Differential long-term outcome in a sibling case of MEGF10-related early-onset congenital multicore myopathy: Potential modifying factors of satellite cell-opathy: A case report

Background Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a rare congenital myopathy caused by biallelic variants in the multiple epidermal growth factor-like domains 10 ( MEGF10 ) gene and is typically associated with respiratory failure in early infancy and poor survival. Disorganized intrafibrillar network with/without multi-minicore structures is the hallmark on muscle pathology, and a disturbed muscle regeneration due to dysfunction of MEGF10 in muscle satellite cells has been hypothesized for the pathogenesis. Case presentation Here, we report a sibling case of EMARDD caused by a novel homozygous nonsense variant in MEGF10 , where two males commonly developed severe respiratory failure in infancy, and required tracheostomy and long-term mechanical ventilation. The elder brother, currently 33 years old, gained the ability to sit, shuffle, and to eat orally during childhood. In contrast, the younger brother remained bedridden, was subjected to trachea-pharyngeal separation and gastrostomy, and he died at 21 years of age after repeated episodes of pneumonia. Muscle biopsies revealed, in addition to the minicore formation, necrotic and small regenerating muscle fibers, a trend of clustering of small fibers in the periphery of muscle fascicles, accumulation of lipid droplets, sarcoplasmic aggregation —possibly precipitating core formation in the cytoplasm, rare rimmed vacuoles, as well as ectopic expression of acetylcholine esterase in the sarcolemma. Interpretation Harboring the same pathogenic variant, severity of muscle weakness can differ between siblings with EMARDD. This suggests that certain factor(s) could modify the pathogenesis of MEGF10 myopathy. Apart from the attenuated regeneration process, some etiologies might contribute to the phenotypic variability in this disorder, including disordered lipid metabolism, aberrant phagocytotic/inflammatory activity, and disrupted neuromuscular junctions.