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La souris scrambler (Dab1scm) est un mutant ataxique cérébelleux qui présente une mutation naturelle du gène mdab1, codant pour une protéine intracellulaire nécessaire à la voie de signalisation de la rééline. Cette protéine joue un rôle crucial dans la mise place et la plasticité des structures laminées telles que le cortex cérébral, l’hippocampe ou le cervelet. Notre objectif a été de caractériser le phénotype comportemental et neurochimique de la souris scrambler au cours du développement post-natal et à l’âge adulte. Les premiers signes de l’ataxie cérébelleuse sont observables dès 8 jours et sont majorés au cours des 2ème et 3ème semaines de vie post-natale. A l’âge adulte, la souris se caractérise par un trouble important de la coordination motrice et une hyperactivité locomotrice exacerbée et stéréotypée (comportement de rotation) lorsque l’animal est placé en milieu aquatique. Les tests du labyrinthe aquatique de Morris et de l’alternance spontanée mettent en évidence des déficiences possiblement causées par un trouble du guidage visuo-moteur et la désinhibition comportementale. Chez ces souris, l’activité métabolique régionale évaluée par le marquage de la cytochrome oxydase est relativement préservée dans le cervelet ; elle est en revanche altérée dans diverses régions du tronc cérébral qui lui sont associées ainsi que dans l’hippocampe et certaines régions corticales. Le comportement de rotation stéréotypé et l’hyperactivité causés possiblement par un déséquilibre neurochimique acétylcholine/dopamine a été évalué dans un rotamètre avec ou sans injection préalable d’un antagoniste des récepteurs D2. Parallèlement, l’innervation cholinergique du système nerveux central, révélée par l’activité de l’acétylcholinestérase était diminuée dans la substance noire pour laquelle nous avons observé une désorganisation et une perte partielle des neurones dopaminergiques. Bien que les atteintes multiples compliquent l’étude structuro- fonctionnelle de ce mutant, nos résultats ont permis de préciser le phénotype scrambler en le comparant aux autres mutants de la voie de la rééline. Ces mutants font l’objet aujourd’hui d’un intérêt croissant pour la modélisation non seulement de l’ataxie mais également de certaines maladies neurologiques et neuro-psychiatriques comme l’autisme et la schizophrénie / The Dab1scm scrambler mice is a cerebellar ataxic mutant spontaneously mutated for a gene encoding a protein of the reelin signaling pathway involved in the development and the plasticity of laminated structures such as the neocortex, the hippocampus, and the cerebellum. Our objective was to characterize the behavioral and neurochemical phenotype of the scrambler mice during postnatal developmental and adult stages. The first signs of cerebellar ataxia are observable as early as 8 days and increase during the 2nd and 3rd weeks of postnatal life. Adult mouse is characterized by a significant disturbance of motor coordination and a locomotor hyperactivity which increases ans becomes stereotyped (circling) when the animal was placed in water. Morris water maze and spontaneous alternation highlight deficiencies possibly caused by disorder of visuomotor control and disinhibitory processes. Brain regional metabolic activity measured by cytochrome oxidase is relatively preserved in the mutant cerebellum. However, it is impaired in various connected regions of the brainstem as well as in the hippocampus and some cortical regions. Circling behavior and hyperactivity, possibly caused by a neurochemical imbalance between acetylcholine and dopamine, were evaluated in a rotameter with or whithout prior injection of D2 receptor antagonist. In parallel, cholinergic innervation of the central nervous system measured by acetylcholinesterase activity is lower in the substantia nigra for which a partial disruption and loss of dopaminergic neurons is observed. Although the multiple alterations complicate the structuro-fonctional study of this mutant, results have clarified the scrambler phenotype by comparison with others mutants of the reelin pathway. This mutants are now subject to a growing interest in not only ataxia modeling but also some neurological and neuropsychiatric diseases

Diss. med. dent. Zürich. / Literaturverz.

