# 618823

CONGENITAL MYOPATHY 9B, PROXIMAL, WITH MINICORE LESIONS; CMYP9B


Alternative titles; symbols

MYOPATHY, CONGENITAL PROXIMAL, WITH MINICORE LESIONS; MYOPMIL


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3q26.33 Congenital myopathy 9B, proximal, with minicore lesions 618823 AR 3 FXR1 600819
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Neck
- Neck muscle weakness
RESPIRATORY
- Respiratory insufficiency
- Obstructive sleep apnea
CHEST
Ribs Sternum Clavicles & Scapulae
- Scapular winging (in some patients)
SKELETAL
Spine
- Scoliosis
- Rigid spine
Limbs
- Distal joint laxity
- Joint contractures
MUSCLE, SOFT TISSUES
- Hypotonia, neonatal
- Axial hypotonia
- Proximal muscle weakness
- Proximal muscle atrophy
- Upper limbs may be affected
- Distal muscle weakness, mild
- Foot drop
- Gowers sign
- Calf muscle hypertrophy
- Difficulty running or climbing
- Myopathic process seen on EMG
- Type 1 fiber predominance seen on muscle biopsy
- Increased internal nuclei
- Fatty infiltration
- Z-band streaming
- Minicores that disrupt the myofibrillar striation pattern
NEUROLOGIC
Central Nervous System
- Delayed motor development
- Delayed walking (3-5 years)
Peripheral Nervous System
- Hyporeflexia
LABORATORY ABNORMALITIES
- Normal creatine kinase
MISCELLANEOUS
- Onset soon after birth
- Slowly progressive
MOLECULAR BASIS
- Caused by mutation in the FMR1 autosomal homolog 1 gene (FXR1, 600819.0002)
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 proximal myopathy-9B with minicore lesions (CMYP9B) is caused by homozygous mutation in the FXR1 gene (600819) on chromosome 3q28.

Biallelic mutation in the FXR1 gene also causes CMYP9A (618822), which has a more severe phenotype.


Description

Congenital myopathy-9B (CMYP9B) is an autosomal recessive early-onset skeletal muscle disorder mainly affecting proximal muscles. Affected individuals have neonatal hypotonia followed by mildly delayed walking in childhood. Muscle weakness is slowly progressive, resulting in positive Gowers sign and difficulty running or climbing, but most patients remain ambulatory. Some patients develop respiratory involvement requiring ventilatory support, whereas cardiac function is unaffected. Muscle biopsy shows type 1 fiber predominance with disorganized Z-lines and multiminicore myopathy (Estan et al., 2019).

For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).


Clinical Features

Estan et al. (2019) reported 3 adult sibs (family 2), ranging in age from 24 to 28 years, with congenital myopathy. The sibs had neonatal hypotonia and mildly delayed gross motor development, with walking around 3 to 5 years of age. They had mildly progressive proximal more than distal muscle weakness with Gowers sign, difficulty running or climbing, and hyporeflexia, but all remained ambulatory. EMG studies were consistent with a myopathic process. None of the sibs had cardiac or cognitive dysfunction, swallowing difficulties, dysarthria, or abnormal ocular movements, but all had obstructive sleep apnea. The oldest sib had cryptorchidism, short stature, obesity, and mild scoliosis. Skeletal muscle biopsy of 1 patient showed type 1 fiber predominance, increased internal nuclei, fatty infiltration, areas of Z-streaming, and minicores that disrupted the myofibrillar striation pattern. Serum creatine kinase was normal. The mother was of Argentinian descent and the father was of Turkish descent; family history revealed 2 spontaneous miscarriages. Genetic analysis identified a homozygous mutation in the FXR1 gene (c.1707delA; 600819.0002). Mroczek et al. (2022) reported follow-up of the family reported by Estan et al. (2019) (family D), noting that all 3 individuals had psychiatric disorders, including depression, anxiety, bipolar, and attention deficit.

