Alternative titles; symbols
SNOMEDCT: 702349003; ORPHA: 171430, 171433, 171436, 171439, 98904; DO: 0110927;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q42.13 | Congenital myopathy 2A, typical, autosomal dominant | 161800 | Autosomal dominant | 3 | ACTA1 | 102610 |
A number sign (#) is used with this entry because of evidence that autosomal dominant typical congenital myopathy-2A (CMYO2A) is caused by heterozygous mutation in the ACTA1 gene (102610) on chromosome 1q42.
Heterozygous mutation in the ACTA1 gene can also cause severe infantile congenital myopathy-2C (CMYO2C; 620278). Biallelic mutation in the ACTA1 gene causes autosomal recessive autosomal recessive congenital myopathy-2B (CMYO2B; 620265).
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).
Ilkovski et al. (2001) reported 2 unrelated patients with a typical form of CMYO2A. P3 had no problems during the neonatal period. At age 5 years, he presented with inability to run and frequent falls. He had poor muscle bulk, pes cavus, and bilateral foot drop. By age 10 years, he showed slowly progressive weakness and involvement of the proximal muscles. P4 had been weak and hypotonic at birth with poor feeding, recurrent infections, and delayed motor development, but the muscle weakness was nonprogressive. At age 45 years, he was physically active and regularly engaged in long-distance competitive cycling, although he had a weak cough and frequent respiratory infections. Genetic analysis identified 2 different heterozygous missense mutations in the ACTA1 gene: P3 carried a de novo G286C mutation (102610.0007), whereas P4 carried a heterozygous I136M mutation (102610.0008) that likely occurred de novo since he had no family history of a similar disorder.
Ilkovski et al. (2001) reported a family (family A) in which a mother and her 2 children were affected with CMYO2A. The 35-year-old mother had typical congenital myopathy with neonatal onset of feeding difficulties, respiratory tract infections, hypotonia, facial diplegia, and proximal muscle weakness in the first weeks of life. Her disease was very slowly progressive or nonprogressive. She had 2 affected children, a daughter aged 19 years and a son aged 4 years at the time of the report. The daughter had onset of disease at age 6 years, with mild proximal weakness and frequent falls, and developed progressive scoliosis requiring surgery at age 14 years. The son had feature of congenital myopathy in infancy, and showed nonprogressive weakness with improvement of mild nocturnal hypoventilation over time. Skeletal muscle biopsy from all patients showed nemaline bodies, although there was marked variability in the percentage of fibers with rods. Genetic analysis identified a heterozygous missense mutation in the ACTA1 gene in all 3 patients (N115S; 102610.0002). The intrafamilial variability observed suggested that the ACTA1 genotype is not the sole determinant of the phenotype and that modifying factors, both genetic and stochastic influence the clinical presentation.
Ryan et al. (2001) reviewed the clinical features of 143 Australian and North American patients with congenital myopathy associated with nemaline rods on skeletal muscle biopsy. Mutations in the ACTA1 gene were identified in 22 of 71 patients tested; some of the patients had previously been reported by Nowak et al. (1999). Mutations in the TPM3 gene (191030) were found in 4 of 46 patients tested. As classified clinically by the guidelines of the European Neuromuscular Centre, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset forms of the disease. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Prenatal expression of nemaline myopathy was reflected in its association with the fetal akinesia sequence and the frequency of obstetric complications, which occurred in 35 cases (51%), including polyhydramnios (29%), decreased fetal movements (39%), and abnormal presentation of fetal distress (49%). Significant respiratory disease occurred in the first year of life in 75 patients, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, most of them during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management was considered warranted in most cases of congenital nemaline myopathy.
Agrawal et al. (2004) identified 4 unrelated families (80, 90, 104, and 120) with autosomal dominant CMYO2A associated with heterozygous missense mutations in the ACTA1 gene. One of the 2 patients in family 90 presented at birth with hypotonia, failure to thrive, and recurrent pneumonia. He was tube-fed for several months. He was alive and ambulatory at 34 years of age with restrictive lung disease and easy fatigability. He had a history of surgery for scoliosis at 18 years of age. The other patient in family 90 presented in infancy with delayed motor development, but no acute issues. He was alive and ambulatory at 7 years of age. Genetic analysis identified a heterozygous K373Q mutation in the ACTA1 gene. Five females in another family (104) segregated typical congenital myopathy associated with a heterozygous Q246R mutation in the ACTA1 gene. The inheritance pattern was clearly autosomal dominant. Four of the patients, ranging from 9 to 41 years of age, had weakness in early childhood, resulting in frequent falls and difficulty with steps. All were ambulatory and had no respiratory or feeding issues. The fifth member of the family had only mild leg weakness in childhood and was ambulatory with no other symptoms at 15 years of age.
