Journal of Neurology, Neurosurgery & Psychiatry最新文献

{"title":"H44 The effects of a specific inpatient multidisciplinary rehabilitation program on postural and gait stability in huntington´s disease- a pilot study","authors":"L. Brabcová, J. Roth, O. Ulmanová, J. Rusz, J. Klempír, O. Horáček, M. Kolářová, P. Košková, P. Rolková, H. Božková, L. Szabó, M. Inemanová, K. Lísalová, F. Jančok, E. Růžička, H. Brožová","doi":"10.1136/jnnp-2018-EHDN.222","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.222","url":null,"abstract":"Background Postural and gait instability in Huntington’s disease (HD) is an essential part of the motor symptomatology causing falls which contribute to morbidity and mortality. Rehabilitation (RHB) is considered beneficial in postural and gait stability treatment. Aims We aimed to evaluate the short- and long-term effects of an inpatient multidisciplinary rehabilitation program on postural and gait stability in HD. Methods A sample of 13 subjects with HD with no severe cognitive deficit or depression underwent a 3-week specific inpatient multidisciplinary rehabilitation program focused on postural and gait stability according to a steady protocol based on typical gait and stability problems in HD. The subjects were examined at the baseline, after the completion of the RHB, and 1 month and 3 months after the program. The testing included: gait stability examination (Dynamic Gait Index; DGI), posturography examination of postural stability- Limits of Stability, tested on a stable (PSS) and 20% unstable (PSU) platform and the total motor score evaluation by Unified Huntington’s Disease Rating Scale (UHDRS). Results There was a significant 3 months lasting improvement in PSS and a significant improvement in DGI immediately after the RHB. There was no significant improvement in PSU and UHDRS total motor score. Conclusions Specific RHB methods may improve postural and gait instability in patients with early and mid-stage HD. The postural instability improvement measured by PSS persisted for at least 3 months. The gait stability improvement in DGI did not persist after 1 month. We found no improvement in PSU. This study offers a specific RHB protocol for stability training in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"88 1","pages":"A82 - A82"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79933173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"J05 Legato-hd study: a phase 2 study assessing the efficacy and safety of laquinimod as a treatment for huntington disease","authors":"R. Reilmann, M. Gordon, K. Anderson, A. Feigin, S. Tabrizi, B. Leavitt, J. Stout, P. Piccini, Gail Rynkowski, Rita Volkinshtein, J. Savola","doi":"10.1136/jnnp-2018-ehdn.265","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.265","url":null,"abstract":"Introduction Laquinimod (Teva Pharmaceuticals) is an orally active small molecule that passively enters the blood brain barrier and has been shown to upregulate BDNF secretion and modulate CNS-resident inflammatory pathways involved in pathology of HD. The LEGATO-HD study originally included three dose arms, 0.5 mg, 1.0 mg and 1.5 mg versus placebo in a 12-month multicenter double blind phase 2 study in patients with HD. Cardiovascular safety concerns were observed in multiple sclerosis studies with laquinimod doses of 1.2 mg and 1.5 mg. Although no similar concern was identified in LEGATO-HD, Teva discontinued the 1.5 mg arm in January 2016 as a precautionary safety measure and continued to evaluate the efficacy and safety of the 0.5 mg and 1.0 mg doses. Aims Evaluate the efficacy and safety of laquinimod in patients with Huntington Disease (HD). Methods Efficacy assessments include the primary endpoint, change from baseline in Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) at month 12, and the secondary endpoint, percent change in caudate volume at month 12. Safety measures include adverse event reporting, clinical laboratory tests, vital signs, ECGs, physical examinations, and suicidality (C-SSRS). Results LEGATO-HD is fully enrolled with 352 patients randomized and is expected to complete in June 2018. Baseline mean (SD) pooled demographics of enrolled patients include females n=172 (49.1%), males n=178 (50.9%), age 44.4(7.6) years, UHDRS-TMS 24.3(13.1), UHDRS-Total Functional Capacity (TFC) 11.1(1.7), and UHDRS-Functional Assessment (FA) 22.7(2.4). The results of the primary and secondary efficacy endpoints and safety measures will be presented at the conference. Conclusion There is a significant unmet medical need to ameliorate the progression of symptoms and the neurodegeneration in HD. LEGATO-HD provides valuable information towards understanding the efficacy and safety of laquinimod as a potential treatment for patients with HD. The LEGATO-HD Study is sponsored by Teva Pharmaceuticals Ltd in collaboration with HSG and EHDN and is registered as NCT02215616-clinicaltrials.gov and 2014–000418–75-EudraCT.