Caractérisation des troubles respiratoires dans l'atrophie multisystématisée (étude de la souris à l'homme)

INTRODUCTION : L'atrophie multisystématisée (AMS) est une maladie neurodégénérative au cours de laquelle une dysrythmie respiratoire de Cheyne Stokes (RCS, patron respiratoire répétitif crescendo/decrescendo) et des troubles respiratoires diurnes ont été décrits. L'origine de ces troubles respiratoires demeure inconnue même si une perte neuronale des centres respiratoires pontiques du complexe de pre-Bötzinger et du Raphé médullaire a été observée. OBJECTIFS : Réalisation d'une étude exploratrice des troubles respiratoires diurnes et nocturnes dans l'AMS. Parallèlement, caractérisation respiratoire fonctionnelle et neuropathologique d'un modèle murin transgénique d'AMS (PLPaSYN) reproduisant les inclusions oligodendrogliales d'alpha-synucléine spécifiques de la maladie. MATERIEL ET METHODE : 22 polygraphies diurnes et nocturnes ont été obtenues chez 23 patients AMS. Parallèlement, la variabilité respirtoire (score d'irrégularité et coefficient de variation) en pléthysmographie de 7 souris PLPaSYN a été comparée à celle de 5 souris sauvages (C-57), avant sacrifice pour comptage stéréologique des neurones du Raphé médullaire et du complexe de pre-Bötzinger. RESULTATS : Chez l'homme, une RCS a été détectée chez 45,5 % des patients, avec une majoration du nombre de désaturations et de cycles entre le jour et la nuit. Chez la souris PLPaSYN, la variabilité respiratoire et la perte neuronale au niveau de Raphé médullaire est supérieure à celles des souris C-57. conclusion : La RCS est une caractéristique des troubles respiratoires diurnes et nocturnes dans l'AMS. Chez la souris PLPaSYN, la présence d'une dysrythmie respiratoire et d'une neurodégénérescence du Raphé médullaire en font un modèle d'étude des troubles respiratoires dans l'AMS. Le suivi de nos cohortes et l'amélioration de la concordance homme/souris permettront de préciser la valeur pronostique d'une RCS et de tester les stratégies thérapeutiques chez la souris avant l'homme.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Multiple system atrophy: current and future approaches to management

Multiple system atrophy (MSA) is a rare neurodegenerative disorder without any effective treatment in slowing or stopping disease progression. It is characterized by poor levodopa responsive Parkinsonism, cerebellar ataxia, pyramidal signs and autonomic failure in any combination. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure. However, symptomatic management remains disappointing and no curative treatment is yet available. Recent experimental evidence has confirmed the key role of alpha-synuclein aggregation in the pathogenesis of MSA. Referring to this hypothesis, transgenic and toxic animal models have been developed to assess candidate drugs for MSA. The standardization of diagnosis criteria and assessment procedures will allow large multicentre clinical trials to be conducted. In this article we review the available symptomatic treatment, recent results of studies investigating potential neuroprotective drugs, and future approaches for the management in MSA

Functional classification of ATM variants in ataxia-telangiectasia patients.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification

Convergence of patient- and physician-reported outcomes in the French National Registry of Facioscapulohumeral Dystrophy

International audienceFacioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials and standards of care. National FSHD registries have been set up to this end. The French National Registry of FSHD combines a clinical evaluation form (CEF) and a self-report questionnaire (SRQ), filled out by a physician with expertise in neuromuscular dystrophies and by the patient, respectively. Aside from favoring recruitment, our strategy was devised to improve data quality. Indeed, the pairwise comparison of data from 281 patients for 39 items allowed for evaluating data accuracy. Kappa or intra-class coefficient (ICC) values were calculated to determine the correlation between answers provided in both the CEF and SRQ. Results Patients and physicians agreed on a majority of questions common to the SRQ and CEF (24 out of 39). Demographic, diagnosis- and care-related questions were generally answered consistently by the patient and the medical practitioner (kappa or ICC values of most items in these groups were greater than 0.8). Muscle function-related items, i.e. FSHD-specific signs, showed an overall medium to poor correlation between data provided in the two forms; the distribution of agreements in this section was markedly spread out and ranged from poor to good. In particular, there was very little agreement regarding the assessment of facial motricity and the presence of a winged scapula. However, patients and physicians agreed very well on the Vignos and Brooke scores. The report of symptoms not specific to FSHD showed general poor consistency. Conclusions Patient and physician answers are largely concordant when addressing quantitative and objective items. Consequently, we updated collection forms by relying more on patient-reported data where appropriate. We hope the revised forms will reduce data collection time while ensuring the same quality standard. With the advent of artificial intelligence and automated decision-making, high-quality and reliable data are critical to develop top-performing algorithms to improve diagnosis, care, and evaluate the efficiency of upcoming treatments

Successful Thrombectomy Improves Functional Outcome in Tandem Occlusions with a Large Ischemic Core

International audienceBackground: Emergent stenting in tandem occlusions and mechanical thrombectomy (MT) of acute ischemic stroke related to large vessel occlusion (LVO-AIS) with a large core are tested independently. We aim to assess the impact of reperfusion with MT in patients with LVO-AIS with a large core and a tandem occlusion and to compare the safety of reperfusion between large core with tandem and nontandem occlusions in current practice. Methods: We analyzed data of all consecutive patients included in the prospective Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and March 2023 who presented with a pretreatment ASPECTS (Alberta Stroke Program Early CT Score) of 0–5 and angiographically proven tandem occlusion. The primary end point was a favorable outcome defined by a modified Rankin Scale (mRS) score of 0–3 at 90 days. Results: Among 262 included patients with a tandem occlusion and ASPECTS 0–5, 203 patients (77.5%) had a successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3). Reperfused patients had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR], 1.57 [1.22–2.03]; P < 0.001), higher rates of mRS score 0–3 (aOR, 7.03 [2.60–19.01]; P < 0.001) and mRS score 0–2 at 90 days (aOR, 3.85 [1.39–10.68]; P = 0.009) compared with nonreperfused. There was a trend between the occurrence of successful reperfusion and a decreased rate of symptomatic intracranial hemorrhage (aOR, 0.5 [0.22–1.13]; P = 0.096). Similar safety outcomes were observed after large core reperfusion in tandem and nontandem occlusions. Conclusions: Successful reperfusion was associated with a higher rate of favorable outcome in large core LVO-AIS with a tandem occlusion, with a safety profile similar to nontandem occlusion