A number sign (#) is used with this entry because of evidence that congenital myopathy-5 with cardiomyopathy (CMYO5), also known as Salih myopathy, is caused by homozygous or compound heterozygous mutation in the gene encoding titin (TTN; 188840) on chromosome 2q31.

Congenital myopathy-5 with cardiomyopathy (CMYO5) is an autosomal recessive disorder characterized by the onset of muscle weakness in infancy manifest as neonatal hypotonia, delayed motor development, and often distal contractures. Affected individuals may have congenital heart defects and most develop severe cardiomyopathy in childhood or adolescence that may lead to death or require heart transplant. Skeletal muscle biopsy shows multiminicore myopathy, centrally located nuclei, and type 1 fiber predominance (Carmignac et al., 2007; Chauveau et al., 2014).

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

Carmignac et al. (2007) reported 5 patients from 2 consanguineous families of Moroccan and Sudanese origin, respectively, with congenital myopathy and fatal dilated cardiomyopathy. All patients showed delayed motor development with symmetric, generalized muscle weakness predominantly of proximal and distal lower limbs. The 3 male sibs of the Moroccan family showed onset in infancy, whereas the 2 sibs of the Sudanese family had onset at birth with neonatal hypotonia. Other features included facial muscle weakness, ptosis, and relative calf hypertrophy. Progressive dilated cardiomyopathy with rhythm disturbances developed between ages 5 and 12 years. Death from cardiomyopathy occurred in all 5 patients; 4 survived into their teenage years. Skeletal muscle biopsies showed minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes were more apparent in the second decade. Cardiac muscle biopsies showed disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. All parents were clinically unaffected. Genetic analysis identified 2 different homozygous deletions in the TTN gene (188840.0012 and 188840.0013).

By Sanger sequencing of the 6 M-line-encoding exons (Mex1-Mex6) in the TTN gene in 31 patients from 23 families segregating congenital core myopathy and primary heart disease, Chauveau et al. (2014) identified homozygous or compound heterozygous mutations in 5 patients from 4 families (see, e.g., 188840.0014 and 188840.0015). The severity of the phenotype varied among the families. All 5 patients had congenital or infantile muscle weakness with axial and distal joint contractures and relatively preserved respiratory function. Muscle biopsies in all showed type 1 fiber predominance or uniformity, and minicore myopathy with central nuclei. In family 1, 2 brothers, born to consanguineous Turkish parents, had moderate to severe elbow and joint contractures. The older brother had an asymptomatic dilated cardiomyopathy at age 19, and his brother had a normal echocardiogram at age 16 years. The patient in family 2 presented with atrial septal defect (ASD) and neonatal hypotonia. She did not walk until age 2 years. She developed elbow and ankle contractures at age 6 and dilated cardiomyopathy at age 16. She also had cardiac septal involvement. The authors considered her phenotype typical of Emery-Dreifuss muscular dystrophy (see 310300). The patient in family 3 presented with ASD and ventricular septal defects (VSD) that required correction in his first year. He developed severe dilated cardiomyopathy at age 13 and underwent cardiac transplantation at age 14. He had mild ankle contractures as well as a cleft soft palate, short webbed neck, hypertelorism, and radioulnar synostosis. Family 4 included 1 affected girl and a female pregnancy termination. The girl was born with a VSD and neonatal hypotonia. She had arthrogryposis, dislocated hips with dysplasia, and elbow, hip, and knee contractures. She had left ventricular noncompaction and required heart transplant at age 4 years. The patients in families 2, 3, and 4 manifested severe scoliosis. None of the parents had any manifestations of myopathy or cardiomyopathy.

The transmission pattern of CMYO5 in the families reported by Carmignac et al. (2007) was consistent with autosomal recessive inheritance.

By linkage analysis, followed by candidate gene sequencing, Carmignac et al. (2007) identified 2 different homozygous deletions in the TTN gene (188840.0012 and 188840.0013, respectively) in affected members of 2 unrelated families with congenital myopathy and fatal cardiomyopathy. The deletions resulted in truncation of the C terminus of the protein, absence of which had been expected to be lethal, and disruption of the sarcomeric M-line protein complex. The consanguineous parents of each family were heterozygous for the respective deletions and were clinically unaffected.

Chauveau et al. (2014) identified 7 novel homozygous or compound heterozygous TTN mutations (5 in the M-line and 5 truncating) in 4 of 23 families with CMYO5 (see, e.g., 188840.0014 and 188840.0015).