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DM1 is characterized by a multisystemic involvement. Our objective was to determine the proportion of adequate follow-up for each affected organ in DM1 patients based on the recently published American and Spanish recommendations. To this end, we conducted a descriptive cross-sectional survey by phone in adult, genetically proven DM1 patients followed in the two French neuromuscular centers of Bayonne and Hendaye located in South Aquitaine, France. The questionnaire selected the most stringent criteria of the two international recommendations for each item of follow-up. Seventy-three patients were included, 55% of which were women (mean age of 48 years) with an average number of 467 CTG repeats. The proportion of patients receiving clinical follow-up in accordance with the recommendations was 90% in cardiology, 60% in neurology, 68% in ophthalmology, 53% in physiotherapy, 23% in pneumology, and 12% in rehabilitation. The high rate of neurological, cardiological, and ophthalmological monitoring might be explained by a locally dense medical demography whereas low rate of respiratory follow up and rehabilitation may reflect an incomplete knowledge of both the disease and the questionnaire. These results should be carefully interpretated as cognitive status may influence such a declarative study. Our study nevertheless disclosed important disparities according to the recommended multidisciplinary follow-up criteria in this French cohort of adult DM1 patients. These results highlight the major role of a multidisciplinary care and monitoring in DM1.

DM1 is characterized by a multisystemic involvement. Our objective was to determine the proportion of adequate follow-up for each affected organ in DM1 patients based on the recently published American and Spanish recommendations. To this end, we conducted a descriptive cross-sectional survey by phone in adult, genetically proven DM1 patients followed in the two French neuromuscular centers of Bayonne and Hendaye located in South Aquitaine, France. The questionnaire selected the most stringent criteria of the two international recommendations for each item of follow-up. Seventy-three patients were included, 55% of which were women (mean age of 48 years) with an average number of 467 CTG repeats. The proportion of patients receiving clinical follow-up in accordance with the recommendations was 90% in cardiology, 60% in neurology, 68% in ophthalmology, 53% in physiotherapy, 23% in pneumology, and 12% in rehabilitation. The high rate of neurological, cardiological, and ophthalmological monitoring might be explained by a locally dense medical demography whereas low rate of respiratory follow up and rehabilitation may reflect an incomplete knowledge of both the disease and the questionnaire. These results should be carefully interpretated as cognitive status may influence such a declarative study. Our study nevertheless disclosed important disparities according to the recommended multidisciplinary follow-up criteria in this French cohort of adult DM1 patients. These results highlight the major role of a multidisciplinary care and monitoring in DM1.

Introduction Le diagnostic de la maladie de Creutzfeldt-Jakob sporadique (MCJS) repose sur des criteres cliniques et paracliniques (Zerr et al., 2009) qui, biologiquement, n’incluent que la detection de la proteine 14-3-3. Observation Nous rapportons un cas de MCJS, chez une patiente de 88 ans. Trois ans auparavant on notait une apraxie melokinetique, puis ideomotrice hemi-corporelle gauche, puis une extinction sensitive et des troubles dysexecutifs suivis de myoclonies proximales des membres superieurs qui la conduisent a l’hopital. L’IRM met en evidence des hypersignaux corticaux (dans 4 lobes), s’etendant progressivement en frontal gauche. A 3 reprises, l’analyse du LCR est negative pour la proteine 14-3-3. On retient une elevation moderee de la proteine Tau (a 786 puis 929 pour une normale inferieure a 512 pg/ml) et une baisse de l’Aβ1-42. La recherche d’une mutation du gene Prion est negative. Il existe une homozygotie Met/Met sur le codon 129. La methode « Real-Time Quaking Induced Conversion » (RT-QuIC) pour la proteine prion, realisee lors de la 3e PL, revient positive. Discussion La patiente ne presente pas les criteres cliniques d’une MCJS, mais l’IRM est tres tot evocatrice. Le diagnostic retenu est celui d’une MCJS d’evolution lente susceptible d’expliquer l’absence detection de la proteine 14-3-3, malgre une specificite de 98 % et une sensibilite de 90 %. Le meilleur test semble la methode RT-QuIC (d’une specificite proche de 100 % pour une sensibilite de 80-96 %). Conclusion En absence de criteres cliniques et biologiques suffisants, l’utilisation de methode RT-QuIC nous a permis de confirmer le diagnostic de MCJS. Elle constitue, en cas de doute, un examen essentiel.