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"31 1","pages":"A99 - A99"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79986647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H15 A multidisciplinary huntington disease clinic’s experience with the new canadian legislation allowing medical assistance in dying","authors":"Clare A. Gibbons, W. Fung, B. Henry, Sherali Esmail","doi":"10.1136/JNNP-2018-EHDN.195","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.195","url":null,"abstract":"Background On June 17, 2016 Canada passed a law making medical assistance in dying (MAID) legal. To be eligible for MAID, the requestor must have a serious illness, be in an advanced state of decline that cannot be reversed, be experiencing unbearable physical or mental suffering that cannot be relieved and natural death must be reasonably foreseeable. The requestor also needs the mental competency to be able to give informed consent which requires an understanding of their medical diagnosis, available forms of treatments and options available to relieve suffering. Under the current legislation, advanced directives are not permitted for MAID requests. Cases: Case 1 – A 34 year old with moderate/severe motor symptoms and mild cognitive impairment. This individual experienced significant decline of ADLs over the past two years. All MAID requirements were met and MAID was completed. Case 2 – A 72 year old with moderate motor symptoms and declining cognitive abilities. This individual expressed an interest having MAID in the near future when quality of life deteriorated. Case 3 – A 48 year old with severe motor symptoms and significant cognitive impairment. For the past ten years, this individual has expressed the plan to pursue medical assisted death but was not able to fulfil the capacity requirements at the time of the MAID request. Case 4 – A 54 year old with mild motor symptoms and mild cognitive impairment. Last year, this individual sustained an injury that affected mobility and quality of life. The individual requested MAID and met the requirements but changed the scheduled date for MAID twice. Conclusion These cases highlight the clinical and emotional challenges for patients, families and professional staff related to assessing the MAID eligibility criteria of being in an advanced state of decline with reasonably foreseeable death while still possessing the cognitive ability needed to request and consent to MAID.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"46 1","pages":"A73 - A73"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83752810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"F49 Machine learning approach in analysis of enroll-hd data for suicidality prediction in huntington disease","authors":"Y. Seliverstov, A. Borzov, E. Duijn, B. Landwehrmeyer, M. Belyaev","doi":"10.1136/jnnp-2018-EHDN.152","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.152","url":null,"abstract":"Background Suicidal ideation and suicidal behaviour are frequently reported, severe features in Huntington disease gene expansion carriers (HDGECs), but it is difficult to predict who are at increased risk. So far, no suicidality prediction models have been developed using machine learning approach (MLA). Objective To develop a model for prediction of suicidal ideation or suicidal behaviour in HDGEC based on Enroll-HD data using MLA. Design/methods We have developed a prediction model based on MLA using the third Enroll-HD study periodic dataset (PDS3). Suicidal ideation/behaviour was measured with the Columbia-Suicide Severity Rating Scale (C–SSRS). HDGECs with no or ‘passive’ suicidal ideations [state 1] at their first visit, who at the follow-up (FUP) either stayed in state 1 or worsened to ‘active’ suicidal ideations and/or suicidal behaviour [state 2] were analyzed. The PBAs scale was used to assess the presence of behavioural symptoms. Prediction algorithm was based on Boosted Trees (implementation from XGBoost Library for Python) and contained 48 variables from the PDS3. We also used Fisher Exact test, Mann–Whitney U-test, and Holm method. Results For 377 HDGECs (114 pre-manifest; 161 males; median age 50 [20;78]; median nCAG=43 [38;65]) C-SSRS data of two consecutive visits were available. At the FUP, 316 remained in state 1 and 61 HDGECs had worsened to state 2. Sixty four percent of the