Though DMD and BMD have been associated with variable degrees of cognitive impairment, the neuropsychological profile of DMD patients, and physiopathological mechanisms underlying cognitive impairment have now to be better delineate. The primary aim of this proposai is to establish a multidisciplinary consortium, that includes physicians, geneticists, neuropsychologists and biologists, to develop integrative research program and address the issue of cognitive impairment in Duchenne and Becker muscular dystrophies and its underlying molecular and cellular processes.

 

The specific objectives of our project are the following:
- Integrate tailored clinical, neuropsychological evaluation, new neuroradiological investigations, and molecular studies in DMD/BMD patients in order to delineate more precisely impaired cognitive profiles and the underlying genotypes, and validate the emerging hypothesis suggesting that mutations in Dp71 are systematically associated with mental retardation (MR). Such demonstration represents a crucial initial step that will provide insights for the understanding of molecular and cellular processes underlying MR in DMD and BMD patients.
- Perform, in selected DMD and BMD patients with or without MR, non-invasive brain imaging and in vitro high-resolution proton magnetic resonance spectroscopy (MR5) to Look for brain abnormalities and metabolic differences (especially of total creatine) that might correlate with the presence of mental retardation. These investigations are driven by the fact that creatine deficiency (by deficit in biosynthesis or transport) in the brain is known to be associated with mental retardation, and the presence of a decreased Ievel of total creatine in skeletal muscle of DMD patients. Detection of a decreased creatine level in brain patients with MR might Iead to simple and efficient therapeutic application.
- Take advantage of the expression of bp7l in lymphocytes and fibroblaste and assess in cell culture assays the effect of pharmacological products (aminoglycosides and PTC 124) on Dp71 protein re-expression in patients with premature stop mutations located in this isoform.

 

Methods will include: (i) multi-centric study based on retrospective analysis on possible cognitive dysfunction in already genetyped patients, (ii) prospective integrated study in a cohort of ambulant DMD boys (100 patients) combined with an exhaustive study of the dystrophin gene to further support potential phenotypegenotype correlations. Also, confirmation of the association between Dp71 loss of function and MR in DMD/BMD patients will be followed by in vitro, ex vivo and in vivo complementary functional studies to assess the function of Dp71 and its rote in the CNS. To this end, we will assess the consequences of Dp71 deficit on brain development architecture, and activity through histological, ultrastructure and electrophysiological studies), and neuronal morphogenesis and synaptic activity. Available mdx, mdx3cmv and Dp71-specific knock out mice models and primary neuronal cultures derived from these models will be used to address this objective.

 

Through studies developed in this project, we expect the establishment of guidelines for neuropsychological evaluation and recommendations for management of learning disabilities and rehabilitation in this population, as well as a contribution into the understanding of molecular etiologies and fundamental aspects involved in cognitive impairment associated with DMD/BMD phenotypes.