Diploma the 'is deals wi th the research of effect of biofeedback in the form of electrotactile stimulation of tongue in the patients with balance disorders eaused by the cerebellar lesion. For the therapeutic program 4 patients with cerebellar ataxia at the age of38 - 74 years were chosen. Subjects have partieipated in the therapeutic program with the application of biofeedback, they were training postural stability while visual control was excluded and they were using electrotacti le signal on the tongue for orientation. I used neurological tests BESTest and Dynamic Oait Index, questionnaire The Activities- Specific Balance Confidence (ABC) Scale, Dizziness I Tandicap Inventory (D ll) a Visual Analogue Scale (VAS), and examination by stati posturography for evaluation of postural stability in the patients. I supposed that therapy by biofeedback in the form of electrotactile stimulation of tongue improves postural stability in the patients with balance disorders caused by cerebellar lesion. Powered by TCPDF (www.tcpdf.org)

INTRODUCTION This graduation theses considers with the influence of rehabilitation by electrotactile stimulation of the tongue on stability of stance and gait in patients with degenerative cerebellar ataxia. Electrotactile stimulation of the tongue is an innovative method based on biofeedback principle, which uses additive sensory information about the position of the head to train the postural stability METHOD We used this method in six patients (four men and two women) with this disease. Patients went through intensive twelve-day therapy. The duration of the lessons was 30 minutes twice a day. We examined postural stability of the patients by using clinical evaluations (Balance Evaluation Systems Test, Dynamic Gait Index), posturography (modified Clinical Test of Sensory Interaction for Balance) and questionnaires (Activities -specific Balance Confidence, Dizziness Handicap Inventory) before and after the therapy. RESULTS The patients showed significant improvement in both clinical tests after the therapy. The results of posturography measurement are not so definite - the significant improvement was achieved only in some measured parameters. Both questionnaires did not show significant improvement. CONCLUSION The results of this study show, that electrotactile stimulation tongue could have a...

Abstract available through Journal of Neurologic Physical Therapy.

Friedreich's Ataxia (FA) is an autosomal-recessive, neurodegenerative disease characterized by progressive lower extremity muscle weakness and sensory loss, balance deficits, limb and gait ataxia, and dysarthria. FA is considered a sensory ataxia because the dorsal root ganglia and spinal cord dorsal columns are involved early in the disease, whereas the cerebellum is affected later. Balance deficits and gait ataxia are often evaluated clinically and in research using clinical rating scales. Recently, quantitative tools such as the Biodex Balance System SD and the GAITRite Walkway System have become available to objectively assess balance and gait, respectively. However, there are limited studies using instrumented measures to quantitatively assess and characterize balance and gait disturbances in FA, and longitudinal, quantitative analyses of both balance and gait have not been investigated in this patient cohort. The purpose of the present study was to characterize gait patterns of adults with FA and to identify changes in gait and balance over time using clinical rating scales and quantitative measures. Additionally, this study investigated the relationship between disease duration, clinical rating scale scores and objective measures of gait and balance. This study used a longitudinal research design to investigate changes in balance and gait in 8 adults with genetically confirmed FA and 8 healthy controls matched for gender, age, height, and weight. Subjects with FA were evaluated using the Berg Balance Scale (BBS), the Friedreich's Ataxia Rating Scale (FARS) and instrumented gait and balance measures at baseline, 6 months, 12 months and 24 months. Controls underwent the same tests at baseline and 12 months. Gait parameters were measured utilizing the GAITRite Walkway system with a focus on gait velocity, cadence, step and stride lengths, step and stride length variability and percent of the gait cycle in swing, stance and double limb support. Balance was assessed using the BBS and the Biodex Balance System; the latter included tests of postural stability and limits of stability. At baseline, there were significant differences in gait and balance parameters, BBS scores and FARS total scores between FA subjects and controls as determined using paired t-tests (p This is the first longitudinal study to demonstrate changes over time in gait and balance of adults with FA using both quantitative measures and clinical rating scales. This study provided a detailed characterization of the gait pattern and balance of adults with FA. The GAITRite Walkway system proved to be a sensitive measure, and able to detect subtle changes in gait parameters over time in adults with FA. In addition, the BBS was an appropriate and sensitive assessment to detect changes in static and dynamic balance in this patient cohort. Finally, results revealed a strong and consistent relationship between clinical rating scale scores, postural stability indices, limits of stability scores, and step and stride length variability in individuals with FA.

