MODERATED POSTER SESSION: Don't look only at the left ventricule: Wednesday 3 December 2014, 09:00-16:00 * Location: Moderated Poster area

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SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study

Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome

Auditory hedonic phenotypes in dementia: A behavioural and neuroanatomical analysis

Patients with dementia may exhibit abnormally altered liking for environmental sounds and music but such altered auditory hedonic responses have not been studied systematically. Here we addressed this issue in a cohort of 73 patients representing major canonical dementia syndromes (behavioural variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA) amnestic Alzheimer's disease (AD)) using a semi-structured caregiver behavioural questionnaire and voxel-based morphometry (VBM) of patients' brain MR images. Behavioural responses signalling abnormal aversion to environmental sounds, aversion to music or heightened pleasure in music (‘musicophilia’) occurred in around half of the cohort but showed clear syndromic and genetic segregation, occurring in most patients with bvFTD but infrequently in PNFA and more commonly in association with MAPT than C9orf72 mutations. Aversion to sounds was the exclusive auditory phenotype in AD whereas more complex phenotypes including musicophilia were common in bvFTD and SD. Auditory hedonic alterations correlated with grey matter loss in a common, distributed, right-lateralised network including antero-mesial temporal lobe, insula, anterior cingulate and nucleus accumbens. Our findings suggest that abnormalities of auditory hedonic processing are a significant issue in common dementias. Sounds may constitute a novel probe of brain mechanisms for emotional salience coding that are targeted by neurodegenerative disease

Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

A (GGGGCC) n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10 e−4 ) but our results suggested that the association was mainly driven by age at collection (p < 10 e−4 ). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

Principes de prise en charge des fentes labio-maxillo-palatines unilatérales totales Propositions de protocole

Les fentes unilatérales totales, résultant d'un rendez-vous manqué entre bourgeon nasal interne et bourgeon nasal externe, sont responsables d'un déséquilibre à la fois des structures superficielles et profondes de la face. Les auteurs, après avoir résumé les principes qui doivent guider la prise en charge de ces anomalies, exposent leur protocole thérapeutique où s'associent étroitement orthopédie et chirurgie. Ils concluent sur les difficultés d'apprécier les résultats définitifs en raison de l'extrême diversité des séquelles obligatoires

Confidence level and feeling of knowing for episodic and semantic memory: an investigation of lorazepam effects on metamemory

The effects of lorazepam (0.026 or 0.038 mg/kg), a benzodiazepine, and of a placebo on metamemory. i.e. knowledge about one's own memory capabilities, were investigated in 36 healthy volunteers. Accuracy of confidence levels (CL) in the correctness of recalled answers and accuracy of feeling of knowing (FOK) the answers when recall fails were measured using a sentence memory task assessing episodic memory and a task consisting of general information questions and assessing semantic memory. Lorazepam impaired episodic memory. Unexpectedly, it also impaired performance in both the recall and recognition phases of the task assessing semantic memory, suggesting that it decreased the ability to distinguish between correct and incorrect information. In episodic memory, lorazepam 0.038 mg/kg-treated subjects exhibited an impaired CL accuracy, compared to placebo-treated subjects, and their FOK accuracy was at chance. In semantic memory. their overall CL and FOK accuracy was apparently spared. However. these subjects selectively overestimated their CL judgements for incorrect answers; moreover, secondary analyses showed that FOK accuracy for a subset of low-accuracy items was virtually nil. These results suggest that lorazepam impairs metamemory for both episodic and semantic memory

A Stepwise Approach to the Management of Postinfarct Ventricular Tachycardia Using Catheter Ablation as the First-Line Treatment: A Single-Center Experience

International audienceBACKGROUND:The occurrence of ventricular tachycardia (VT) after myocardial infarction is associated with poorer prognosis. In such patients, implantable cardioverter-defibrillators are recommended. Catheter ablation of VT is currently recommended only as an adjunctive therapy. Whether a successful VT ablation alone might be a viable strategy in some of these patients, however, remains unknown. The aim of the present study was to evaluate this strategy.METHODS AND RESULTS:Between January 2002 and December 2011, 189 patients with cardiomyopathy underwent 259 VT ablations in our center. Forty-five patients (mean age, 65.2±9.6 years; 91% men) with a history of myocardial infarction and mean left ventricular ejection fraction of 39.7±9.7% matched the study criteria and were included in this analysis. Acute success was obtained in 40 of 45 patients (88.9%). During a follow-up, on the basis of our stepwise algorithm (using acute success, repeat electrophysiological study, and recurrence of VT), 19 of 45 patients (42.2%) underwent implantable cardioverter-defibrillators implantation. During a median follow-up of 4.5 (interquartile range, 2.1-7.0) years, all-cause mortality occurred in 14 of 45 patients (31.1%). Using multivariate Cox regression analysis, age (hazard ratio, 1.13; 95% confidence interval, 1.03-1.22; P=0.007) was the only independent predictor of mortality, whereas implantable cardioverter-defibrillators implantation was not (hazard ratio, 0.54; 95% confidence interval, 0.18-1.64; P=0.28)CONCLUSIONS:Our results suggest that a stepwise approach to the management of VT with ablation as a first-line treatment in postinfarct patients presenting with VT might be a reasonable option. Further studies are required to confirm these results