Un appel du vendredi soir pour une patiente en coma calme, mais qui voit double… la perspective d’un week-end agite pour le neurologue d’astreinte en CHG.

Introduction Quinze cas d’œdemes cerebelleux (OC) attribues a une hypomagnesemie (HypoMg) ont ete rapportes dans la litterature. Les signes neurologiques apparaissent en regle pour un taux inferieur a 0,5 mMoles/L (N > 1). Objectifs Decrire les caracteristiques cliniques, biologiques et radiologiques de 7 patients hospitalises au centre hospitalier de la Cote Basque qui presentaient l’association d’un OC et d’une HypoMg. Patients et methodes Il s’agit d’une etude retrospective (2013–2020) realisee au moyen du codage informatique de l’activite medicale, en recherchant parmi les patients avec HypoMg, ceux qui presentaient un OC, defini par un hypersignal des hemispheres cerebelleux en FLAIR, avec elevation du coefficient de diffusion. L’analyse des dossiers cliniques a permis d’analyser la semiologie neurologique, l’aspect radiologique et les etiologies. Resultats Parmi 69 patients presentant une HypoMg, sept (10 %) avaient un OC bilateral. Ils etaient âges de 52 a 79 ans, presentaient une ataxie statique et cinetique (5/7), une dysarthrie (2/7) ou une hypovigilance (1/7). Deux patients avaient un hypermetabolisme cerebelleux (PET et SPECT). Les causes etaient parfois multiples, surtout digestives (5/7) et iatrogenes (4/7). Apres supplementation en Mg, l’evolution fut favorable 4 fois sur 7 (2 deces lies aux comorbidites, 1 perdu de vue). Discussion Le lien entre HypoMg et OC n’est connu que depuis 2011. La correction de l’hypoMg permet la disparition rapide des signes cliniques et anomalies IRM, mais le diagnostic est parfois difficile en l’absence de dosage systematique du Magnesium. Une fuite d’origine digestive ou renale, et la prise d’inhibiteurs des pompes a protons sont les causes les plus frequentes. Conclusion Le dosage du magnesium serique doit etre systematique devant un syndrome cerebelleux et/ou un OC bilateral en IRM, car l’HypoMg est une cause curable et rapidement reversible.

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.

Objective To assess the diagnostic accuracy of portable polygraphy (PG) for the detection of sleep apnea (SA) in multiple system atrophy (MSA). Methods Thirty consecutive patients with probable MSA underwent PG (overnight recording of nasal flow, thoracic/abdominal movements and pulse oximetry), followed 4 weeks later by full polysomnography (PSG) (reference standard). The accuracy of PG was first assessed using the same threshold as for PSG (apnea–hypopnea index [AHI] ⩾ 5), then for all possible AHI thresholds using the area under the receiver operating characteristics (AUROC) curve. Inter-rater reliability of PG was assessed using the kappa coefficient. Results Among 30 patients enrolled, seven were excluded for technical problems on PG or PSG and 23 were included in the main analysis. Eight out of 23 had an AHI ⩾ 5 on PSG. With the same threshold, sensitivity, specificity, positive and negative predictive values of PG for the diagnosis of SA were 87.5% (95% confidence interval: 47–99), 80% (52–96), 70% (35–93) and 92.3% (64–99), respectively. The kappa between PG raters was 0.75 (0.49–1.00) indicating good agreement. The AUROC was 0.93 (0.82–1.00). No association was found between sleep and excessive daytime sleepiness questionnaires and SA. Conclusion Portable PG seems to be valuable for ruling out SA in MSA.

