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Our knowledge of congenital myopathies is expanding. Recent genes have been identified in troponin variants, among them only 2 families with TNNC2 mutations have been described. We report an 18 yo man with a severe neonatal congenital myopathy that slowly improved over time. He was born with significant hypotonia and feeding difficulties. He was fed through a gastrostomy until 5 years of age. He walked independently at 4 yo. He is now able to ride a mountain bike on a regular basis. His physical examination showed a distal more than proximal weakness in upper limb and a more pelvic girdle weakness in lower limbs. Striking features include mild oculoparesia and hypomimic face with high arch palate. CK levels were normal. Two EMGs showed nonspecific myopathic features. Muscle biopsy demonstrated nonspecific moderate myopathic features. Interestingly, muscle MRI showed very discrete fatty infiltration in the thigh. Next generation sequencing panels for dystrophic and non-dystrophic myopathies were negative. Whole exome sequencing identified a novel heterozygous mutation c.204 C>A in TNNC2. This case expands the clinical phenotype of patients with congenital myopathy related to TNNC2. [ABSTRACT FROM AUTHOR]

Congenital Myopathy with tremor, currently classified as Congenital Myopathy-16, represents a very rare disease phenotype, associated with domain-specific variants in the MYBPC1 gene. This gene encodes Myosin binding protein-C slow (sMyBP-C), a cytoskeletal protein expressed in skeletal muscle tissues with at least 10 different isoforms. This protein plays a crucial role in stabilizing the thick filament and regulating actin-myosin binding during cross-bridge formation. Previous research has suggested that observed sarcomeric deficits may underlie the molecular mechanisms causing the disease. We have created a mouse model for this disease, harboring a patient-specific variant (c.739T>C, p.(Y247H)). Here, we present a comprehensive description of the observed phenotype using a plethora of quantitative and qualitative methods, including behavioral tests, microscopy, protein quantification, biochemical assays including spectrophotometric measurements of OXPHOS enzyme activities, transcriptome analysis by RNA-seq, and proteomics. Our findings demonstrate strength deficits, myogenic tremor, and homozygous lethality in the model, as well as the localization of the mutant protein, similar to a previous model, carrying another patient-specific variant in the MYBPC1 gene. While we observed expected sarcomere disorder and misalignment, they were not as pronounced. Transcriptome data and biochemical assays unveil not only morphological abnormalities in mitochondria but also functional deficits in the oxidative phosphorylation system. This research reinforces the myogenic tremor phenotype observed in patients and the initial animal model, emphasizing the correlation between phenotypic severity and alterations in the binding potential of the mutant protein, as suggested in our previous work. Additionally, we provide evidence indicating mitochondrial dysregulation as a component of this disease. We thank ERAF Nr. 1.1.1.1/18/A/097. [ABSTRACT FROM AUTHOR]