Mroczek et al. (2022) reported 5 patients from 3 unrelated families with CMYP9B. Three adult patients from families A and B had a history of hypotonia and delayed motor development from infancy or early childhood. Features included proximal muscle weakness and atrophy, difficulties running and jumping, and upper limb weakness with scapular winging; foot drop and distal muscle weakness were also observed. Additional variable features included distal joint laxity, hypertrophy of the anterior thigh and calf muscles, scoliosis, and rigid spine. The disorder was slowly progressive: at ages 45, 58, and 53, they had variable muscle weakness and walking difficulties. The patient from family B developed severe respiratory dysfunction around 20 years of age. Muscle biopsies demonstrated minicores, cores, internal nuclei, type 1 fiber predominance, and fiber size variability. MRI showed relative sparing of the quadriceps femoris muscle. Exome sequencing identified a homozygous frameshift mutation in the FXR1 gene (c.1707dupA; 600819.0003) in the 3 patients from families A and B.

Mroczek et al. (2022) also reported 2 sibs, born of consanguineous Turkish parents (family C), who presented soon after birth with hypotonia, reduced antigravity movements, and respiratory distress. They showed delayed motor development with axial hypotonia and neck muscle weakness. The older sib had a slow deterioration with progressive scoliosis, poor head control, dependency on a wheelchair, mild joint contractures, and recurrent respiratory infections, which led to her death at age 17 years. Her 2.5-year-old brother was unable to walk and had neck muscle weakness with axial hypotonia and absent deep tendon reflexes. Genetic analysis identified a homozygous frameshift mutation in the FXR1 gene (c.1699dupG; 600819.0004) in these sibs.


Inheritance

The transmission pattern of CMYP9B in the family reported by Estan et al. (2019) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 3 adult sibs, born of unrelated parents (family 2), with CMYP9B, Estan et al. (2019) identified a homozygous 1-bp deletion (c.1707delA; 600819.0002) at the 5-prime end of exon 15 of the FXR1 gene, predicted to result in a frameshift and premature termination (Lys569AsnfsTer57). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in the unaffected mother; array CGH of the paternal allele indicated that the deceased father may have carried the mutation. The mutation was predicted to result in nonsense-mediated mRNA decay (NMD).

In 3 patients from 2 unrelated families (A and B) with CMYP9B, Mroczek et al. (2022) identified a homozygous frameshift mutation in the FXR1 gene (c.1707dupA; 600819.0003). Two sibs, born of consanguineous Turkish parents (family C), with CMYP9B carried a homozygous frameshift mutation in the FXR1 gene (c.1699dupG; 600819.0004). Both mutations occurred at the 5-prime end of exon 15 of the FXR1 muscle isoform. The mutations were found by exome sequencing and segregated with the disorder in families B and C. Functional studies of the variants were not performed.


Animal Model

Estan et al. (2019) found that inactivation of all isoforms of Fxr1 specifically in skeletal muscle myoblasts in mice resulted in neonatal lethality. Generation of mutant mice with a 1-bp duplication (dupA) in the Fxr1 gene showed a myopathic phenotype with decreased muscle strength, reduced fiber size, and mild Z-line abnormalities. RT-PCR analysis showed that the dupA mutation was subjected to NMD with decreased Fxr1 expression at about 30% of control levels. Fxr1 protein expression was essentially absent in dupA myotubes; there were no abnormal ring-shaped granules, and cores were only sporadically observed. These findings indicated that skeletal muscle-specific FXR1 82- and 84-kD proteins are required for maintaining alignment and organization of Z-lines, and that dysregulated translation of specific mRNAs involved in Z-line organization may underlie the myopathic phenotype.


REFERENCES

  1. Estan, M. C., Fernandez-Nunez, E., Zaki, M. S., Esteban, M. I., Donkervoort, S., Hawkins, C., Caparros-Martin, J. A., Saade, D., Hu, Y., Bolduc, V., Chao, K. R.-Y., Nevado, J., and 18 others. Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. Nature Commun. 10: 797, 2019. Note: Electronic Article. [PubMed: 30770808, images, related citations] [Full Text]

  2. Mroczek, M., Longman, C., Farrugia, M. E., Kapetanovic Garcia, S., Ardicli, D., Topaloglu, H., Hernandez-Lain, A., Orhan, D., Alikasifoglu, M., Duff, J., Specht, S., Nowak, K., Ravenscroft, G., Chao, K., Valivullah, Z., Donkervoort, S., Saade, D., Bonnemann, C., Straub, V., Yoon, G. FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum. J. Med. Genet. 59: 1069-1074, 2022. [PubMed: 35393337, related citations] [Full Text]


