# 618524

CONGENITAL MYOPATHY 16; CMYP16


Alternative titles; symbols

MYOPATHY, CONGENITAL, WITH TREMOR; MYOTREM
MYOGENIC TREMOR


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
12q23.2 Congenital myopathy 16 618524 AD 3 MYBPC1 160794
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Myopathic facies
- Dysmorphic features, mild (in some patients)
- Prominent nasolabial folds
- Micrognathia
Eyes
- Ptosis
Mouth
- High-arched palate Microstomia
- Pouting lips
- Lip tremor
- Tongue tremor on protrusion
CHEST
Ribs Sternum Clavicles & Scapulae
- Scapular winging
SKELETAL
Spine
- Scoliosis
- Lordosis
- Spinal rigidity
Limbs
- Contractures, mild, postnatal onset (in some patients)
MUSCLE, SOFT TISSUES
- Hypotonia, neonatal
- Muscle weakness, proximal more than distal
- Axial muscle weakness
- Waddling gait
- Poor stamina
- Muscle atrophy (in some patients)
- Myalgia (in some patients)
- Tremor, resting and intentional, high-frequency
- Myopathic pattern seen on ERG
NEUROLOGIC
Central Nervous System
- Delayed walking, mild
- Normal cognition
Peripheral Nervous System
- Hyporeflexia
MISCELLANEOUS
- Onset in infancy
- Slow progression during childhood
- Plateau and stability in adolescence and adulthood
MOLECULAR BASIS
- Caused by mutation in the myosin-binding protein C, slow type gene (MYBPC1, 160794.0004)
Myopathy, congenital (see also nemaline myopathy (PS161800), myofibrillar myopathy (PS601419), and centronuclear myopathy (PS160150) - PS117000 - 31 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.13 Congenital myopathy 19 AR 3 618578 PAX7 167410
1p36.11 Congenital myopathy 3 with rigid spine AR 3 602771 SELENON 606210
1p31.1 Congenital myopathy 21 with early respiratory failure AR 3 620326 DNAJB4 611327
1q21.3 Congenital myopathy 4B, autosomal recessive AR 3 609284 TPM3 191030
1q21.3 Congenital myopathy 4A, autosomal dominant AD 3 255310 TPM3 191030
1q32.1 Congenital myopathy 18 due to dihydropyridine receptor defect AD, AR 3 620246 CACNA1S 114208
1q42.13 Congenital myopathy 2C, severe infantile, autosomal dominant AD 3 620278 ACTA1 102610
1q42.13 Congenital myopathy 2A, typical, autosomal dominant AD 3 161800 ACTA1 102610
1q42.13 Congenital myopathy 2B, severe infantile, autosomal recessive AR 3 620265 ACTA1 102610
1q43 Congenital myopathy 8 AD 3 618654 ACTN2 102573
2q31.2 Congenital myopathy 5 with cardiomyopathy AR 3 611705 TTN 188840
2q34 Congenital myopathy 14 AR 3 618414 MYL1 160780
3q26.33 Congenital myopathy 9B, proximal, with minicore lesions AR 3 618823 FXR1 600819
3q26.33 ?Congenital myopathy 9A with respiratory insufficiency and bone fractures AR 3 618822 FXR1 600819
5q23.2 Congenital myopathy 10B, mild variant AR 3 620249 MEGF10 612453
5q23.2 Congenital myopathy 10A, severe variant AR 3 614399 MEGF10 612453
9p13.3 Congenital myopathy 23 AD 3 609285 TPM2 190990
10p12.33 Congenital myopathy 11 AR 3 619967 HACD1 610467
11p15.1 Congenital myopathy 17 AR 3 618975 MYOD1 159970
12q12 ?Congenital myopathy 12 AR 3 612540 CNTN1 600016
12q13.3 Congenital myopathy 13 AR 3 255995 STAC3 615521
12q23.2 Congenital myopathy 16 AD 3 618524 MYBPC1 160794
14q11.2 Congenital myopathy 7B, myosin storage, autosomal recessive AR 3 255160 MYH7 160760
14q11.2 Congenital myopathy 7A, myosin storage, autosomal dominant AD 3 608358 MYH7 160760
15q13.3-q14 Congenital myopathy 20 AR 3 620310 RYR3 180903
17p13.1 Congenital myopathy 6 with ophthalmoplegia AD, AR 3 605637 MYH2 160740
17q23.3 Congenital myopathy 22B, severe fetal AR 3 620369 SCN4A 603967
17q23.3 Congenital myopathy 22A, classic AR 3 620351 SCN4A 603967
19q13.2 Congenital myopathy 1B, autosomal recessive AR 3 255320 RYR1 180901
19q13.2 Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia AD 3 117000 RYR1 180901
20q13.12 Congenital myopathy 15 AD 3 620161 TNNC2 191039

TEXT

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.


Description

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).


Clinical Features

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.


Inheritance

The transmission pattern of CMYP16 in the families reported by Stavusis et al. (2019) was consistent with autosomal dominant inheritance.


Molecular Genetics

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.


REFERENCES

  1. 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, images, related citations] [Full Text]

  2. 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, images, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 08/20/2019
alopez : 03/10/2023
alopez : 03/10/2023
carol : 08/22/2019
carol : 08/21/2019
ckniffin : 08/20/2019

# 618524

CONGENITAL MYOPATHY 16; CMYP16


Alternative titles; symbols

MYOPATHY, CONGENITAL, WITH TREMOR; MYOTREM
MYOGENIC TREMOR


DO: 0081348;  


Phenotype-Gene Relationships

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

TEXT

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.


Description

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).


Clinical Features

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.


Inheritance

The transmission pattern of CMYP16 in the families reported by Stavusis et al. (2019) was consistent with autosomal dominant inheritance.


Molecular Genetics

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.


REFERENCES

  1. 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]

  2. 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]


Creation Date:
Cassandra L. Kniffin : 08/20/2019

Edit History:
alopez : 03/10/2023
alopez : 03/10/2023
carol : 08/22/2019
carol : 08/21/2019
ckniffin : 08/20/2019