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild-type α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were compared with age-matched controls. Using whole-body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP-αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative correlation between α-synuclein burden and raphe pallidus cell counts (P < 0.05). There was no significant neuronal loss in the pre-Botzinger complex. The PLP-αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA.

Introduction Sleep apnea is very frequent in multiple system atrophy (MSA) and may contribute to the poor prognosis. The aim of the present study was to prospectively assess the relation between sleep apnea and survival in 30 consecutive MSA patients recruited at the French Reference Center for MSA. Methods Patients with “probable” MSA according to current consensus diagnosis criteria were enrolled in this prospective cohort study. All patients received full polysomnography at baseline and were then followed for up to 4.5 years. The prognostic role of sleep apnea was assessed by a Cox model in an univariate analysis and then adjusted on other potential factors. Results Analyzable polysomnographic recordings were available for 28 patients. Sleep apnea was found in 11 patients. During follow-up, 15 patients died, including 9 with baseline sleep apnea. In an univariate analysis, sleep apnea, Unified MSA Rating Scale I + II score at baseline and at year one, and disease duration were associated with mortality. However, when adjusting for disease duration and baseline Unified MSA Rating Scale score, the association between sleep apnea and mortality was no longer significant. Conclusions Sleep apnea was not an independent factor associated with mortality in this prospective cohort study.

Introduction Distincte de l’angiopathie amyloide, l’amylose AL intracerebrale sans hemopathie est exceptionnelle. L’efficacite du lenalidomide dans cette indication n’a pas ete etudiee, nous rapportons 3 cas. Observation Trois femmes de 45, 56 et 64 ans presentaient des troubles neurologiques varies d’allure centrale et d’installation progressive : troubles visuels et syndrome pyramidal gauche pour la premiere, hemiparesie droite pour la seconde, crise partielle complexe temporale droite chez la troisieme. Les imageries par resonance magnetique (IRM) cerebrales montraient chez ces 3 patientes des hypersignaux fluid-attenuated inversion-recovery (FLAIR) en region occipitale et fronto-insulaire droite dans le premier cas, capsulo-thalamique et centre semi-ovale gauche dans le deuxieme cas et temporale droite pour le troisieme. On notait surtout des prises de contraste inhabituelles des espaces perivasculaires et leptomeningees au sein de ces lesions. Les explorations systemiques ne montraient pas d’orientation et une biopsie cerebrale etait realisee chez ces 3 patientes, confirmant des depots monotypiques d’amylose a chaine legere d’immunoglobulines (amylose AL). Il n’y avait pas d’hemopathie associee et les dosages circulants de chaines legeres etaient normaux. Les 3 patientes furent traitees par lenalidomide et dexamethasone en cures mensuelles, avec une stabilisation clinique a 2 ans et une diminution des prises de contraste a l’IRM chez 2 sur 3. Discussion Nous presentons 3 cas d’amylose AL intracerebrale pour lesquels le traitement par lenalidomide pourrait etre efficace. Ces cas doivent etre differencies des autres formes d’amylose cerebrale AL associees aux tumeurs, qu’il s’agisse du lymphome primitif avec differentiation plasmocytaire et du plasmocytome solitaire intracerebral, ou d’autres formes plus diffuses d’amylose vasculaire sous-corticale avec leucopathie. Conclusion La forme intracerebrale d’amylose AL sans hemopathie est une entite rare et d’evolutivite incertaine. Le lenalidomide pourrait etre efficace dans sa prise en charge therapeutique. Informations complementaires Cette etude n’a beneficie d’aucun financement particulier, public ou prive.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

MSA is a progressive neurodegenerative disorder characterized by autonomic failure and a variable combination of poor levodopa-responsive parkinsonism and cerebellar ataxia (CA). Current therapeutic management is based on symptomatic treatment. Almost one third of MSA patients may benefit from l-dopa for the symptomatic treatment of parkinsonism, whereas physiotherapy remains the best therapeutic option for CA. Only midodrine and droxidopa were found to be efficient for neurogenic hypotension in double-blind, controlled studies, whereas other symptoms of autonomic failure may be managed with off-label treatments. To date, no curative treatment is available for MSA. Recent results of neuroprotective and -restorative trials have provided some hope for future advances. Considerations for future clinical trials are also discussed in this review.

