Nemaline myopathy caused by absence of α-skeletal muscle actin

• Published in: Annals of neurology Vol. 61; no. 2; pp. 175 - 184
• Main Authors: Nowak, Kristen J., Sewry, Caroline A., Navarro, Carmen, Squier, Waney, Reina, Cristina, Ricoy, Jose R., Jayawant, Sandeep S., Childs, Anne-Marie, Dobbie, J. Angus, Appleton, Richard E., Mountford, Roger C., Walker, Kendall R., Clement, Sophie, Barois, Annie, Muntoni, Francesco, Romero, Norma B., Laing, Nigel G.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2007; Willey-Liss
• Subjects: Actins - deficiency; Actins - genetics; Actins - metabolism; Arginine; Aspartic Acid; Biological and medical sciences; Blotting, Western; Child, Preschool; Digestive system; Diseases of striated muscles. Neuromuscular diseases; Homozygote; Humans; Immunohistochemistry; Infant; Male; Medical sciences; Microscopy, Electron; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Mutation; Myocardium - metabolism; Myopathies, Nemaline - ethnology; Myopathies, Nemaline - etiology; Myopathies, Nemaline - pathology; Neurology; Pharmacology. Drug treatments; Tyrosine; Striated muscle disease; Nervous system diseases; Striated muscle; Nemaline myopathy; Congenital disease; Genetic disease
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21035

Objective To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator‐dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected. Methods The α‐skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry, western blotting, or both. Results Three homozygous ACTA1 null mutations were identified: p.Arg41X in the French patient, p.Tyr364fsX in the Spanish patient, and p.Asp181fsX10 in all five British patients. An absence of α‐skeletal muscle actin protein but presence of α‐cardiac actin was shown in all muscle biopsies examined, with more α‐cardiac actin in the biopsy from the child with the greatest muscle function. Muscle biopsies from all patients exhibited nemaline bodies whereas three also contained zebra bodies. Interpretation The seven patients have recessive nemaline myopathy caused by absence of α‐skeletal muscle actin. The level of retention of α‐cardiac actin, the skeletal muscle fetal actin isoform, may determine α‐skeletal muscle actin disease severity. This has implications for possible future therapy. Ann Neurol 2006