HDGECs who remained in state 1 at FUP were accurately classified (probability as having state 2 <30%). HDGECs who worsened to state 2 were correctly predicted in 38% cases (probability of being classified as having state 2 >60%). We then compared the poorly (probability <30%; 31 subjects) with the well (probability >60%; 23 subjects) classified groups in state 2 at FUP and found significant difference in the PBAs total scores for depression, anxiety, aggression, and apathy, with more severe baseline scores in the well classified HDGECs. However, regression analysis did not show a significant relationship of these behavioural symptoms and the probability of being classified as subject in state 2 at FUP. Conclusions Our model showed moderate accuracy. Further research is needed to understand the risk for development of suicidal ideation/behaviour in HDGECs with mild behavioural symptoms.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"50 1","pages":"A57 - A57"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85170867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H24 Continuous professional development in hd: learning to support and empower families","authors":"L. McCabe, J. Eden","doi":"10.1136/jnnp-2018-EHDN.203","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.203","url":null,"abstract":"In partnership Scottish Huntington’s Association and Stirling University developed a Continuous Professional Development Module which delivers 200 hours of blended learning in HD. The course takes the unique approach if integrating family stories and experiences with five models of care: person centred, family systems, biopsychosocial, personalisation and palliative care. The course focuses on the lived experience of HD and how these models can assist health and social care practitioners to support and enable families to enhance their quality of life. The module won the Scottish Council for Voluntary Organisations Award for best partnership in 2015 and we are currently working with Lancashire University to extend the course to practitioners in England and Wales.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A76 - A76"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73456115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"F56 Psychiatric symptoms in huntington’s disease: relationship to disease stage in the CAPIT-HD2 beta-testing study","authors":"I. Mcmillan, D. McLauchlan, M. Busse, A. Bachoud-Lévi, R. Reilmann, A. Rosser, D. Craufurd","doi":"10.1136/jnnp-2018-EHDN.157","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.157","url":null,"abstract":"Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to functional impairment. Low mood, anxiety and irritability can all occur many years before motor onset, but are also common in the general population. Apathy and perseveration (repetitive thinking or behavior) can occur before motor onset, but usually appear after diagnosis and are worst from stage 3 onwards. Previous studies have found that apathy correlates with motor and cognitive measures of disease progression, while the mood disorder does not. Methods One of the objectives of the Repair-HD study was to develop and validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes a psychiatric interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures. The 12-month follow-up is now complete and analysis underway. We report a preliminary analysis of data from the baseline psychiatric measures. Results Cases (N=73) and controls (N=50) differed significantly for PBA-s apathy (p<0.001), anger (p<0.05), repetitive behavior (p<0.001), modified total PBA score (mPBA) (p<0.001) and the extended 7-item PBA-s composite apathy score (p<0.001), but not for the composite affect score. In patients, Total Functional Capacity (TFC) scores correlated significantly with apathy (rs=−0.415, p<0.001), composite apathy (rs=−0.459, p<0.01), repetitive behaviours (rs=−0.326, p<0.01) and mPBA (rs=−0.265, p<0.05), but not the affect or anger scores. Significant differences between cases and controls and significant correlations with TFC scores were also found with the Apathy subscale of the Frontal Systems Behaviour Scale (FrSBe) and the Apathy Evaluation Scale (AES), but not with PRO measures of anxiety, depression or irritability. Conclusions This preliminary analysis confirms that apathy and perseveration correlate with disease stage, while disorders of mood (depression and anxiety) and irritability are more variable over time, and from person to person. This may reflect the complex aetiology of affective symptoms, involving psychological variables and variation in genetic susceptibility as well as HD. Symptomatic treatment with antidepressants may also mask any relationship with disease progression.