neurobiology of Huntington’s Disease and Parkinson’s Disease: Springer; 2014. p. 81-100.
11. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. The Lancet Neurology. 2011;10(1):83-98.
12. Conneally PM, Haines JL, Tanzi RE, Wexler NS, Penchaszadeh GK, Harper PS, et al. Huntington disease: no evidence for locus heterogeneity. Genomics. 1989;5(2):304-8.
13. Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, et al. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain. 2003;126(4):946-55.
14. Nopoulos PC. Huntington disease: a single-gene degenerative disorder of the striatum. Dialogues Clin Neurosci. 2016;18(1):91-8.
15. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nature genetics. 1993;4(4):398.
16. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, Hayden MR, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78(10):690-5.
17. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman J-J, et al. Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. American journal of human genetics. 1996;59(1):16.
18. McNeil SM, Novelletto A, Srinidhi J, Barnes G, Kornbluth I, Altherr MR, et al. Reduced penetrance of the Huntington’s disease mutation. Human molecular genetics. 1997;6(5):775-9.
19. Walker FO. Huntington’s disease. The Lancet. 2007;369(9557):218-28.
20. Hendricks AE, Latourelle JC, Lunetta KL, Cupples LA, Wheeler V, MacDonald ME, et al. Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27–35 CAG). American Journal of Medical Genetics Part A. 2009;149(7):1375-81.
21. Semaka A, Balneaves L, Hayden M. “Grasping the grey”: patient understanding and interpretation of an intermediate allele predictive test result for Huntington disease. Journal of genetic counseling. 2013;22(2):200-17.
22. Creighton S, Almqvist E, MacGregor D, Fernandez B, Hogg H, Beis J, et al. Predictive, pre-natal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987 to 2000. Clinical Genetics. 2003;63(6):462-75.
23. Hayden MR. Predictive testing for Huntington’s disease: the calm after the storm. The Lancet. 2000;356(9246):1944-5.
24. MacLeod R, Tibben A, Frontali M, Evers-Kiebooms G, Jones A, Martinez-Descales A, et al. Recommendations for the predictive genetic test in Huntington’s disease. Clinical Genetics. 2013;83(3):221-31.
25. Bustamante‐Aragones A, Trujillo‐Tiebas M, Gallego‐Merlo J, Rodriguez de Alba M, Gonzalez‐Gonzalez C, Cantalapiedra D, et al. Prenatal diagnosis of Huntington disease in maternal plasma: direct and indirect study. European journal of neurology. 2008;15(12):1338-44.
26. van den Oever JME, Bijlsma EK, Feenstra I, Muntjewerff N, Mathijssen IB, Bakker E, et al. Noninvasive prenatal diagnosis of Huntington disease: detection of the paternally inherited expanded CAG repeat in maternal plasma. Prenatal Diagnosis. 2015;35(10):945-9.
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27. Baig SS, Strong M, Rosser E, Taverner NV, Glew R, Miedzybrodzka Z, et al. 22 Years of predictive testing for Huntington’s disease: the experience of the UK Huntington’s Prediction Consortium. European Journal of Human Genetics. 2016:1396.
28. Ramond F, Quadrio I, Le Vavasseur L, Chaumet H, Boyer F, Bost M, et al. Predictive testing for Huntington disease over 24 years: Evolution of the profile of the participants and analysis of symptoms. Molecular Genetics & Genomic Medicine. 2019;0(0):e881.
29. Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC, Group P-HIotHS. Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biological psychiatry. 2007;62(12):1341-6.
30. Codori A-M, Brandt J. Psychological costs and benefits of predictive testing for Huntington’s disease. American Journal of Medical Genetics. 1994;54(3):174-84.
31. Kolli N, Lu M, Maiti P, Rossignol J, Dunbar G. CRISPR-Cas9 mediated gene-silencing of the mutant huntingtin gene in an in vitro model of Huntington’s disease. International journal of molecular sciences. 2017;18(4):754.
32. Shin JW, Kim K-H, Chao MJ, Atwal RS, Gillis T, MacDonald ME, et al. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Human molecular genetics. 2016;25(20):4566-76.
33. Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. The Journal of clinical investigation. 2017;127(7):2719-24.
34. Zeitler B, Froelich S, Yu Q, Pearl J, Paschon DE, Miller JC, et al., editors. Allele-specific repression of mutant Huntingtin expression by engineered zinc finger transcriptional repressors as a potential therapy for Huntington’s disease. Molecular Therapy; 2014: NATURE PUBLISHING GROUP 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA.
35. Garriga-Canut M, Agustín-Pavón C, Herrmann F, Sánchez A, Dierssen M, Fillat C, et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proceedings of the National Academy of Sciences. 2012;109(45):E3136-E45.
36. Agustín-Pavón C, Mielcarek M, Garriga-Canut M, Isalan M. Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Molecular neurodegeneration. 2016;11(1):64.
37. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. New England Journal of Medicine. 2019;380(24):2307-16.
38. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. The Lancet Neurology. 2017;16(10):837-47.
39. Dabrowska M, Juzwa W, Krzyzosiak WJ, Olejniczak M. Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases. Front Neurosci. 2018;12:75-.
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