P404 Deep Phenotyping and Characterization of a Patient with a Novel Autosomal Dominant TNNI1-related Hypercontractile Muscle Disease

The troponin complex regulates Ca2+ sensitivity of the myofibrillar contractile apparatus in striated muscles. This complex is comprised of three associated troponin proteins: troponin I (TNNI), T, and C. TNNI is the inhibitory subunit, TNNI1 is predominantly expressed in slow-twitch (type 1) skeletal muscle fibers and has not been conclusively established to cause skeletal myopathy. We report a family with a novel dominantly acting heterozygous TNNI1 substitution p.R174Q in three similarly affected siblings, two males (44 and 37 years) and one female (39 years). The youngest sibling was evaluated at the NIH Clinical Center. Per history, he had abnormal stiffness in his first year of life but normal motor development. Muscle cramps, myalgias, stiffness, and swallowing difficulties have been lifelong issues. Examination showed normal muscle bulk and strength without myotonia. Handheld computer myometry showed increased muscle relaxation time (mean, SD: 0.63±0.19 sec; normal reference: 0.32±0.23). Creatine kinase (CK) levels had been consistently elevated (800-1,330U/L range; normal < 200U/L). Muscle MRI was normal, while a swallowing study revealed a cricopharyngeal bar with significant esophageal narrowing, caused by an enlarged cricopharyngeal muscle, which consists of mostly type-1-slow-twitch fibers. Pulmonary function tests, an electrodiagnostic study, and echocardiography were normal. Muscle histopathology (from the patient's brother's biopsy) showed type 1 fiber hypertrophy with internalized nuclei and eosinophilic inclusions with corresponding cores on NADH staining. Single fiber contractility studies revealed increased force response of sarcomeres to submaximal Ca2+ consistent with a gain-of-function hypercontractile mechanism due to Ca2+ hypersensitivity mediated by the variant troponin I1. This case thus establishes TNNI1-associated hypercontractile muscle disease manifesting with cramping, abnormal relaxation, and swallowing difficulties. Understanding the specific disease mechanism for variants in sarcomeric proteins is essential for the consideration of potential pharmacological interventions, in this case fiber type-1 Ca2+ desensitizers. The troponin complex regulates Ca2+ sensitivity of the myofibrillar contractile apparatus in striated muscles. This complex is comprised of three associated troponin proteins: troponin I (TNNI), T, and C. TNNI is the inhibitory subunit, TNNI1 is predominantly expressed in slow-twitch (type 1) skeletal muscle fibers and has not been conclusively established to cause skeletal myopathy. We report a family with a novel dominantly acting heterozygous TNNI1 substitution p.R174Q in three similarly affected siblings, two males (44 and 37 years) and one female (39 years). The youngest sibling was evaluated at the NIH Clinical Center. Per history, he had abnormal stiffness in his first year of life but normal motor development. Muscle cramps, myalgias, stiffness, and swallowing difficulties have been lifelong issues. Examination showed normal muscle bulk and strength without myotonia. Handheld computer myometry showed increased muscle relaxation time (mean, SD: 0.63±0.19 sec; normal reference: 0.32±0.23). Creatine kinase (CK) levels had been consistently elevated (800-1,330U/L range; normal < 200U/L). Muscle MRI was normal, while a swallowing study revealed a cricopharyngeal bar with significant esophageal narrowing, caused by an enlarged cricopharyngeal muscle, which consists of mostly type-1-slow-twitch fibers. Pulmonary function tests, an electrodiagnostic study, and echocardiography were normal. Muscle histopathology (from the patient's brother's biopsy) showed type 1 fiber hypertrophy with internalized nuclei and eosinophilic inclusions with corresponding cores on NADH staining. Single fiber contractility studies revealed increased force response of sarcomeres to submaximal Ca2+ consistent with a gain-of-function hypercontractile mechanism due to Ca2+ hypersensitivity mediated by the variant troponin I1. This case thus establishes TNNI1-associated hypercontractile muscle disease manifesting with cramping, abnormal relaxation, and swallowing difficulties. Understanding the specific disease mechanism for variants in sarcomeric proteins is essential for the consideration of potential pharmacological interventions, in this case fiber type-1 Ca2+ desensitizers.