title: Distal myopathy caused by homozygous missense mutations in the nebulin gene.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland. carina.wallgren@helsinki.fi
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Elina
authors.initials: E
authors.lastname: Nuutinen
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005385:Fingers / Q000503:physiopathology; D006801:Humans; D007866:Leg / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D009124:Muscle Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000503:physiopathology / Q000648:ultrastructure; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D009124:Muscle Proteins; C035620:nebulin