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Abstract

Rare Neurodegenerative Diseases with Motor Expression (RNDME) are a very heterogeneous group of neurodegenerative pathologies of acquired or innate physiopathology that can occur at any age. They have a targeted impact on the central or peripheral neurological structures involved in motor activity. These structures are functionally and topographically close to the centers of cognition. Thus, under certain conditions, the neurodegeneration of motor structures impacts cognitive functions.They result in gait and/or balance disorders, a decrease or absence of movement, a varied cognitive impairment that can go as far as dementia.RNDME are sporadic or family based. The latter have a hereditary component and therefore represent interesting study models because they offer the possibility of analyzing the DNA of relatives and thus increase the research power of genetic factors involved in a family symptomatology.The scientific literature indicates an important number of genetic pathogenic variation responsible for RNDMEs, which allows classification but also makes it more complex because it can be observed that the same gene can be involved in several pathologies and a pathology can be caused by different genes. Consequently, in RNDMEs, atypical symptoms, clinical overlaps or allelic diseases are observed.In the French West Indies, the data in the literature on RNDMEs are limited but rich in certain observations confirming the atypical RNDMEs seach as the atypical Caribbean Parkinson's syndrome.On the genetic level, diagnostic investigations are limited to medical fields based in metropolitan France and most often about the comparison of genomic data of Caucasian populations.The thesis work is about 2 aspects: the first, clinical and genetic, has allowed to draw up an inventory of the RNDMEs in Martinique by characterizing them on these plans, the second on the search for causal variants by a Next Generation Sequencing (NGS) technique called CoDEseq (Copy number variation Detection and Exome sequencing). The inventory of RNDMEs in Martinique and the experimental work of data analysis of NGS, are the first works of this type, in the field and in our region.The CoDEseq method is innovative because it allows whole exome analysis in the detection of Single Nucleodis Variants (SNVs) and Copy Number Variants (CNVs). It had almost never been used in the analysis of RNDMEs. We used it because it is a method of choice for searching for both simple and structural variants. The results show a diagnostic cost-effectiveness of 58% since we identified a variant probably pathogenic in 7 patients out of 12 tested. We found these variants in known RNDMEs genes sometimes described in Asian populations, but also of African or Caucasian descent. Some of these genes may be involved in several symptomatologies, confirming the finding of overlap in these diseases.This work lays the epidemiological basis for RNDMEs in the West Indies and provides a basis for a registry in this area. On the experimental level, it allow to propose a molecular cause associated with previously described or new variations. It is also a proof of concept regarding the bioinformatics means of analyzing NGS data in Martinique. It paves the way for other work of the same kind, susceptible to draw up the gene specificities of the RNDMEs in our region and to expand the data in the scientific and medical literature.

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