Alternative titles; symbols
DO: 0081348;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
12q23.2 | Congenital myopathy 16 | 618524 | Autosomal dominant | 3 | MYBPC1 | 160794 |
A number sign (#) is used with this entry because of evidence that congenital myopathy-16 (CMYP16) is caused by heterozygous mutation in the MYBPC1 gene (160794) on chromosome 12q23.
Congenital myopathy-16 (CMYP16) is an autosomal dominant muscle disorder characterized by onset of hypotonia and tremor in infancy. Patients have mildly delayed walking, unsteady gait, proximal muscle weakness, and a high-frequency tremor of the limbs. Some may develop secondary mild contractures or spinal deformities. Cognition is normal and the disease course tends to stabilize after adolescence (summary by Stavusis et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Shashi et al. (2019) reported 2 unrelated Caucasian children and a Korean father and daughter with a similar mild form of congenital myopathy. The patients presented with severe hypotonia in infancy; none had contractures. The hypotonia improved over time, and 3 individuals achieved ambulation in the first years of life, although 2 had an unsteady gait. The youngest patient, who was 23 months of age, was not able to walk, but could sit with support and scoot. The patients also had hypotonic facies, lingual tremor with protrusion, lip tremor, postural and intention tremor of the extremities, poor stamina, proximal muscle weakness affecting the shoulder girdle, and hypotonic facies. None had cerebellar features or abnormal brain imaging, and cognition was normal.
Stavusis et al. (2019) described a similar congenital myopathy with tremor in 8 patients from 2 unrelated multigenerational families, of Latvian and German descent, respectively. The patients ranged in age from 6 months to 57 years. The patients had hypotonia and postural hand tremor from infancy, although the probands did not present until adulthood. Features included muscle weakness, more proximal than distal, variable muscle atrophy, myalgia, and steppage gait. Secondary features included high-arched palate, mild contractures of the elbows, ankles, or feet, scapular winging, scoliosis, lordosis, spinal rigidity, and thoracic asymmetry. Some had mild facial dysmorphisms, such as micrognathia, prominent nasolabial folds, and microstomia with pouting lips. All had a high-frequency postural tremor that was not thought to be neurogenic in origin. EMG studies in 2 patients showed a myopathic pattern. The features tended to show slow progression during childhood, with a plateau in adolescence and subsequent stability. Cognition was normal.
The transmission pattern of CMYP16 in the families reported by Stavusis et al. (2019) was consistent with autosomal dominant inheritance.
In 4 patients from 3 families with CMYP16, Shashi et al. (2019) identified heterozygous missense mutations in the MYBPC1 gene (L263R, 160794.0004 and L259P, 160794.0005). Both mutations occurred at highly conserved residues in the M-motif. The variants were found by whole-exome sequencing and confirmed by Sanger sequencing; the mutations occurred de novo in 3 patients and was inherited in the fourth. In vitro functional expression studies showed that the L263R mutation resulted in significantly decreased binding of the M-motif to myosin compared to wildtype, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Actin binding was similar to wildtype. In contrast, the L259P mutation did not affect MYBPC1 myosin or actin binding, but molecular modeling and dynamic studies showed that the L259P mutation affected helicity of certain domains and that the mutant protein was more susceptible to cleavage than wildtype following trypsin digestion.
In 7 patients from 2 multigenerational families with CMYP16, Stavusis et al. (2019) identified heterozygous missense mutations in the MYBPC1 gene (E248K, 160794.0006 and Y247H, 160794.0007). The mutations, which were found by exome sequencing or next-generation sequencing of a panel and confirmed by Sanger sequencing, segregated with the disorder in the families. Both mutations occurred in the M-motif and were shown in vitro to cause increased myosin binding compared to wildtype. Molecular modeling and dynamic studies confirmed that the altered binding activity likely results from changes in electrostatic interactions. Stavusis et al. (2019) suggested that the abnormal binding to myosin may interfere with normal cross-bridge kinetics, resulting in the myopathic phenotype. In particular, the authors postulated that the tremor observed in all patients was sarcomeric and myogenic in origin, possibly resulting from abnormal synchronization or oscillation of effector muscles.
Shashi, V., Geist, J., Lee, Y., Yoo, Y., Shin, U., Schoch, K., Sullivan, J., Stong, N., Smith, E., Jasien, J., Kranz, P., Undiagnosed Diseases Network, Lee, Y., Shin, Y. B., Wright, N. T., Choi, M., Kontrogianni-Konstantopoulos, A. Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis. Hum. Mutat. 40: 1115-1126, 2019. [PubMed: 31264822] [Full Text: https://doi.org/10.1002/humu.23760]
Stavusis, J., Lace, B., Schafer, J., Geist, J., Inashkina, I., Kidere, D., Pajusalu, S., Wright, N. T., Saak, A., Weinhold, M., Haubenberger, D., Jackson, S., Kontrogianni-Konstantopoulos, A., Bonnemann, C. G. Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy. Ann. Neurol. 86: 129-142, 2019. [PubMed: 31025394] [Full Text: https://doi.org/10.1002/ana.25494]