MYBPC1-associated congenital myopathy with tremor: further delineation of the clinical and pathological phenotype in the first Italian case

The MYBPC1 gene, mapping to chromosome 12q23.2, encodes the slow myosin binding protein-C (sMyBP-C), a sarcomeric accessory protein, expressed mainly in slow skeletal muscle fibers, that aids in the regulation of actomyosin cross-bridges and provides thick filament stability. Biallelic molecular defects in MYBPC1 are associated with a lethal congenital form of myopathy (Lethal congenital contracture syndrome 4); meanwhile, heterozygous damaging variants lead to a form of distal arthrogryposis (distal arthrogryposis type 1B) and an early‐onset congenital myopathy with tremor (congenital myopathy-16, CMYO16). To date, only 20 cases have been documented, all presenting a mild axial–proximal myopathy consistently coupled with a distinctive tremor phenotype. We report the case of a young Italian woman presenting with mild axial and proximal weakness, associated with a high-frequency postural tremor affecting the limbs and tongue, with apparent exacerbation of symptoms after hormonal stimulation. Laboratory tests showed normal creatine kinase levels. Electromyography revealed diffuse mild myopathic changes. Muscle MRI was substantially normal. Polygraphic tremor analysis confirmed the presence of a postural tremor at a frequency of 10–11 Hz. Muscle biopsy showed selective type 1 fiber hypotrophy. Clinical exome sequencing revealed the heterozygous c.788T>G p.(Leu263Arg) variant in exon 11 in the MYBPC1 gene. This variant has been previously reported in multiple independent subjects displaying skeletal muscle weakness and myogenic tremor. Our case helps further define the phenotypic spectrum of this disorder, providing additional clinical and pathologically relevant insides, including the possible influence of hormonal stimulation and a detailed characterization of muscle biopsy findings. Knowledge of this myopathic phenotype may allow identification of individuals with MYBPC1 variants without arthrogryposis.