Agrawal et al. (2004) reported several patients with typical or mild CMYO2A confirmed by genetic analysis and no family history of the disorder. Although most patients had symptom onset at birth or in infancy, they were alive and ambulatory in childhood and adulthood. Some had easy fatigability or mild respiratory symptoms.
Kaindl et al. (2004) reported 2 unrelated families with onset of proximal or generalized weakness in early childhood. There was moderate muscle weakness with delayed motor milestones, facial weakness, and mild skeletal anomalies, including scoliosis, high-arched palate, genu valgum or varum, and funnel chest. One family had onset in infancy. In the second family, 2 affected individuals developed hypertrophic cardiomyopathy associated with respiratory difficulties in the middle adult years. The disease course in both families was nonprogressive. Histologically, 'cores' were detected in the muscle fibers of at least 1 patient in each family, whereas nemaline bodies or rods and actin filament accumulation were absent. The cores were unstructured, poorly circumscribed, central or eccentric, and were atypical of central core disease. One patient did not have cores on biopsy. There was type 1 fiber type predominance. Genetic analysis identified heterozygous missense mutations in the ACTA1 gene in the 2 families (102610.0009 and 102610.0010, respectively). Kaindl et al. (2004) concluded that their findings established mutation in the ACTA1 gene as a cause of dominant congenital myopathy with cores, and delineated another clinicopathologic phenotype for ACTA1.
Hutchinson et al. (2006) reported 4 patients from a 3-generation family with autosomal dominant CMYO2A. Three of the patients had onset in infancy with hypotonia and failure to thrive; the fourth patient had onset before age 5 years. All had muscle weakness throughout life and a thin face with thin limbs. Skeletal muscle biopsies showed variation in fiber diameter, type 1 fiber predominance, and intranuclear rods within muscle fibers, although the number of nemaline rods varied between patients. Genetic analysis identified a heterozygous mutation in the ACTA1 gene (V163M; 102610.0014) that segregated with the disorder.
Gatayama et al. (2013) reported a 9-year-old Japanese boy with congenital myopathy associated with a heterozygous mutation in the ACTA1 gene (W358C; 102610.0017) who developed fatal dilated cardiomyopathy in childhood. He had no family history of the disorder, suggesting that the mutation occurred de novo. The patient had normal motor development in early childhood, but showed mild nonprogressive skeletal muscle weakness, such as slowed running compared to his peers. Other features included hypotonia, myopathic facies, high-arched palate, and mild weakness of proximal and distal muscles. He presented at age 9 years with acute deterioration of cardiac function, and died of cardiac failure 6 months later. Postmortem examination of cardiac muscle showed variation in myocardial fiber size and a few electron-dense fine structures related to Z lines. Skeletal muscle biopsy had previously shown typical nemaline rods. Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations.
Sewry et al. (2015) provided follow-up of a patient previously reported by Lake and Wilson (1975) as having congenital myopathy associated with 'zebra bodies' on skeletal muscle biopsy. He had hypotonia at birth and delayed motor development with inability to run or climb stairs. At age 14, he had 2 episodes of torticollis and showed a waddling gait and positive Gowers sign. Serum creatine kinase had been normal in childhood, but was later elevated. A repeat muscle biopsy at age 29 years showed wide variation in fiber size, internal nuclei, nemaline rods, a few zebra bodies, and accumulation of actin-like thin filaments. He was wheelchair-bound at age 55. Genetic analysis identified a heterozygous, likely de novo, missense mutation in the ACTA1 gene (L348Q). This case demonstrated some patients with ACTA1 mutations can have a milder phenotype.
Most heterozygous ACTA1 mutations causing typical congenital myopathy-2A occur de novo. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life (summary by Laing et al., 2009).
The transmission pattern of CMYO2A in the 4 families reported by Agrawal et al. (2004) was consistent with autosomal dominant inheritance.
Agrawal et al. (2004) identified 29 mutations in the ACTA1 gene (see, e.g., 102610.0025 and 102610.0026) in 38 patients from 28 families with congenital myopathy. Most had no family history of the disorder (24 of 28) and carried de novo heterozygous missense variants. Four families showing autosomal dominant transmission of the mutation were identified, and 1 family with recessive transmission was identified (see CMYO2B, 620265). Although there was phenotypic variability, even within families, most individuals had a severe clinical presentation in the neonatal period, sometimes resulting in death. The authors noted that heterozygous missense mutations in the ACTA1 gene most likely result in a dominant-negative effect.
Laing et al. (2009) described 177 different disease-causing variants in the ACTA1 gene, including ones previously reported in the literature and ones identified in their study. Of the 177 mutations, 74 arose de novo, 21 showed dominant inheritance within a family, and 17 showed recessive inheritance.