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"127 1","pages":"A59 - A59"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72863557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"I05 Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of huntington disease minipigs mediated by AAV5-MIHTT gene therapy","authors":"Astrid Valls, C. Brouwers, Roberta Pintauro, J. Snapper, B. Bohuslavova, Marina Sogorb-González, V. Fodale, A. Bresciani, Z. Ellederová, B. Blits, J. Motlík, S. Deventer, M. Evers, P. Konstantinova","doi":"10.1136/jnnp-2018-EHDN.241","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.241","url":null,"abstract":"Background HTT-lowering therapies hold great promise to slow-down or halt neurodegeneration in Huntington disease (HD). We have developed an engineered microRNA targeting human huntingtin (HTT), delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT), leading to efficient HTT-lowering in vitro and in vivo in rodent models. Aim To assess the translatability of our approach in a large animal model: transgenic HD (tgHD) minipigs. Methods Animals were injected with AAV5-miHTT (1.2 × 1013 gc/brain), bilaterally into striatum (caudate and putamen) and sacrificed 6 months post-treatment. Across different brain regions, vector DNA, miHTT and mutant HTT (mHTT) mRNA were measured by Q-PCR, and mHTT protein using an ultrasensitive immunoassay. In longitudinal cerebrospinal fluid (CSF) samples, miHTT and mHTT protein expression were assessed by Q-PCR and ultrasensitive immunoassay, respectively. Results Widespread brain biodistribution of vector DNA was observed, with the highest levels in target (striatal) regions but also in thalamus and cortical regions, in both grey and white matter. Expression of miHTT was highly correlated with vector DNA in all brain areas. Corresponding to the vector DNA and miHTT expression, a reduction of mHTT mRNA and protein was observed in AAV5-miHTT treated animals with respect to controls. mHTT protein lowering was on average more than 75% in the injected areas, and between 30–50% in most of the distal regions. Translational pharmacokinetic and pharmacodynamic measures in the CSF were in line with the effects observed in the brain. We detected CSF miHTT, and CSF mHTT protein lowering up to 50% at 3 and 70% at 6 months post-dosing. Conclusions This study demonstrates widespread biodistribution and durable efficiency of AAV5-miHTT in disease-relevant regions in a large brain, and the potential of CSF translational measures to follow-up efficacy.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"35 1","pages":"A89 - A90"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76654298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H02 Outcome mapping for care delivery interventions for huntington’s disease patients in the community","authors":"D. Rae, A. McDermott, Z. Miedzybrodzka, K. Gillies","doi":"10.1136/jnnp-2018-EHDN.183","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.183","url":null,"abstract":"Background The production of meaningful evidence about the effectiveness of complex care delivery interventions requires clear definition and consistent use of outcomes that matter to key stakeholders (service users and professionals). Outcomes for the evaluation of such interventions in multifaceted neurodegenerative progressive conditions, such as Huntington’s disease (HD) have not been previously reviewed. Objective The objectives of this article are 1) to comprehensively map outcomes reported in the existing literature on care delivery interventions in HD and 2) to identify any convergences/divergences in patterns and stakeholder perspectives across the identified outcomes. Main results A total of 16 studies and supplementary documents were identified measuring 48 outcomes. These were categorised into three outcome categories, 34 outcome types and 47 variables. Only two outcome types, ’Specialist Knowledge and understanding’ and ’Confidence’, previously suggested by service users as important (n=10) were considered in formal care delivery evaluations. Conclusion A large number of outcomes are currently measured and suggested in the evaluation and description of care delivery in HD. This outcome map highlights the inconsistent use of outcomes important to and suggested by key stakeholders. Clear understanding of what intervention mechanisms and interactions may be relevant (and to whom) and produce desired outcomes is missing in existing literature.