Neuromuscular NGS Panel

Imported from OMIM

Congenital myopathy-2A (CMYO2A) is an autosomal dominant disorder of the skeletal muscle characterized by infantile- or childhood-onset myopathy with delayed motor milestones and nonprogressive muscle weakness. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype (CMYO2C; 620278). Some patients with de novo mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life. Of note, intrafamilial variability has also been reported: a severely affected proband may be identified and then mildly affected or even asymptomatic relatives are found to carry the same mutation. The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). The most common histologic finding on muscle biopsy in patients with ACTA1 mutations is the presence of 'nemaline rods,' which represent abnormal thread- or rod-like structures ('nema' is Greek for 'thread'). However, skeletal muscle biopsy from patients with mutations in the ACTA1 gene can show a range of pathologic phenotypes. These include classic rods, intranuclear rods, clumped filaments, cores, or fiber-type disproportion, all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. Most patients have clinically severe disease, regardless of the histopathologic phenotype (Nowak et al., 2007; Sewry et al., 2019). ACTA1 mutations are the second most common cause of congenital myopathies classified histologically as 'nemaline myopathy' after mutations in the NEB gene (161650). ACTA1 mutations are overrepresented in the severe phenotype with early death (Laing et al., 2009). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Imported from Human Phenotype Ontology (HPO)

• Primary dilated cardiomyopathy
• Dysphagia
• Polyhydramnios
• Hyperlordosis
• Hypertonia
• Rigidity
• Respiratory insufficiency
• Retrognathia
• Scoliosis
• Hyperreflexia
• Proximal muscle weakness
• Waddling gait
• Areflexia
• Decreased fetal movement
• High palate
• Myopathic facies
• Facial palsy
• Mask-like facies
• Limb muscle weakness
• Hyporeflexia
• Pes cavus
• Generalized muscle weakness
• Frequent falls
• Neck flexor weakness
• Mildly elevated creatine kinase
• Slender build
• Motor delay
• Type 1 muscle fiber predominance
• Spinal rigidity
• Neonatal hypotonia
• Feeding difficulties in infancy
• Respiratory insufficiency due to muscle weakness
• Nemaline bodies
• EMG: myopathic abnormalities
• EMG: neuropathic changes
• Late-onset distal muscle weakness
• Bulbar palsy
• Arthrogryposis multiplex congenita