A number sign (#) is used with this entry because of evidence that nemaline myopathy-7 (NEM7) is caused by homozygous mutation in the CFL2 gene (601443) on chromosome 14q13.

Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by Ockeloen et al., 2012).

For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.

Agrawal et al. (2007) described 2 sibs from a large consanguineous Middle Eastern family, identified in a screen of patients with congenital myopathies, with nemaline myopathy. Both patients had similar clinical presentations, with hypotonia noted at birth, delayed early motor milestones, frequent falls, and inability to run. The elder sister at age 16 years could walk short distances but used a wheelchair outside the house. Muscle biopsy showed nonspecific myopathic changes. The younger sib at age 9 years was ambulant. Muscle biopsy showed characteristic nemaline bodies as well as occasional fibers with minicores, concentric laminated bodies, and areas of F-actin accumulation. The course of the disease in both sibs was like that of typical nemaline myopathy, but the distribution of weakness was distinct, without significant facial weakness or foot drop.

Ockeloen et al. (2012) reported 2 sisters, born of consanguineous Iraqi parents, with congenital myopathy. The proband was a 21-year-old woman who had delayed walking at age 2 years, 6 months, and slowly progressive muscle weakness affecting the neck muscles, shoulder girdle muscles, and legs. She had a high-arched palate, mild facial muscle weakness, severe kyphoscoliosis, areflexia, and chronic respiratory insufficiency due to muscle weakness; she was wheelchair-bound. Her 5-year-old sister, who was also affected, showed delayed walking, hypotonia, occasional head drop, Gowers sign, waddling gait, and hyperextension of the knees and elbows. Both patients had normal cognition. Skeletal muscle biopsy showed a dystrophic pattern with increased fiber variability. Immunohistochemical staining showed some irregular cytoplasmic aggregates and the presence of nemaline rods. Enzyme histochemistry with ATPase showed 'rubbed out' areas in some muscle fibers. Electron microscopy of 1 biopsy showed areas with Z-band streaming and rods, often in large aggregates. The aggregates were accompanied by osmiophilic granular material, degenerating membranous organelles, and cytoplasmic bodies.

The transmission pattern of NEM7 in the families reported by Agrawal et al. (2007) and Ockeloen et al. (2012) was consistent with autosomal recessive inheritance.

On the basis of the role of cofilin-2 in regulation of sarcomeric actin filaments, Agrawal et al. (2007) screened 113 unrelated patients with nemaline myopathy and 58 patients with clinicopathologic diagnoses of other congenital myopathies for mutations in the CFL2 gene. They found a homozygous missense mutation (601443.0001) in 2 sibs from a large consanguineous Middle Eastern family with nemaline myopathy. Agrawal et al. (2007) estimated that the frequency of CFL2 mutations in patients with nemaline myopathy is well below 0.6%.

In 2 Iraqi sisters with nemaline myopathy and features of myofibrillar myopathy, Ockeloen et al. (2012) identified a homozygous mutation in the CFL2 gene (601443.0002). The mutation was found by homozygosity mapping followed by candidate gene sequencing.