Distal myopathy caused by homozygous missense mutations in the nebulin gene

We describe a novel, recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene (NEB), in which other combinations of mutations are known to cause nemaline (rod) myopathy (NM). Two different missense mutations were identified in homozygous form in seven Finnish patients from four unrelated families with childhood or adult-onset foot drop. Both mutations, when combined in compound heterozygous form with more disruptive mutations in NEB, are known to cause NM. Hitherto, no patients with NM have been found to have two missense mutations in NEB. Muscle weakness predominantly affected ankle dorsiflexors, finger extensors and neck flexors, a distribution different both from the patterns of weakness seen in NM caused by NEB mutations, and those of the known recessively inherited distal myopathies. Singleton cases need to be distinguished from the Laing type of distal myopathy. Histologically, this myopathy differs from NM in that nemaline bodies were not detectable with routine light microscopy, and they were inconspicuous or absent even with electron microscopy. Rimmed vacuoles, commonly seen in other distal myopathies, were not a feature. We conclude that homozygous missense mutations in NEB cause a novel distal myopathy, predominantly involving lower leg extensor muscles, finger extensors and neck flexors.