Typical Congenital Myopathy 2A
In 2 unrelated patients (P7 and P10) with a milder form of CMYO2A, Nowak et al. (1999) identified heterozygous missense mutations in the ACTA1 gene (M132V and G182D). Clinical details were limited, but these patients were classified as having a milder disease; they were alive at 3 and 39 years of age.
In a mother and her 2 affected children with variable manifestations of CMYO2A, Nowak et al. (1999) identified a heterozygous missense mutation in the ACTA1 gene (N115S; 102610.0002).
In 3 affected members of a 2-generation family (family A) with autosomal dominant CMYO2A, Ilkovski et al. (2001) identified a heterozygosity for the N115S missense mutation in the ACTA1 gene (102610.0002). The intrafamilial variability observed suggested that the ACTA1 genotype is not the sole determinant of the phenotype and that modifying factors, both genetic and stochastic influence the clinical presentation.
In 2 unrelated patients (P3 and P4) with a typical form of CMYO2A, Ilkovski et al. (2001) identified 2 different heterozygous missense mutations in the ACTA1 gene: P3 carried a de novo G286C mutation (102610.0007), whereas P4 carried a heterozygous I136M mutation (102610.0008) that likely occurred de novo since he had no family history of a similar disorder.
In affected members of 2 unrelated families with CMYO2A, Kaindl et al. (2004) identified heterozygous missense mutations in the ACTA1 gene (D1Y; 102610.0009 and E334A; 102610.0010, respectively).
In 4 patients from a 3-generation family with autosomal dominant CMYO2A, Hutchinson et al. (2006) identified a heterozygous mutation in the ACTA1 gene (V163M; 102610.0014) that segregated with the disorder.
In a Japanese boy with CMYO2A who died of cardiomyopathy at age 9.5 years, Gatayama et al. (2013) identified a heterozygous missense mutation in the ACTA1 gene (W358C; 102610.0017). Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations.
In a 55-year-old man with CMYO2A previously reported by Lake and Wilson (1975), Sewry et al. (2015) identified a heterozygous, likely de novo, missense mutation in the ACTA1 gene (L348Q).
By pathologic investigations of muscle biopsies from 3 patients with nemaline myopathy, Price et al. (1965) determined that the pathologic fibrillar material was similar to and continuous with the material that constituted the Z band, and suggested that it was excessive accumulation of tropomyosin B (190990). Price et al. (1965) noted that central core disease (117000) and nemaline myopathy had been reported in the same family (Afifi et al., 1965).
Jennekens et al. (1983) reviewed the evidence that the nemaline bodies could be derived from lateral expansions of Z discs, and found that alpha-actinin (see, e.g., ACTN2; 102573) was one of the main protein components of both the Z disc and the nemaline body. The defect in alpha-actinin was restricted to skeletal muscle cells; there was no abnormality of actin or alpha-actinin in nonmuscle cells.
Wallgren-Pettersson et al. (1988) studied repeated biopsies for periods varying from 5 to 18 years in 13 patients with congenital nemaline myopathy. Their most important conclusion was that this is a progressive disorder. One of the patients, a brother of the proband, had no nemaline bodies in his first biopsy, taken from the same muscle as the later biopsy which was diagnostic. A deficiency of type 2 fibers was suggested as the basis of the inability of the patients to run and otherwise engage in fast gross motor activity. In 9 of 13 patients with nemaline myopathy, Wallgren-Pettersson et al. (1990) found reduced or absent alpha-actinin, which led them to conclude that the abnormality in this disorder resides in that molecule.
Rifai et al. (1993) compared the muscle pathology and clinical course in 8 patients with congenital nemaline myopathy. The family history was positive in 2 cases: one had 2 affected sisters and another had a single affected sister. In 1 patient with a negative family history and a rapid, fatal course, they found an abundance of large intranuclear rods in the muscle fibers, whereas these were absent in the muscles of the other 7 patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-alpha-actinin antibodies. Rifai et al. (1993) suggested that the accumulation of alpha-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since 2 previously reported infants with intranuclear nemaline rods also had a fatal outcome, Rifai et al. (1993) suggested that the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.
By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from patients with CMYO2A had increased levels of gamma-filamin (FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and alpha-actinin (ACTN1; 102575), consistent with accumulation of Z line-derived nemaline bodies. Intranuclear aggregates were observed upon transfecting myoblasts with V163L- (102610.0004), V163M- (102610.0014), and R183G-null acting transgene constructs, and modeling showed these residues to be adjacent to the nuclear export signal of actin. Transfection studies further showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble acting filaments. In vitro studies suggested that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms may be common properties of ACTA1 mutants. A combination of these effects may contribute to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization.
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