A number sign (#) is used with this entry because of evidence that autosomal recessive congenital myopathy-4B (CMYO4B) is caused by homozygous or compound heterozygous mutation in the alpha-tropomyosin-3 gene (TPM3; 191030) on chromosome 1q21.

Heterozygous mutation in the TPM3 gene causes autosomal dominant CMYO4A (255310), which shows overlapping features.

Congenital myopathy-4B (CMYO4B) is an autosomal recessive disorder of the skeletal muscle characterized by the onset of muscle weakness in infancy or early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show congenital contractures, delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty walking or inability to walk. Affected individuals have respiratory insufficiency due to muscle weakness, which may be life-threatening. Other common features include myopathic facies, chest deformities, distal joint laxity, and scoliosis. Variable histologic findings on skeletal muscle biopsy are observed, including nemaline rods, type 1 fiber predomination, and centralized nuclei (Tan et al., 1999; Lehtokari et al., 2008).

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

Tan et al. (1999) reported an Iranian patient, born of consanguineous parents, with severe infantile congenital myopathy. Although no neonatal problems were reported, the infant showed extremely delayed motor development and died at age 21 months due to respiratory insufficiency resulting from an infectious illness. Muscle biopsy showed type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2 fibers. Skeletal muscle biopsy showed nemaline bodies in type 1 fibers only. Genetic analysis identified a homozygous nonsense mutation in the TPM3 gene (Q32X; 191030.0004).

Wattanasirichaigoon et al. (2002) reported a 14-year-old boy (patient 13-2) with congenital myopathy. He was hypotonic as a neonate and showed delayed motor development with frequent falls around age 2. At age 3, he had a long face with open mouth and severely decreased ankle dorsiflexion. By age six, he became wheelchair bound, and subsequently developed multiple joint contractures. Moderate restrictive lung disease was documented at age 10. At age 14, he remained thin, but was medically stable. Family history was noncontributory. Muscle biopsy showed subsarcolemmal and intracytoplasmic nemaline rods in type 1 fibers, type 1 fiber predominance, central nuclei, and increased endomysial connective tissue. Genetic analysis identified compound heterozygous mutations in the TPM3 gene (191030.0002-191030.0003).

Lehtokari et al. (2008) reported 2 unrelated Turkish families, each with 2 children affected with autosomal recessive congenital myopathy. Only 1 of the families was known to be consanguineous. In the first family, 2 affected boys were born with contractures of the knees and ankles, and later showed delayed motor development with weakness of the neck and facial muscles. One child did not achieve walking, while the other walked slowly with a waddling gait from the age of 2.5 to 3 years. Both patients had restricted vital capacity requiring nocturnal noninvasive ventilation. Other features included pectus carinatum deformity and scoliosis. Skeletal muscle biopsy of 1 brother showed hypotrophic type 1 fibers containing nemaline bodies. In the second family, both children had muscle hypotonia during the first month of life. Particular features were pronounced facial weakness, lack of head control, lax distal joints, and scoliosis. Motor milestones were delayed, and both became wheelchair-bound in childhood. Both children developed generalized joint contractures and mild chest deformities. Genetic analysis identified a homozygous mutation in the TPM3 gene (191030.0006).

The transmission pattern of CMYO4B in the families reported by Lehtokari et al. (2008) was consistent with autosomal recessive inheritance.

In a patient, born of consanguineous Iranian parents, with severe infantile CMYO4B who died at age 21 months, Tan et al. (1999) identified a homozygous nonsense mutation in the TPM3 gene (Q32X; 191030.0004)

Among 40 unrelated patients with a diagnosis of nemaline myopathy, Wattanasirichaigoon et al. (2002) identified 1 patient who was compound heterozygous for 2 mutations in the TPM3 gene (191030.0002-191030.0003). Each parent was heterozygous for one of the mutations. The authors noted that mutations in the TPM3 gene are a rare cause of nemaline myopathy.

In affected members of 2 Turkish families with autosomal recessive nemaline myopathy, Lehtokari et al. (2008) identified a homozygous mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a founder effect.