Alternative titles; symbols
DO: 0081344;
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 |
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.
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).
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.
The transmission pattern of CMYP9B in the family reported by Estan et al. (2019) was consistent with autosomal recessive inheritance.
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.
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.
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]
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]