Contributors:
Cassandra L. Kniffin - updated : 03/08/2023
Creation Date:
Cassandra L. Kniffin : 03/23/2020
carol : 03/13/2023
alopez : 03/10/2023
alopez : 03/09/2023
ckniffin : 03/08/2023
carol : 03/26/2020
carol : 03/25/2020
ckniffin : 03/23/2020
ckniffin : 03/23/2020

# 618823

CONGENITAL MYOPATHY 9B, PROXIMAL, WITH MINICORE LESIONS; CMYP9B


Alternative titles; symbols

MYOPATHY, CONGENITAL PROXIMAL, WITH MINICORE LESIONS; MYOPMIL


DO: 0081344;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3q26.33 Congenital myopathy 9B, proximal, with minicore lesions 618823 Autosomal recessive 3 FXR1 600819

TEXT

A number sign (#) is used with this entry because of evidence that congenital proximal myopathy-9B with minicore lesions (CMYP9B) is caused by homozygous mutation in the FXR1 gene (600819) on chromosome 3q28.

Biallelic mutation in the FXR1 gene also causes CMYP9A (618822), which has a more severe phenotype.


Description

Congenital myopathy-9B (CMYP9B) is an autosomal recessive early-onset skeletal muscle disorder mainly affecting proximal muscles. Affected individuals have neonatal hypotonia followed by mildly delayed walking in childhood. Muscle weakness is slowly progressive, resulting in positive Gowers sign and difficulty running or climbing, but most patients remain ambulatory. Some patients develop respiratory involvement requiring ventilatory support, whereas cardiac function is unaffected. Muscle biopsy shows type 1 fiber predominance with disorganized Z-lines and multiminicore myopathy (Estan et al., 2019).

For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).


Clinical Features

Estan et al. (2019) reported 3 adult sibs (family 2), ranging in age from 24 to 28 years, with congenital myopathy. The sibs had neonatal hypotonia and mildly delayed gross motor development, with walking around 3 to 5 years of age. They had mildly progressive proximal more than distal muscle weakness with Gowers sign, difficulty running or climbing, and hyporeflexia, but all remained ambulatory. EMG studies were consistent with a myopathic process. None of the sibs had cardiac or cognitive dysfunction, swallowing difficulties, dysarthria, or abnormal ocular movements, but all had obstructive sleep apnea. The oldest sib had cryptorchidism, short stature, obesity, and mild scoliosis. Skeletal muscle biopsy of 1 patient showed type 1 fiber predominance, increased internal nuclei, fatty infiltration, areas of Z-streaming, and minicores that disrupted the myofibrillar striation pattern. Serum creatine kinase was normal. The mother was of Argentinian descent and the father was of Turkish descent; family history revealed 2 spontaneous miscarriages. Genetic analysis identified a homozygous mutation in the FXR1 gene (c.1707delA; 600819.0002). Mroczek et al. (2022) reported follow-up of the family reported by Estan et al. (2019) (family D), noting that all 3 individuals had psychiatric disorders, including depression, anxiety, bipolar, and attention deficit.

Mroczek et al. (2022) reported 5 patients from 3 unrelated families with CMYP9B. Three adult patients from families A and B had a history of hypotonia and delayed motor development from infancy or early childhood. Features included proximal muscle weakness and atrophy, difficulties running and jumping, and upper limb weakness with scapular winging; foot drop and distal muscle weakness were also observed. Additional variable features included distal joint laxity, hypertrophy of the anterior thigh and calf muscles, scoliosis, and rigid spine. The disorder was slowly progressive: at ages 45, 58, and 53, they had variable muscle weakness and walking difficulties. The patient from family B developed severe respiratory dysfunction around 20 years of age. Muscle biopsies demonstrated minicores, cores, internal nuclei, type 1 fiber predominance, and fiber size variability. MRI showed relative sparing of the quadriceps femoris muscle. Exome sequencing identified a homozygous frameshift mutation in the FXR1 gene (c.1707dupA; 600819.0003) in the 3 patients from families A and B.

