Wallgren-Pettersson et al. (1999) reported 41 unrelated families with NEM2 suggested by linkage analysis. All were consistent with autosomal recessive inheritance. Wallgren-Pettersson et al. (1999) noted that phenotypic classification of nemaline myopathy is difficult because the disease spectrum ... Wallgren-Pettersson et al. (1999) reported 41 unrelated families with NEM2 suggested by linkage analysis. All were consistent with autosomal recessive inheritance. Wallgren-Pettersson et al. (1999) noted that phenotypic classification of nemaline myopathy is difficult because the disease spectrum forms a continuum; however, the authors described 2 main forms, 'typical' and 'severe.' Typical patients had generalized hypotonia at birth, with particular involvement of the bulbar, neck flexor, and respiratory muscles. Proximal limb muscles were weaker initially, but distal limb muscle weakness eventually occurred. The extraocular muscles were spared. The facies was myopathic with a high-arched palate. The spine was hyperlordotic, sometimes rigid, and scoliosis sometimes developed at puberty. Deep tendon reflexes were decreased or absent, and the gag reflex was often absent. Chest deformities were common, but there was no cardiac involvement. Imaging showed decreased muscle density with increased fatty infiltration. Serum creatine kinase was normal or mildly elevated. Muscle biopsies characteristically showed nemaline bodies and type 1 fiber predominance. Although myopathic changes were observed, there were no dystrophic or inflammatory changes. Despite delayed motor development and waddling gait, many patients with typical disease remained ambulatory as adults. Intelligence was normal. A subset of patients had severe disease, characterized by absence of spontaneous movements or respiration at birth. These patients often had contractures or fractures at birth and usually never achieved independent sitting or ambulation. Wallgren-Pettersson et al. (2002) reported 7 patients from 5 families with severe NEM2 confirmed by mutation in the NEB gene. Four pregnancies were complicated by polyhydramnios, and 4 patients had arthrogryposis. Most affected infants did show show spontaneous respiration or antigravity movements. Several previous infant deaths or miscarriages were reported in the families. Two affected brothers in 1 family had large fontanels, low-set ears, adducted thumbs, hypospadias, and micropenis. Another affected child had cleft palate, rocker-bottom feet, and undescended testes. Death occurred between 30 minutes and 19 months of age. Muscle biopsies showed nemaline bodies in up to 90% of muscle fibers. Romero et al. (2009) reported a 27-year-old man with NEM2 confirmed by genetic analysis. He presented at birth with generalized hypotonia, poor spontaneous movements, and restrictive respiratory insufficiency requiring mechanical ventilation. He showed diffuse muscle weakness with axial predominance, never acquired independent ambulation, and developed multiple joint contractures. As an adult, he was quadriplegic with mild facial weakness. No cardiac symptoms were observed. Muscle biopsy showed numerous fibers with distinctive rods and well-delineated cores in type 1 fibers. Electron microscopy showed rods with characteristic striation and cores with some sarcomeric disorganization and depletion of mitochondria. The histologic findings indicated that cores, in addition to rods, may be found in patients with NEM2.
Pelin et al. (1999) demonstrated mutations in the NEB gene in autosomal recessive typical nemaline myopathy (161650.0001-161650.0006).
Wallgren-Pettersson et al. (2002) identified mutations in the NEB gene in patients with severe congenital nemaline myopathy (see, e.g., ... Pelin et al. (1999) demonstrated mutations in the NEB gene in autosomal recessive typical nemaline myopathy (161650.0001-161650.0006). Wallgren-Pettersson et al. (2002) identified mutations in the NEB gene in patients with severe congenital nemaline myopathy (see, e.g., 161650.0003 and 161650.0004). In 5 affected individuals from 5 Ashkenazi Jewish families with autosomal recessive typical nemaline myopathy, Anderson et al. (2004) identified a 2,502-bp deletion in the NEB gene (161650.0007), resulting in removal of exon 55. Using denaturing high-performance liquid chromatography (DHPLC), Lehtokari et al. (2006) identified 45 novel mutations in the NEB gene in affected members of 44 unrelated families with nemaline myopathy. Mutations were identified in patients representing all clinical categories of disease severity. The majority (55%) of mutations were frameshift or nonsense mutations resulting in premature termination of the protein. Mutations were distributed throughout the gene, with no obvious hotspots. Lehtokari et al. (2006) concluded that mutations in the NEB gene are the most common cause of nemaline myopathy.
Anderson et al. (2004) screened for 2,503-bp deletion in a random sample of 4,090 Ashkenazi Jewish individuals, revealing a carrier frequency of 1 in 108. Lehtokari et al. (2009) identified the 2,502-bp deletion in 14 of 355 probands ... Anderson et al. (2004) screened for 2,503-bp deletion in a random sample of 4,090 Ashkenazi Jewish individuals, revealing a carrier frequency of 1 in 108. Lehtokari et al. (2009) identified the 2,502-bp deletion in 14 of 355 probands with nemaline myopathy from around the world; 2 of the probands had been reported by Anderson et al. (2004). Seven probands were homozygous for the deletion, and 7 carried the mutation in heterozygosity. Two of the families were not of known Ashkenazi Jewish descent, but carried the common haplotype identified in Ashkenazi Jews. The findings were consistent with a founder effect.