Introduction La presence de microbleeds sous-corticaux est evocatrice, apres 55 ans, d’une angiopathie amyloide (AA). Celle-ci peut se reveler par la survenue d’une angeite inflammatoire reactionnelle (a-beta-related angiitis ou ABRA). Objectifs Evaluer la frequence des formes inflammatoires d’AA, au sein du recrutement hospitalier et de la consultation memoire d’un CHG. Methodes Etude retrospective sur la periode de 2008 a 2014. Nous avons recense tous les cas d’AA, sur la base du codage des pathologies (PMSI) et etendu notre recherche aux cas de demences vasculaires recenses dans la base de donnees Calliope (consultations « memoire »). Afin de verifier le diagnostic d’AA, nous avons applique les criteres de Boston modifies et les criteres proposes par Chung et al. pour le diagnostic d’ABRA. Resultats Soixante-huit cas d’AA probables et 2 cas d’AA possibles furent recenses, a partir du PMSI, ainsi que 35 autres cas d’AA probables, a partir des 156 cas de demences vasculaires issus de la base de donnees Calliope. Parmi eux, 6 cas d’ABRA furent identifies. Les signes d’appel etaient les suivants : crises comitiales (2 cas), confusion/troubles du langage (2 cas), cephalees/gene visuelle (1 cas) et confusion/trouble visuel (1 cas). L’evolution a toujours ete spontanement favorable. Discussion La frequence de l’ABRA n’est pas connue. En 2014, 94 cas etaient recenses dans la litterature. Des criteres cliniques (debut aigu, pas d’autre cause, âge ; 40 ans, cephalee/trouble cognitif ou du comportement/crise ou deficit focal) et radiologiques (AA avec hypersignal asymetrique en FLAIR) ont ete proposes (Chung et al.). Si un traitement est souvent propose, certaines formes sont d’evolution spontanement favorable. Conclusion Une confusion, une crise comitiale, un trouble visuel ou du langage chez un patient souffrant d’une AA doit faire rechercher une ABRA. La frequence de cette affection parait sous-estimee, mais reste a determiner. Informations complementaires Cette etude n’a pas beneficie de financement particulier.

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild-type α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were compared with age-matched controls. Using whole-body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN mice (P0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP-αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P0.001) and pallidus (P0.01). There was a negative correlation between α-synuclein burden and raphe pallidus cell counts (P0.05). There was no significant neuronal loss in the pre-Botzinger complex. The PLP-αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA.

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.

A 31-year-old woman with Crohn disease presented with tinnitus, headache, apathy, blurred vision, and nystagmus after 3 weeks of IV nutrition and partial colectomy. MRI showed abnormalities of the inferior colliculi (figure). Serum thiamine was …