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"172 1","pages":"A69 - A69"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85564308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A54 The role of excitotoxicity for neuropathology in the lateral hypothalamus in mouse models of huntington disease","authors":"J. Henningsen, Barbara Baldo, M. Björkqvist, Å. Petersén","doi":"10.1136/jnnp-2018-EHDN.52","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.52","url":null,"abstract":"Background In Huntington disease (HD), the typical motor symptoms are associated with selective degeneration of striatal neurons. Importantly, non-motor aspects develop earlier and include changes in sleep and circadian rhythm, metabolic dysfunction and psychiatric symptoms. Recent studies point to selective vulnerability also of the lateral hypothalamic area (LHA) in HD, which may mediate several of the non-motor features of HD. Excitotoxicity, i.e. excessive glutamate signaling, has been linked to striatal degeneration in HD. Similar to the striatum, LHA receives glutamatergic synaptic inputs and excitotoxicity could thus be an important driving force in the development of LHA neuropathology. Aims The aim of the study is to determine if excitotoxicity plays a role in the development of LHA neuropathology. Methods Quantitative real time polymerase chain reaction (qRT-PCR) was used to assess mRNA levels of different components of the glutamate signaling machinery in the LHA of tissue dissected from the transgenic R6/2 and the BACHD mouse models as well as from mice expressing mutant huntingtin selectively in the hypothalamus using an adeno-associated viral vector approach. Vulnerability to exposure of intra-hypothalamic injections of the excitotoxin quinolinic acid was moreover evaluated in the same HD mouse models. Results We detected changes in mRNA levels of several markers involved in glutamate signaling in the LHA. In our model of LHA excitotoxicity, we found that neurons expressing melanin concentrating hormone but not orexin were sensitive to excitotoxicity. Interestingly, orexin neurons in the R6/2 mouse model displays increased sensitivity to excitotoxicity. Conclusions Excitotoxicity may play a role in the vulnerability of orexin neurons to the expression of mutant huntingtin in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"34 1","pages":"A19 - A20"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88160542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C07 Intergenerational cag stability across chromosome 4 haplogroups","authors":"J. Sipilä, S. Ylönen, K. Majamaa","doi":"10.1136/jnnp-2018-EHDN.78","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.78","url":null,"abstract":"Background Variation in the prevalence of Huntington’s disease (HD) is associated with differences in chromosome 4 haplogroup proportions between populations. No data have been published on mutant HTT (mHTT) repeat stability in different haplogroups. Aim To study intergenerational CAG repeat stability in different mHTT haplotypes. Methods A previously identified Finnish cohort of 207 HD patients and data on mHTT repeat lengths obtained from the diagnostic laboratories were used as a basis to identify parent-offspring pairs using several national registries. DNA remaining from diagnostic testing was analysed to determine haplogroups defined by the SNPs rs762855 and rs4690073. Haplogroup A haplotypes were further defined using four additional SNPs, rs2857936, rs363096, rs2276881 and rs362307. (Warby et al. 2009) The SNPs were determined either with restriction fragment analysis, allele specific amplification using locked nucleic acid primers or by sequencing. Results mHTT haplogroup and CAG repeat could be phased in 49 transmissions (haplogroup A, 38; haplogroup C, 10; other haplogroup, 1). The mean change in the length of CAG repeats differed between haplogroups A and C in paternal inheritances (p=0.038), but not in maternal inheritances (p=0.17). The change in haplogroup C was negative in paternal as well as maternal transmissions (p=0.74 for difference; figure 1), whereas the repeats in haplogroup A expanded in paternal transmissions in comparison to maternal transmissions (p=0.008). The difference was most obvious in haplotype A1 inheritances (p=0.022).Abstract C07 Figure 1 The mean change (%) in the length of CAG repeats in haplogroups A and C in paternal and maternal transmissions Conclusions Intergenerational stability of the CAG repeat differed between mHTT haplogroups in a sex-dependent manner.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A29 - A29"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88633748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}