A number sign (#) is used with this entry because of evidence that classic congenital myopathy-22A (CMYO22A) is caused by homozygous or compound heterozygous mutation in the SCN4A gene (603967) on chromosome 17q23.

Biallelic mutation in the SCN4A gene also causes severe fetal congenital myopathy-22B (CMYO22B; 620369).

Classic congenital myopathy-22A (CMYO22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016).

For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Zaharieva et al. (2016) reported 5 patients, ranging in age from 2.5 to 35 years, from 4 unrelated families (families 1-4) with CMYO22A apparent in utero or at birth. Two patients showed fetal hypokinesia; 2 of the pregnancies were complicated by polyhydramnios and 2 by breech presentation. As infants, the patients had moderate to severe generalized hypotonia with facial, neck, axial, and limb muscle weakness, weak cry, absent reflexes, and reduced muscle mass. They had bulbar involvement with oromotor weakness and swallowing difficulties, often requiring tube feeding or respiratory support. The patients had delayed motor development with proximal muscle weakness of the upper and lower limbs and neck muscle weakness, but all were ambulatory with an unsteady gait and showed clinical improvement during the first decade. Some needed assistance for longer distances. Additional features included elongated face, high-arched palate, hypernasal speech, mild dysmorphic features, limb contractures, foot deformities, hyporeflexia, ophthalmoplegia, easy fatigability, and decreased respiratory forced vital capacity. Two had oromotor weakness and expressive language delay. Less common features included scoliosis, kyphosis, spinal rigidity, chest wall deformities, joint hypermobility, and scapular winging. Muscle biopsies showed nonspecific myopathic features, including fiber size variability, without structural abnormalities. MRI, performed in 2 patients, showed involvement of the gluteus, sartorius, adductor magnus, and soleus muscles. EMG studies were normal or showed myopathic changes. Repetitive stimulation testing in the oldest patient showed a 60% decrement at 10 Hz. Family 4 contained an 8-year-old girl who was resuscitated at birth and tube-fed until age 4 years, but later improved and was able to walk with an unstable gait and run; her sister was born in the breech position, showed no movement or respiratory effort at birth, and died 5 hours post-delivery.

Gonorazky et al. (2017) reported 2 brothers, born of unrelated parents of East Indian descent, with CMYO22A. The patients, who were 21 and 18 years of age, had hypotonia at birth and walked around 14 months of age with an unsteady gait and frequent falls due to proximal muscle weakness. Upper limbs were mildly affected, although scapular winging and ophthalmoplegia were not observed. The younger sib had a history of recurrent episodes of flaccid paralysis after fever. Additional features included ptosis, facial muscle weakness, high-arched palate, distal joint hypermobility, pseudohypertrophy of the calves, and scaphocephaly. Serum creatine kinase was mildly elevated, and muscle MRI showed involvement of the gluteus maximus, sartorius, adductor magnus, and soleus muscles. Muscle biopsy was myopathic with mild fiber size variation, multiple internal nuclei with a 'crown' or 'corona' appearance surrounding core-like regions, fatty replacement, and fibrosis. Electron microscopy showed myofibrillar disarray.

Berghold et al. (2022) reported an 18-year-old girl with CMYO22A. She was born at term to unrelated parents by C-section due to breech presentation. The mother reported decreased fetal movements. Soon after birth, the infant showed severe hypotonia, respiratory insufficiency requiring tracheostomy, and feeding difficulties requiring tube feeding. Her motor development was severely delayed; she never achieved proper head control or independent sitting or standing and was wheelchair-bound with muscle weakness and atrophy affecting both the lower and upper limbs. Additional features included elongated hypotonic face, open mouth, strabismus, ptosis, external ophthalmoplegia, scoliosis, and osteoporosis. Cognitive function was preserved, speech was normal, and she was able to finish school and find a sheltered job. Laboratory studies initially suggested a mitochondrial disorder (decreased complex I activity), but whole-exome sequencing identified compound heterozygous mutations in the SCN4A gene that were inherited from her unaffected parents.

The transmission pattern of CMYO22A in the families reported by Zaharieva et al. (2016) was consistent with autosomal recessive inheritance.

In 8 patients from 4 unrelated families (families 1-4) with CMYO22A, Zaharieva et al. (2016) identified compound heterozygous mutations in the SCN4A gene (see, e.g., R225W, 603967.0034 and C1209F, 603967.0035). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. There were missense, nonsense, frameshift, and splice site mutations distributed throughout the gene. Electrophysiologic studies of the missense variants in HEK293 cells showed that they caused loss-of-function effects to varying degrees. In families 1, 2, and 4, the patients carried a complete loss-of-function mutation in combination with a hypomorphic allele. The patient in family 3 carried a putative loss-of-function mutation on 1 allele (Q470X) and a frameshift mutation on the other allele (c.5345dup, H1782QfsTer65) at the C terminus, generating a protein that was 9 amino acids longer than wildtype. Functional analysis of the H1782QfsTer65 variant showed that it did not cause any loss of channel function or alterations of channel kinetics. However, the authors postulated that this frameshift mutation could disrupt channel function in a tissue-specific manner or cause loss-of-function effects not identified in the studies. The patient in family 1 carried a loss-of-function missense mutation (R104H) on 1 allele and R1135C on the other allele. R1135C caused a loss of function by enhancing fast inactivation. None of the carrier parents was affected, indicating that loss of function in only 1 SCN4A allele is insufficient to cause a clinical phenotype.

In 2 brothers, born of unrelated parents of East Indian descent, with CMYO22A, Gonorazky et al. (2017) identified compound heterozygous missense mutations in the SCN4A gene (C375R, 603967.0039 and R1142Q, 603967.0040). The mutations, which were found by exome sequencing, segregated with the disorder in the family. In vitro electrophysiologic studies in HEK293 cells showed that the C375R mutation abolished sodium activity and caused a complete loss of SCN4A function, whereas the R1142Q mutation was hypomorphic with reduced peak current densities due to a 4-mV depolarizing shift of activation. Fast inactivation properties of the R1142Q mutant channel were also mildly affected.

In an 18-year-old girl, born of unrelated parents, with CMYO22A, Berghold et al. (2022) identified compound heterozygous missense mutations in the SCN4A gene (R1454W, 603967.0041 and N1205K, 603967.0042). The mutations, which were found by whole-exome sequencing, were inherited from the unaffected parents. R1454W, located in the voltage sensor of domain IV, had been demonstrated to be a loss-of-function variant by Habbout et al. (2016). N1205K, located in a region forming the channel pore, was a novel variant. No functional studies of N1205K were performed, but it was predicted to cause a loss of function based on studies of paralogous variants in other SCNA genes.