A number sign (#) is used with this entry because of evidence that congenital myopathy-18 (CMYO18) is caused by compound heterozygous, homozygous, or heterozygous mutation in the CACNA1S gene (114208) on chromosome 1q32.

Congenital myopathy-18 (CMYO18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency, which can lead to death in severe cases. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. The disorder results from a defect in excitation-contraction coupling in skeletal muscle (Schartner et al., 2017; Ravenscroft et al., 2021; Mauri et al., 2021; Yis et al., 2019).

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

Schartner et al. (2017) reported 11 patients, ranging from 8 to 60 years of age, from 7 unrelated families with congenital myopathy. Four families (families 1-4, of Caucasian, Argentinian, and Vietnamese descent) demonstrated autosomal recessive inheritance, whereas 3 (families 5-7, all of Caucasian origin) demonstrated autosomal dominant inheritance; there were no phenotypic differences between these 2 groups. All patients presented with a congenital myopathy with early-onset hypotonia, delayed motor milestones, and progressive muscle weakness with prominent axial involvement. Decreased fetal movements and breech presentation suggested antenatal involvement in several patients. There was mild facial involvement with a high-arched palate, ophthalmoplegia, and ptosis (1 patient). One patient (P5) also had periodic paralysis with loss of speech during periods of illness and stress. The respiratory system was variably affected, ranging from normal to severely impaired. Most patients had swallowing difficulties, including 1 who required a feeding tube. Serum CK levels were normal in 9 patients, but elevated in the 2 patients from family 7. Scoliosis was present in about half of patients. Skeletal muscle biopsies from 6 patients showed variable morphologic changes. Four patients showed an alveolar aspect of the intermyofibrillar network, and 1 had a reticular pattern of intermyofibrillar network with rare whorled fibers. Fiber size variability, centralized or internalized nuclei, and core-like or focal disorganization of the structure was also observed. There was uniformity of type I fibers and predominance of type I fibers. Ultrastructural studies of patient muscle showed dilated T-tubules and sarcoplasmic reticulum and focal zones of myofibrillar disorganization. The overall findings were suggestive of a diagnosis of centronuclear or core myopathy.

Ravenscroft et al. (2021) reported 2 Caucasian sibs with CMYO18 manifest as fetal akinesia sequence leading to death in utero (the pregnancy was terminated at 26 weeks' gestation in 1 patient) or in infancy (death at 10 days of age in the other patient). Both pregnancies were complicated by polyhydramnios and reduced fetal movements. The patients had wrist contractures, foot deformities, and dysmorphic features.

Yis et al. (2019) reported 3 sibs, born of consanguineous Turkish parents, with a severe form of CMYO18. They all presented soon after birth with axial hypotonia, respiratory failure, external ophthalmoplegia, absent suck, and foot deformities. Two individuals (P1 and P3) died at 3 months of age. P2 was a 5-year-old girl with severe hypotonia, swallowing difficulties requiring tube feeding, scoliosis, lack of neck control, respiratory insufficiency requiring mechanical ventilation, and cognitive delay with mild brain abnormalities that may have been partially due to high oxygen exposure or respiratory insufficiency. Skeletal muscle biopsy showed mild dystrophic and myopathic changes. There was also fiber-type grouping, suggesting a neurogenic process.

Clinical Variability

Mauri et al. (2021) reported a 61-year-old Italian woman who developed ptosis, proximal muscle weakness, cramps, hypophonia, dysphagia, and obstructive sleep apnea requiring nighttime noninvasive ventilation by age 50. No abnormalities were noticed during the neonatal period or childhood, but she was observed to have long limbs, scoliosis, and pectus excavatum during adolescence. The muscle weakness was slowly progressive. Skeletal muscle biopsy showed mild neurogenic alterations, including fiber-type grouping and angulated fibers, as well as focal zones of myofibrillar disorganization and streaming or absence of Z-discs. The 85-year-old mother of the proband, who also carried the CACNA1S mutation, had blepharoplasty for ptosis in her seventies and later developed progressive head drop. The 35-year-old son of the proband, who carried the mutation, was asymptomatic, although he had a thin constitution and long limbs.