Le syndrome CANVAS (Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome) est une ataxie cérébelleuse rare qui apparaît à l'âge adulte, et se caractérise par des déséquilibres et une neuropathie sensorielle. Des expansions répétées introniques bialléliques dans l’intron 2 du gène RFC1 ont été identifiées comme cause du CANVAS. Le gène RFC1 code pour la plus grande sous-unité du Facteur de Réplication C, important à la réplication et la réparation de l'ADN. Alors que onze répétitions pentanucléotidiques (AAAAG)11 sont normalement retrouvées, les expansions pathogènes comprennent généralement des centaines de répétitions (AAGGG)exp. Toutefois, les mécanismes selon lesquels ces expansions répétées provoquent ce trouble neurologique sont inconnus. Des articles récents ont identifié des mutations de décalage de cadre dans RFC1, suggérant la perte de fonction comme mécanisme pathogénique. De manière intéressante, nous avons montré que rfc1 est exprimé dans le cervelet en développement chez la souris et le poisson-zèbre, ce qui indique qu'il pourrait jouer un rôle crucial dans son développement et son activité. Étant donné que l'inactivation de RFC1 chez les mammifères entraîne une létalité embryonnaire, nous avons généré un modèle de poissons-zèbres avec une perte de fonction rfc1-KO en utilisant la méthode CRISPR/Cas9. Nous avons constaté que les larves rfc1-/- survivent jusqu'à 10 jours après la fécondation (dpf) et présentent un phénotype morphologique sévère à partir de 2 dpf. Plus important encore, nous avons montré que le développement du cervelet est sévèrement affecté avec une diminution de la prolifération associée à une augmentation de l’apoptose dans le cervelet des mutants rfc1-/-, conduisant à une désorganisation des cellules de Purkinje et une perte des cellules granulaires. Grâce au séquençage de l'ARNm à cellule unique (single cell RNA sequencing, scRNAseq), nous avons démontré l'importance de rfc1 pour la neurogenèse cérébelleuse et que sa perte de fonction conduit à de graves défauts de progéniteurs. Ce travail est le premier à générer un modèle de poissons-zèbres rfc1-KO et à montrer que RFC1 est important pour le développement du cervelet, suggérant que CANVAS pourrait être causé par un mécanisme de perte de fonction de RFC1. / The Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is a rare adult-onset ataxia with a prevalence of less than 1 in a million, characterized mainly by imbalance and sensory neuropathy. Although CANVAS remained only clinically defined, recent findings identified a biallelic intronic repeat expansion (AAGGG)exp in the RFC1 gene as a major cause of CANVAS. RFC1 encodes the largest subunit of the Replication Factor C required for DNA replication and repair. Whereas the reference allele contains eleven pentanucleotide (AAAAG)11 repeats, the pathogenic expansion usually comprises hundreds of AAGGG repeats. However, the mechanisms by which this repeat expansion in the second intron of the RFC1 gene is causing this neurological disorder are unknown. Recent papers also identified frameshift mutations in RFC1, suggesting that a loss of function could drive pathogenicity. Interestingly, we showed that rfc1 is expressed in the mice and zebrafish developing cerebellum, indicating that it might play a crucial role in its development and activity. Since knocking-out (KO) RFC1 in mammals leads to embryonic lethality, we generated a zebrafish loss-of-function model of rfc1 using CRISPR/Cas9 mutagenesis. We found that rfc1-/- larvae survive until 10 days post-fertilization (dpf), thus leaving us a convenient time to study neurodevelopment without rfc1. We showed that rfc1-/- embryos depict a severe morphological phenotype from 2 dpf onwards. More importantly, we showed that the development of the cerebellum is severely affected, with decreased proliferation associated with increased apoptosis in the cerebellum of rfc1-/- mutants, as well as disorganization of Purkinje cells and a severe reduction in the number of granule cells at 5 dpf. Using scRNAseq, we have demonstrated the importance of rfc1 for cerebellar neurogenesis and that its loss of function leads to severe progenitor defects. This work is the first to generate a KO-rfc1 zebrafish model. Altogether, our work is the first to show that RFC1 is important for the development of the cerebellum and suggests that RFC1's loss of function mechanisms partially causes CANVAS.

