Les ataxies cérébelleuses héréditaires sont des pathologies neuro-dégénératives rares, hétérogènes, complexes affectant le cervelet et parfois la moelle épinière et/ou les nerfs périphériques. Elles se transmettent sur le mode autosomique récessif (ARCA), dominant (SCA) ou lié à l’X. Les objectifs de cette thèse de sciences étaient la description phénotypique d’ataxies cérébelleuses héréditaires, la mise en évidence de corrélations du génotype au phénotype et la description de stratégies diagnostiques pour mettre en évidence ces pathologies rares.Grâce à nos résultats, nous avons pu élargir le spectre phénotypique clinique, biologique, radiologique d’ataxies cérébelleuses héréditaires connues : Fragile X Tremor Ataxia Syndrome (FXTAS), ataxie récessive lentement progressive liée au gène PEX 10 impliqué dans la biogénèse du peroxysome, ataxie avec apraxie oculomotrice de type 1 (AOA1). Nous avons pu mettre en évidence des corrélations du génotype au phénotype dans AOA1 et montré que l’âge moyen de début était plus élevé et que la pathologie était moins sévère chez les patients avec au moins un faux sens (p <0,01) par rapport aux patients avec deux mutations tronquantes. Nous avons réussi également à établir un algorithme pour faciliter le diagnostic des ataxies cérébelleuses autosomiques récessives et aider à l’interprétation du séquençage à haut débit. Il est important dans ce type de pathologies rares de pouvoir établir au maximum un diagnostic moléculaire afin de guider le conseil génétique et mettre en évidence les ataxies accessibles à une thérapeutique. / Hereditary cerebellar ataxias are a group of rare and heterogeneous neurodegenerative diseases. The transmission mode is recessive, dominant or X-linked. Our objectives were to better describe the phenotype of some inherited ataxias, to provide genotype-phenotype correlations and to improve the diagnostic strategies for these rare diseases. We enlarged the clinical, biological, radiological phenotype of Fragile X Tremor Ataxia Syndrome (FXTAS), recessive ataxia due to PEX10 related peroxisomal biogenesis disorders, ataxia with oculomotor apraxia type 1 (AOA1). We showed genotype-phenotype correlations in AOA1 patients: mean age at onset was higher with at least one missense mutation. A ranking algorithm has been created to predicting the molecular diagnoses of recessive cerebellar ataxia in order to guide the diagnosis and facilitate interpretation of next generation sequencing. The establishment of a molecular diagnosis is important in this type of rare pathologies to guide the genetic counseling and to diagnosis the ataxias accessible to a treatment.

Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the FMR1 premutation. Carriers of the FMR1 premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS), which involves progressive symptoms of tremor, ataxia and cognitive decline. Evidence also suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. The present study aimed to investigate and delineate neurodegenerative and neurodevelopmental aspects of the premutation utilising primarily fMRI, clinical assessments and molecular measurements in 17 premutation carrier participants and 17 age-matched control participants, aged between 20 and 70 years. The functional imaging protocol included a motor task and an emotional processing task. A battery of clinical and neuropsychological tests outside of the scanner and blood-based measurements of FMR1 CGG repeat length, FMRP levels and FMR1 mRNA levels were also carried out. In the motor task, premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Quantative real-time PCR analysis revealed that mean age-matched FMR1 mRNA levels display a trend towards being higher in carriers and clinical testing of motor skills additionally showed significantly worse tremor and co-ordination scores in non-FXTAS carriers. No significant associations were seen between these measurements and neuroimaging data. During the emotional processing task, carriers exhibited significantly lower activation compared to controls (FWEcorr < 0.001) at the bilateral superior parietal lobe, bilateral Brodmann Area (BA) 17 (V1), right intraparietal area and right BA18 (V2) when comparing high arousal and low arousal conditions. Group by age interaction analyses indicated no significant between group differences at a whole brain level. Clinical assessment revealed that carriers displayed significantly worse symptoms of obsessive-compulsiveness, anxiety, global severity of psychiatric symptoms, facial emotion recognition and autistic traits compared to controls and FMRP levels were comparable between groups. No significant associations were seen between these measurements and neuroimaging data. Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability. Additionally, we show significantly altered emotional processing at neuropsychological, clinical and functional neuroimaging levels in carriers compared to controls, which appear to display stability over age. Overall, we present new evidence in keeping with possible neurodegenerative and neurodevelopmental traits in FMR1 premutation carriers.