The aim of the Neuromuscular and Neurogenetic Disorders of Childhood Section (NNDCS) is to identify the causation and treatment avenues for genetic disorders of the nervous and neuromuscular system with onset at birth, early infancy, and childhood. This includes the characterization of mechanisms in animal models and human biopsies, the identification of novel genes as well as the development of clinical outcome measures and biomarkers that will allow us to proceed to clinical trials in these conditions. A particular focus in the section is on early onset muscle disorders caused by mutations in genes coding for components of the muscle extracellular matrix and its receptors (often falling within the group of Congenital Muscular Dystrophies, CMD) and on reducing body myopathy, a severe early onset myopathy with aggregate formation. For the matrix myopathies we will be studying the mechanisms of muscle involvement in mouse models, in particular as they relate to atrophy and failing regeneration in the muscle. We will be confirming and broadening the analysis for these and other pathways in a systematic analysis of patient muscle biopsies. A pathway independent approach directed at the causative mutation will be developed for dominant negative mutations in collagen VI. For the congenital muscular dystrophies with brain involvement (alpha-dystroglycanopathies) we will be studying the cellular basis of the neurological involvement in neuron generated from patient derived iPSC, with the intention of characterizing the phenotype and evaluating it for its translational potential. In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2) we are preparing for clinical trial with a careful natural history and clinical outcomes study. Reducing body myopathy is caused by mutations in FHL1. In order to understand whether it is the aggregation process rather the the function of the mutated gene that is driving the disease and to find opportunities for therapeutic intervention we are generating mouse and fly models of the disease. Finally, we are using next generation sequencing technology to identify new genes in our cohort of undiagnosed patients, including a novel syndrome of congenital muscular dystrophy with sensorineural deafness and a group of patients with collagen VI-like disorders.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$2,295,629
Indirect Cost
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State
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