The transmission pattern of CMYO18 in 4 families reported by Schartner et al. (2017) was consistent with autosomal recessive inheritance. Two families with the disorder showed autosomal dominant inheritance, and 1 patient had a heterozygous de novo mutation in the CACNA1S gene.

In 5 patients from 4 unrelated families (families 1-4) with autosomal recessive CMYO18, Schartner et al. (2017) identified compound heterozygous mutations in the CACNA1S gene (see, e.g., 114208.0010-114208.0014). All patients carried a frameshift or nonsense mutation on at least 1 allele, resulting in decreased expression of the mutant protein in skeletal muscle samples. In addition, 6 patients from 3 families (families 5-7) with the disorder were found to carry heterozygous missense mutations in the CACNA1S gene (see, e.g., 114208.0015-114207.0017), consistent with autosomal dominant inheritance. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Three patients carried de novo mutations, 2 of whom transmitted the mutation to affected offspring. Western blot analysis of patient skeletal muscle samples from both recessive and dominant cases showed decreased levels of the CACNA1S protein, suggesting instability of the mutant proteins. In vitro functional expression studies of myotubes derived from 2 patients, P1 (recessive inheritance) and P10 (dominant inheritance), showed impaired calcium release in response to depolarization in both, suggesting impaired excitation-contraction coupling due to the CACNA1S mutations. Intracellular calcium stores were normal.

In 2 sibs, born of unrelated Caucasian parents, with CMYO18 manifest as fetal akinesia, Ravenscroft et al. (2021) identified compound heterozygous missense mutations in the CACNA1S gene (M222K, 114208.0018 and R789C, 114208.0019). The mutations, which were found by panel-based sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but they were predicted to reduce protein stability. Both patients died: 1 was terminated at 26 weeks' gestation and the other died at 10 days of age.

In 3 members of an Italian family with a very mild form of CMYO18, Mauri et al. (2021) identified a heterozygous missense variant in the CACNA1S gene (Y1122H). The variant, which was found by next generation sequencing panel analysis and confirmed by Sanger sequencing, was present at a low frequency in gnomAD (1.6 x 10(-5)). The variant occurred at a conserved residue in the first transmembrane segment of domain IV. Functional studies of the variant were not performed, but it was hypothesized to adversely affect excitation-contraction coupling. The authors noted the mild phenotype and late onset in this family, and also suggested that incomplete penetrance may be possible.

In 2 sisters, born of consanguineous Turkish parents, with CMYO18 manifest as neonatal respiratory insufficiency, Yis et al. (2019) identified a homozygous missense mutation in the CACNA1S gene (R789H; 114208.0020). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that R789 localizes to the cytoplasmic loop II-III of CACNA1S, which is critical for proper calcium release during excitation-contraction coupling. Both girls presented soon after birth with severe respiratory insufficiency and hypotonia, resulting in death in 1 at 3 months of age. Family history revealed that an older sib was similarly affected and died of respiratory failure at 3 months of age.

In the mouse, the gene for the alpha-1 subunit, symbolized Cchl1a3, is mutant in 'muscular dysgenesis' (mdg), a lethal autosomal recessive disorder in which there is total lack of excitation-contraction coupling in homozygotes (Gluecksohn-Waelsch, 1963; Pai, 1965). In the affected muscle, the reduction of the level of slow Ca(2+) channel/dihydropyridine receptor and the lack of L type Ca(2+) current indicate that this channel may be implicated in the mutation. The alpha-1 subunit of the channel, which contains the DHP binding site and the voltage sensor element, is missing in mdg/mdg animals. In mice, Tanabe et al. (1988) found that microinjection of alpha-1 cDNA into mdg/mdg myotubes can restore a normal excitation-contraction coupling. Chaudhari (1992) reported that the mdg mutation is characterized by deletion of nucleotide 4010 in the cDNA transcribed from the gene encoding the alpha-1 subunit, resulting in a shift of the translational reading frame.