The making of a famous nineteenth century neurologist: Jean-Martin Charcot (1825-1893)

The setting of this thesis is the medical world of Paris in the second half of the nineteenth century. This essay answers the question of how Jean-Martin Charcot became famous. In placing Charcot s career in its historical context, it provides an analysis of the strategies used by him to ensure his status as one of the most famous French physicians of the latter half of the nineteenth century. It presents a study of two important chapters of the history of French academic medicine, placing both in the conceptual framework of the transition between knowledge and power. It discusses the youth and early careers of Charcot and his medical ally Alfred Vulpian (1826-1887). It analyses the increasing influence of the members of the Societe de Biologie' in the medical world of Paris, suggesting that the Society served as a forum for young ambitious physicians such as Charcot who wanted French medicine to be reformed into a bonafide science. It shows that when the take over by the members of the "Societe de Biologie" of the Medical Faculty of Paris was completed by the mid 1870's, conflicting individual aspirations started to surface and cause profound divisions in the previously cohesive group. It analyses how Charcot was able to successfully break ahead of many of his colleagues. It shows Charcot at the zenith of his fame during the 1880's. Finally Charcot s rapid decline in the early 1890's is reviewed. In summary, this thesis analyses how Charcot, due to the successful scientific reform of French medicine, was able to become one of the most famous physicians of the nineteenth century

Impact des récentes transformations démographiques liées à l’urbanisation sur le bassin génétique de la région de Lanaudière

Au Québec, comme dans la plus grande partie des populations mondiales, la mobilité interrégionale vers les zones urbaines et leur périphérie a gagné en importance au cours du 20e siècle. Ce travail vise à estimer, au moyen d’une approche généalogique, les effets de ces mouvements migratoires sur la variabilité du pool génique de la région de Lanaudière, située au nord-est de Montréal. Pour ce faire, la région de Lanaudière a été divisée en deux sous-régions, soit le nord et le sud. Quatre cents ascendances généalogiques d’individus mariés dans chacune des sous-régions durant deux périodes (1945-55 et 1985-95) ont été reconstruites à l’aide du fichier de population BALSAC. Pour la période 1945-55, les indices généalogiques des deux sous-régions sont très similaires, alors que pour 1985-95, ceux-ci indiquent une plus grande hétérogénéité au sud de la région, ce qui est cohérent avec le récent boom démographique enregistré dans cette partie du territoire. En outre, on a observé une réduction marquée des coefficients d’apparentement et de consanguinité et un changement des trajectoires migratoires interrégionales au cours de cette période de cinquante ans. Ces événements peuvent être clairement associés aux migrations récentes vers les zones urbaines.Interregional mobility towards urban areas and their periphery has become increasingly important throughout the 20th century. The effects of these migratory movements on the variability of the Lanaudiere gene pool were estimated through the use of a genealogical approach. The region of Lanaudiere was divided into two subregions, namely north and south. Four hundred ascending genealogies of individuals married within each subregion during two periods (1945-55 and 1985-95) were reconstructed using the BALSAC database. For the 1945-55 period, genealogical indices of the two subregions are quite similar, while they display much more heterogeneity in the southern part of the region in 1985-95, which is consistent with the recent demographic boom in this area. Overall, a marked reduction of kinship and consanguinity levels in Lanaudiere is observed in this fifty-year period, which can be clearly associated with changing interregional migratory trajectories toward urban areas

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing

IntroductionRare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.MethodsEach of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.ResultsFollowing different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.DiscussionThis study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies

Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients

Ashton C et al report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common feature of episodic ataxia and other episodic features, as well as the inefficacy of acetazolamide in these patients

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes.While SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%.This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. This article is protected by copyright. All rights reserved

Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy

BACKGROUND: Intronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat expansions in patients with an unexplained CANVAS-like phenotype. METHODS: We recruited 45 patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the FGF14 repeat locus. Phenotypic features of GAA-FGF14-positive versus GAA-FGF14-negative patients were compared. RESULTS: Frequency of FGF14 GAA repeat expansions was 38% (17/45) in the entire cohort, 38% (5/13) in the subgroup with cerebellar ataxia plus polyneuropathy, 43% (9/21) in the subgroup with cerebellar ataxia plus BVP and 27% (3/11) in patients with all three features. BVP was observed in 75% (12/16) of GAA-FGF14-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-FGF14-positive patients. Family history of ataxia (59% vs 15%; p=0.007) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%; p=0.009) significantly less frequent in GAA-FGF14-positive than in GAA-FGF14-negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R2=0.45; p=0.0031). CONCLUSIONS: GAA-FGF14-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum