Nemaline Myopathy 10
A number sign (#) is used with this entry because of evidence that nemaline myopathy-10 (NEM10) is caused by homozygous or compound heterozygous mutation in the LMOD3 gene (616112) on chromosome 3p14.Description
Nemaline myopathy-10 is an autosomal recessive severe congenital myopathy characterized by early-onset generalized muscle weakness and hypotonia with respiratory insufficiency and feeding difficulties. Many patients present antenatally with decreased fetal movements, and most die of respiratory failure in early infancy (summary by Yuen et al., 2014). Patients with a stable and much milder disease course have been described (Schatz et al., 2018).
For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).Clinical Features
Yuen et al. (2014) reported 21 patients from 14 families with a severe form of congenital nemaline myopathy. Most patients had antenatal features of the disorder, including polyhydramnios (62%), decreased or absent fetal movements (48%), and joint contractures (48%). Premature birth occurred in 35%. All patients had severe generalized hypotonia and weakness at birth, respiratory insufficiency, feeding difficulties, and bulbar weakness. Ophthalmoplegia was observed in 29%. Most patients died of respiratory failure in the neonatal period. Two sisters remained alive at ages 10 and 4 years, with bulbar weakness and ability to walk either independently or with support. No cardiac abnormalities were reported. Skeletal muscle biopsy showed nemaline bodies and atrophic myofibers with increased connective tissue. Electron microscopy showed that the nemaline bodies resembled short, thickened Z discs, often in doublets interconnected by filaments. Some nemaline bodies were surrounded by a short thin filament. Some biopsies showed no discernible sarcomeric structure, whereas others showed thin filament shortening and disorganization.
Schatz et al. (2018) described 4 patients from Austria or southern Germany with NEM10 based on identification of nemaline bodies on muscle biopsy and molecular confirmation. The patients were alive at ages 18, 18, 20 and 30 years, and all but 1 were ambulatory. All showed marked weakness of facial, oral, and pharyngeal muscles. All had swallowing difficulties at birth, but these had resolved by adulthood, and all had dysarthric speech. Reduced fetal movements were noted in 1 patient, and intrauterine growth restriction and polyhydramnios in another; pregnancy and delivery were normal in the remaining 2 patients.
Abbott et al. (2017) reported 3 sisters, born to Turkish first-cousin parents, with a severe form of congenital nemaline myopathy. The patients had an early lethal presentation with decreased fetal movements, hypotonia, and neonatal respiratory failure requiring ventilator support. All had perinatal fractures, demonstrating the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures. No tissue from the patients was available to confirm the presence of nemaline bodies.Inheritance
The transmission pattern of nemaline myopathy-10 in the families reported by Yuen et al. (2014) and Schatz et al. (2018) was consistent with autosomal recessive inheritance.Molecular Genetics
In 21 patients from 14 families with severe congenital nemaline myopathy-10, Yuen et al. (2014) identified homozygous or compound heterozygous mutations in the LMOD3 gene (see, e.g., 616112.0001-616112.0005). The mutations in the first 2 families were found by whole-exome sequencing; subsequent mutations were identified by direct sequencing of the LMOD3 gene in over 540 additional probands with nemaline myopathy. Almost all mutations were nonsense or frameshift and were predicted to result in a truncated protein; most skeletal muscle biopsies showed loss of LMOD3 protein, consistent with a loss of function.
In 4 unrelated adolescent or adult patients with a mild form of nemaline myopathy-10 from Austria or southern Germany, Schatz et al. (2018) identified biallelic missense mutations in the LMOD3 gene. All 4 patients carried an L550F mutation (616112.0006) in homozygosity or in compound heterozygosity with a Q335R mutation (616112.0007). The mutations were identified by whole-exome sequencing or by next-generation sequencing-based panel analysis.
In 2 sisters with severe congenital nemaline myopathy-10, born to Turkish first-cousin parents, Abbott et al. (2017) identified a homozygous frameshift mutation in the LMOD3 gene (616112.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygosity in the parents. DNA from a third affected female sib was not available for testing.Animal Model
Yuen et al. (2014) found that morpholino-mediated knockdown of zebrafish lmod3 resulted in larvae with short bodies, bent tails, and reduced tail birefringence, consistent with abnormal skeletal muscle organization. Immunostaining revealed that lmod3-morphant muscle lacked well-ordered sarcomeres and showed aberrant accumulation of the Z-disc protein alpha-actinin (see 102575), a major component of nemaline bodies. Electron microscopy confirmed abnormal skeletal muscle organization in lmod3 morphants. Behaviorally, lmod3 morphants showed reduced spontaneous coiling and touch-evoked escape responses. They also exhibited trunk muscle weakness due to reduced muscle size.