Mroczek et al. (2022) also reported 2 sibs, born of consanguineous Turkish parents (family C), who presented soon after birth with hypotonia, reduced antigravity movements, and respiratory distress. They showed delayed motor development with axial hypotonia and neck muscle weakness. The older sib had a slow deterioration with progressive scoliosis, poor head control, dependency on a wheelchair, mild joint contractures, and recurrent respiratory infections, which led to her death at age 17 years. Her 2.5-year-old brother was unable to walk and had neck muscle weakness with axial hypotonia and absent deep tendon reflexes. Genetic analysis identified a homozygous frameshift mutation in the FXR1 gene (c.1699dupG; 600819.0004) in these sibs.


Inheritance

The transmission pattern of CMYP9B in the family reported by Estan et al. (2019) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 3 adult sibs, born of unrelated parents (family 2), with CMYP9B, Estan et al. (2019) identified a homozygous 1-bp deletion (c.1707delA; 600819.0002) at the 5-prime end of exon 15 of the FXR1 gene, predicted to result in a frameshift and premature termination (Lys569AsnfsTer57). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in the unaffected mother; array CGH of the paternal allele indicated that the deceased father may have carried the mutation. The mutation was predicted to result in nonsense-mediated mRNA decay (NMD).

In 3 patients from 2 unrelated families (A and B) with CMYP9B, Mroczek et al. (2022) identified a homozygous frameshift mutation in the FXR1 gene (c.1707dupA; 600819.0003). Two sibs, born of consanguineous Turkish parents (family C), with CMYP9B carried a homozygous frameshift mutation in the FXR1 gene (c.1699dupG; 600819.0004). Both mutations occurred at the 5-prime end of exon 15 of the FXR1 muscle isoform. The mutations were found by exome sequencing and segregated with the disorder in families B and C. Functional studies of the variants were not performed.


Animal Model

Estan et al. (2019) found that inactivation of all isoforms of Fxr1 specifically in skeletal muscle myoblasts in mice resulted in neonatal lethality. Generation of mutant mice with a 1-bp duplication (dupA) in the Fxr1 gene showed a myopathic phenotype with decreased muscle strength, reduced fiber size, and mild Z-line abnormalities. RT-PCR analysis showed that the dupA mutation was subjected to NMD with decreased Fxr1 expression at about 30% of control levels. Fxr1 protein expression was essentially absent in dupA myotubes; there were no abnormal ring-shaped granules, and cores were only sporadically observed. These findings indicated that skeletal muscle-specific FXR1 82- and 84-kD proteins are required for maintaining alignment and organization of Z-lines, and that dysregulated translation of specific mRNAs involved in Z-line organization may underlie the myopathic phenotype.


REFERENCES

  1. Estan, M. C., Fernandez-Nunez, E., Zaki, M. S., Esteban, M. I., Donkervoort, S., Hawkins, C., Caparros-Martin, J. A., Saade, D., Hu, Y., Bolduc, V., Chao, K. R.-Y., Nevado, J., and 18 others. Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. Nature Commun. 10: 797, 2019. Note: Electronic Article. [PubMed: 30770808] [Full Text: https://doi.org/10.1038/s41467-019-08548-9]

  2. Mroczek, M., Longman, C., Farrugia, M. E., Kapetanovic Garcia, S., Ardicli, D., Topaloglu, H., Hernandez-Lain, A., Orhan, D., Alikasifoglu, M., Duff, J., Specht, S., Nowak, K., Ravenscroft, G., Chao, K., Valivullah, Z., Donkervoort, S., Saade, D., Bonnemann, C., Straub, V., Yoon, G. FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum. J. Med. Genet. 59: 1069-1074, 2022. [PubMed: 35393337] [Full Text: https://doi.org/10.1136/jmedgenet-2021-108341]


Contributors:
Cassandra L. Kniffin - updated : 03/08/2023

Creation Date:
Cassandra L. Kniffin : 03/23/2020

Edit History:
carol : 03/13/2023
alopez : 03/10/2023
alopez : 03/09/2023
ckniffin : 03/08/2023
carol : 03/26/2020
carol : 03/25/2020
ckniffin : 03/23/2020
ckniffin : 03/23/2020