Recommended panel testing at BREDA GENETICS for this condition (EXOME PANEL):
Making a genetic diagnosis of congenital myopathies is not easy, but it’s necessary to assess the recurrence risk. Nance JR et al (PMID: 22392505) have very clearly stated that the three main categories of classical congenital myopathies are: nemaline myopathy, core myopathy, and centronuclear myopathy.
Nemaline myopathy (NEM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Six forms of NEM have been identified and classified by onset and severity. The severe, congenital form affects 16% of all patients with NEM. No clear genotype-phenotype correlations have been established, as overlap is frequently observed. The congenital form may be caused by mutations in one off the following genes: NEB, ACTA1, TNNT1, TPM3, TPM2 and CFL2 (for KBTBD13 only childhood onset is so far described).
Core myopathy, also known as multiminicore disease, is classified into four forms: classic (75% of individuals), moderate (<10%), antenatal with arthrogryposis multiplex congenita (<10%), and ophthalmoplegic (<10%). Onset of the classic form is usually congenital or early in childhood. It is characterized by neonatal hypotonia, delayed motor development, axial muscle weakness, scoliosis, and respiratory involvement. Multiple “minicores” are visible on muscle biopsy and are characteristics. Mutations have been identified in SEPN1 and RYR1, although such mutations account for only 50% of all cases. Thus, genetic heterogeneity has been suggested, even if no other loci has been identified yet.
Centronuclear myopathy refers to a group of genetically heterogeneous disorders. Centronuclear myopathy 1 (CNM1) is characterized by involvement of limb girdle, trunk and neck. Distal muscles may be also affected. Onset is in childhood or adolescence or in the third decade. Mutations are in the DNM2 gene and the disorder is autosomal dominantly inherited. Tosch et al (PMID 17008356) provided evidence that mutations in the MTMR14 gene may act as modifiers of the centronuclear myopathy phenotype. CNM2 is caused by BIN1 mutations and the transmission is in this case autosomal recessive. Onset ranges from birth to childhood to adolescence. Of note, Wallgren-Pettersson et al. (1995) noted that the age of onset of CNM2 is generally later than in the X-linked form (CNMX) and earlier than in the autosomal dominant form (CNM1 and CNM3). The severity of the disease seems to be intermediate between the other two forms (PMID 8544184). The only case known of CNM3 has been reported by Kerst et al 2000 (PMID 11053684): a boy affected with a mild form of the disease who showed the first signs at the age of 9 years. X-Linked centronuclear myopathy (CNMX, also known myotubular myopathy) is also distinguishable in different forms: severe or classic CNMX (it presents prenatally with polyhydramnios and decreased fetal movement and in newborns with weakness, hypotonia and respiratory distress), moderate CNMX and mild CNMX. Female carriers of CNMX are generally asymptomatic, but in rare cases they may show signs of the disease. MTM1 is the only gene known to cause CNMX and a mutation is identifiable in 60%-98% of patients. Of note, congenital myotonic dystrophy type 1 (DM1, Steinert dystrophy, caused by repeat expansion in DMPK) is the most likely differential diagnosis for a male with severe CNMX.
Summarizing, genetic testing for congenital myopathy should include at least NEB, ACTA1, TNNT1, TPM3, TPM2, CFL2, KBTBD13, DNM2, BIN1, SEPN1, RYR1 and MTM1.
Recommended panel testing at BREDA GENETICS for this condition (EXOME PANEL):
