Disease mechanisms in myofibrillar myopathy (MFM): Myofibrillar myopathy caused by dominant mutations in the Z-disc associated LIM Domain Binding protein 3 (LDB3) is a prominent distal myopathy defined by the Z-disc disruption, dissolution of actin filaments and accumulations of degraded myofibrillar proteins in the sarcoplasm of muscle fibers. Mutations in at least 8 other Z-disc associated proteins cause a similar muscle pathology indicating shared disease mechanism for this group of myopathies. The disease mechanisms underlying these pathological changes are not yet known. We generated knock-in mice harboring the most common disease -causing mutation p.A165V in mouse Ldb3 gene. These mice reproduce hallmark features of myofibrillar myopathy. (manuscript in submission). Both heterozygous and homozygous mice develop a similar progressive myopathy indicating a toxic gain-of-function by the mutant protein. Currently, we are testing therapeutic drugs for reversal or stabilization of pathology. We anticipate that these preclinical studies will ultimately translate in patients during future clinical trials. There is a growing interest from patient community to develop therapeutics for MFM. Patient studies: We began the data analysis of 113 patients participated across 6 sites (24 patients at NIH CC) for all 3 study visits in the myotonic dystrophy (DM) clinical research network study (DMCRN; 2014-N-132). We completed the data analysis of the ankle dorsiflexion strength and myotonia measurements in 24 NIH participants (2014-N-0132) by the ankle intellistretch device (developed at the NIH). We enrolled age-and gender matched healthy participants for comparison (n = 5, target n = 10). We developed novel handgrip relaxometer devices to measure hand grip myotonia and conducted a pilot study to characterize and validate the devices in 20 DM1 patients and 10 healthy participants (2014-N-0132). data analysis. is complete (manuscript in draft stage) We got PIRC and IRB approval of a new clinical protocol titled,Assessing Clinical Endpoints and Biomarkers in Myotonic Dystrophy Type 1 and Type 2 (ASCEND-DM) (2018-T-N-4295). MFM patients with LDB3 p.A165V mutation have been enrolled for a longitudinal follow up study. We completed exome analysis of about 50 patients with rare undiagnosed neurodegenerative neuromuscular diseases seen in the Neurogenetics Clinic (2000-N-0043) and identified novel mutations, atypical phenotypes and very rare but potentially treatable hereditary neurodegenerative diseases (manuscript in draft stage).
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