Case Report: MYBPC1-associated congenital myopathy with tremor (CMYO16): a multigenerational family report

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We report a family with congenital myopathy-16 (CMYO16; MIM 618524) due to a novel heterozygous MYBPC1 M-motif variant, c.779G>A p (Arg260His), in whom oral pyridostigmine was associated with apparent clinical benefit in all four affected members across three generations. To our knowledge, this is the first report of a possible clinical response to pyridostigmine in MYBPC1 -associated congenital myopathy with tremor. The MYBPC1 gene encodes slow skeletal myosin-binding protein C (sMyBP-C), a sarcomeric accessory protein that regulates actomyosin cross-bridge cycling and stabilizes the thick filament. Heterozygous variants, most commonly involving the highly conserved M-motif, cause CMYO16, a mild, early-onset, slowly progressive disorder characterized by hypotonia, fatigability, proximal and axial weakness, and a distinctive high-frequency tremor. Few than thirty affected individuals have been reported, and no disease-specific or symptom-directed pharmacologic therapy has been described. In this family, the variant co-segregated with the phenotype in four affected individuals: a young boy (the proband), his father, paternal aunt, and paternal grandfather. Because of disabling fatigability, clinical features suggestive of congenital myasthenia, and the presence of a CHRND variant of uncertain significance in three family members, a trial of oral pyridostigmine was initiated in the proband at 16 months of age. A blinded one-week-on/one-week-off assessment by a physical therapist suggested improvement in tone, energy, and gait, and caregivers reported improved stamina and reduced tremors. Objective assessments could not be obtained because of the patient’s young age. Concurrent improvement in gastrointestinal symptoms most likely reflects the known prokinetic cholinergic effects of pyridostigmine rather than a muscle-specific benefit. Open-label, self-reported benefit was subsequently described by the three affected adults. Because the outcomes were open-label and largely subjective, these observations are preliminary and hypothesis-generating. The affected paternal aunt did not carry the CHRND variant, arguing against attributing the response to CHRND alone; however, her prior diagnosis of fibromyalgia makes her self-reported improvement particularly susceptible to placebo effects. We report that four affected family members, ranging in age from 2 to 65 years, showed a positive and well-tolerated response to pyridostigmine, with improvement in clinical symptoms likely attributable to CMYO16.