A number sign (#) is used with this entry because nemaline myopathy-9 (NEM9) is caused by homozygous or compound heterozygous mutation in the KLHL41 gene (607701) on chromosome 2q31.

Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by Gupta et al., 2013).

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

Gupta et al. (2013) reported 5 unrelated children with nemaline myopathy and variable severity. Two infants presented at birth in breech presentation and with severe fetal akinesia, consistent with onset of muscle weakness in utero; they showed poor or no antigravity movements and died at ages 1 day and 3 months. Other features in these 2 patients included arthrogryposis, dislocation of hips and knees, micrognathia, and narrow chest. The other 3 patients had more intermediate forms of the disorder: 2 were ambulant at age 5 and 12 years, respectively, whereas the third was wheelchair-bound and on artificial ventilation at age 16 years. Additional features, present in 1 patient each, included high-arched palate, scoliosis, and ventricular septal defect. Two had distal contractures. Muscle biopsy of all patients showed sarcoplasmic rods in multiple myofibers, consistent with nemaline myopathy.

The transmission pattern of nemaline myopathy-9 in the families reported by Gupta et al. (2013) was consistent with autosomal recessive inheritance.

In 5 unrelated children with nemaline myopathy-9, Gupta et al. (2013) identified homozygous or compound heterozygous mutations in the KLHL41 gene (see, e.g., 607701.0001-607701.0005). The mutations in 4 patients were found by homozygosity mapping combined with whole-exome sequencing; the fifth patient was identified from a cohort of 116 patients who underwent Sanger sequencing of the KLHL41 gene. There was a clear genotype-phenotype correlation, with truncating mutations resulting in severe phenotypes with neonatal death, and missense changes resulting in impaired motor function with survival into late childhood and/or early adulthood. Immunoblotting of patient skeletal muscle showed decreased levels of KLHL41 compared to wildtype. Functional studies in zebrafish showed that loss of klhl41 resulted in highly diminished motor function and myofibrillar disorganization with nemaline body formation.