Introduction: DM1 represents the most frequent form of myopathy in adults, and is characterized by multisystemic involvement requiring regular, comprehensive, and coordinated multidisciplinary monitoring. Recently, american and spanish recommendations concerning this follow-up have been published. Objective: to determine, among adult DM1 patients followed in Neuromuscular Competence Centers in Sud Aquitaine, the proportion benefiting from medical follow-up in line with the recommendations. Methods: we carried out a descriptive cross-sectional survey by telephone questionnaire among adult DM1 patients and their primary caregiver. This questionnaire was established by choosing the most rigorous follow-up of each item resulting from these two recommendations. The inclusion criteria were: patient with genetically proven DM1, adult, having given his consent to participate in the study. Results: out of 89 adult patients followed in our cohort, 73 could be included, of which 55% were women; the average age was 48 years, and the average number of CTG repeats was 467. The proportion of patients receiving clinical follow\u0002up in accordance with the recommendations was 60% in neurology, 90% in cardiology, 23% in pulmonology, 68 % in ophthalmology, and 12% in physical medicine and rehabilitation; 53% received at least weekly physiotherapy, 18% had annual occupational therapy follow-up, and 12% received speech therapy at least once a year. 37% of respondents had already consulted a hepato-gastroenterologist, 47% a mental health professional, and 15% had already undergone a neuropsychological assessment. The proportion of patients receiving paraclinical examinations as recommended was 90% for ECG, 84% for echocardiography, 73% for Holter-ECG, 16% for spirometry, and about 65% for biological plan. Discussion: the high rate of neurological, cardiological, and ophthalmological monitoring could be explained by a locally dense medical demography allowing privileged access to care. While the causes of the deficiencies in pulmonary, rehabilitation, digestive and neuropsychological follow-up still have to be precisely determined, a lack of knowledge of the pathology as well as reduced compliance due to frequent cognitive disorders could be involved. The results should be taken with caution as this is a declarative study. Conclusion: there are significant disparities in the exhaustivity of multidisciplinary follow-up for DM1. These results highlight the major role of multidisciplinary monitoring coordination, and should lead to changes in practices., Introduction : la DM1 représente la forme la plus fréquente de myopathie de l'adulte, et se caractérise par une atteinte multisystémique nécessitant un suivi multidisciplinaire régulier, complet, et coordonné. Récemment, des recommandations américaines et espagnoles concernant ce suivi ont été publiées. Objectif : déterminer, au sein des patients DM1 adultes suivis en Centres de compétences neuromusculaires de Sud Aquitaine, la proportion bénéficiant d’un suivi médical en adéquation avec les recommandations. Méthodes : nous avons réalisé une enquête descriptive transversale par questionnaire téléphonique auprès de patients DM1 adultes et de leur aidant principal. Ce questionnaire a été établi en choisissant le suivi le plus rigoureux de chaque item issu de ces deux recommandations. Les critères d’inclusion étaient : patient atteint de DM1 prouvée génétiquement, adulte, ayant donné son consentement pour participer à l’étude. Résultats : sur 89 patients adultes suivis dans notre cohorte, 73 ont pu être inclus, dont 55 % de femmes ; l’âge moyen était de 48 ans, et le nombre de répétition CTG moyen de 467. La proportion de patients bénéficiant d’un suivi clinique conforme aux recommandations était de 60 % en neurologie, 90 % en cardiologie, 23 % en pneumologie, 68 % en ophtalmologie, et 12 % en médecine physique et de réadaptation ; 53 % bénéficiaient de kinésithérapie au moins hebdomadaire, 18 % avaient un suivi ergothérapique annuel, et 12 % bénéficiaient d’un suivi orthophonique au moins annuel. 37 % des répondants avaient déjà consulté un hépato-gastro-entérologue, 47 % un professionnel de la santé mentale, et 15 % avaient déjà bénéficié d’un bilan neuropsychologique. La proportion de patients bénéficiant d’examens paracliniques conformément aux recommandations était de 90 % pour l’ECG, 84 % pour l’échographie cardiaque, 73 % pour l’Holter-ECG, 16 % pour la spirométrie, et environ 65 % sur le plan biologique. Discussion : l’importance du suivi neurologique, cardiologique, et ophtalmologique pourrait être expliquée par une démographie médicale dense localement permettant un accès aux soins privilégié. Si les causes des carences de suivi pneumologique, rééducatif, digestif, et neuropsychologique restent à déterminer précisément, un défaut de connaissance de la pathologie ainsi qu’une moindre observance en raison de troubles cognitifs fréquents pourraient y participer. Les résultats sont à prendre avec précaution s’agissant d’une étude déclarative. Conclusion : il existe d’importantes disparités dans l’exhaustivité du suivi multidisciplinaire de la DM1. Ces résultats mettent en lumière le rôle majeur de la coordination du suivi multidisciplinaire, et doivent amener à modifier les pratiques.