Nous présentons ici la description clinique et génétique d’un syndrome neurocutané unique. Le laboratoire du Dr Cossette a entrepris la caractérisation clinique et génétique d'une famille canadienne-française qui a été identifiée par les Drs Giroux et Barbeau en 1972 et qui comprend plus de 100 personnes sur six générations. Les membres atteints de cette famille présentent des lésions typiques d'érythrokératodermie (EK) (OMIM 133190, EKV1 et EKV2), associées à une ataxie spinocérébelleuse pure. Dans cette famille, l'ataxie est caractérisée par des troubles de la coordination et de la démarche causés par une dégénérescence du cervelet et de la moelle épinière. Cette ataxie est transmise selon un mode autosomique dominant. Une étude antérieure de cette variante d'EK avec ataxie avait suggéré une liaison sur le chromosome 1p34-p35, soit la même région que les formes EKV de type 1 et 2, causées respectivement par des mutations dans les gènes connexin-31 (GJB3; OMIM 603324) et connexin-30.3 (GJB4; OMIM 605425). Cependant, aucune mutation n'a été retrouvée dans ces gènes pour la famille canadienne-française. Nous avons récemment recontacté la famille et effectué des examens détaillés, incluant une imagerie par résonance magnétique (IRM) et un électromyogramme (EMG). Les manifestations neurologiques des individus atteints sont compatibles avec une nouvelle forme d’ataxie cérébelleuse pure à transmission autosomique dominante (ADCA de type III dans la classification de Harding) que nous avons appelée SCA34. Une cartographie complète du génome nous a permis de localiser le gène SCA34 sur le chromosome 6p12.3-q16.2. Également, en collaboration avec les Drs Alexis Brice (Hôpital Pitié-La Salpêtrière, Paris) et Alfredo Brusco (Hôpital San Giovanni Battista di Torino, Italie), nous avons confirmé que trois autres familles européennes avec SCA inexpliquée étaient également liées au locus SCA34. Notre laboratoire a récemment entrepris la recherche des mutations responsables de SCA34. Les résultats de ce criblage de gènes candidats sont présentés dans le chapitre 3 de cette thèse. / We present here the clinical and genetic description of a unique neuro-cutaneous syndrome. Dr. Cossette’s laboratory began the clinical and genetic characterization of a French-Canadian family who was identified by Drs. Giroux and Barbeau in 1972 and includes more than 100 people over six generations. The affected members of this family have typical lesions of erythrokeratodermia (EK) (OMIM 133190, and EKV1 EKV2), associated with pure spinocerebellar ataxia. In this family, the clinical phenotype is characterized by gait ataxia caused by degeneration of the cerebellum and spinal cord and the pattern of inheritance is compatible with an autosomal dominant trait. In a previous study of this variant of ataxia with EK, putative linkage was found on chromosome 1p34-p35, the same chromosomal region of EKV1 and EKV2 that are respectively caused by mutations in the connexin-31 gene (GJB3, OMIM 603324) and connexin -30.3 (GJB4, OMIM 605425). However, no mutations have been found in these latter genes for the French-Canadian family. We recently contacted the family and carried out detailed examinations, including a magnetic resonance imaging (MRI) and electromyography (EMG). Neurological manifestations of affected individuals are consistent with a new form of pure autosomal dominant cerebellar ataxia, (ADCA type III in the classification of Harding) that we named SCA34. A whole genome scan allowed us to map the gene on chromosome 6p12.3-q16.2. Interestingly, in collaboration with Dr. Alexis Brice (Hôpital Pitié-La Salpêtrière, Paris), and Alfredo Brusco (San Giovanni Battista Hospital, Turin, Italy), we found that three additional European families with unexplained SCA were also linked to the SCA34 locus. Our laboratory has recently begun the search for mutations causing SCA34. The results of this screening of candidate genes are presented in Chapter 3 of this thesis.

Introduction: Biofeedback based on sensory substitution is a new method to treat patients with postural disorders. BrainPort provides tongue electrotactile stimulation. This innovative technique was developed for vestibular dysfunction of peripheral origin. Primarily for patients who had no benefits from conventional rehabilitation. Tongue electrotactile stimulation seems to be useful for central vestibula dysfunction as well. We are dealing with effect of BrainPort in therapy of degenerative cerebellar ataxia. We are interested in whether the effects persist for one month after the rehabilitation program. Methods: The methods are applied in 6 patients with degenerative cerebellar ataxia, verified by clinical testing, posturography, and genetic testing or verification of cerebellar lesions by MRI. Patients underwent an 12-day intensive rehabilitation program with BrainPort. Treatment was carried out 2 times a day. Patients were learning appropriate postural corrections to maintain signal in the middle of the tongue. To assess the effect of therapy we used posturography, standardized clinical tests - BESTest, Dynamic Gait Index (DGI) and standardized questionnaires - The Activities-Specific Balance Confidence Scale (ABC) and Dizzines Inventroy Handicap (DHI). The examination was performed before...