Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy Vilma-Lotta Lehtokari a , Katarina Pelin b , Agnes Herczegfalvi c , Veronika Karcagi d , Jean Pouget e , Jero ˆ me Franques e , Jean Franc ßois Pellissier f , Dominique Figarella-Branger f , Maja von der Hagen g , Angela Huebner g , Benedikt Schoser h , Hanns Lochmu ¨ ller i , Carina Wallgren-Pettersson a,⇑ a The Folkha ¨ lsan Institute of Genetics and The Department of Medical Genetics, University of Helsinki, Haartman Institute, Helsinki, Finland b Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland c Department of Paediatric Neurology, Heim Pal Hospital, Budapest, Hungary d Department of Molecular Genetics and Diagnostics, NIEH, Budapest, Hungary e Reference Center for Neuromuscular disorders and ALS, Ho ˆpital La Timone, Marseille, France f Service d’Anatomie Pathologique et de Neuropathologie, Ho ˆpital La Timone, Marseille, France g University Children’s Hospital, Technical University Dresden, Germany h Friedrich-Baur-Institut, Department of Neurology, Ludwig Maximilians University, Munich, Germany i Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom Received 21 February 2011; received in revised form 10 May 2011; accepted 27 May 2011 Abstract Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy. Ó 2011 Elsevier B.V. All rights reserved. Keywords: Nemaline myopathy; Distal myopathy; Nebulin; Mutations 1. Introduction Nemaline myopathy (NM) and distal myopathies (DM) constitute clinically and genetically heterogeneous groups of muscle disorders. NM has been classified into six clinical categories based on the severity of the disease, the age of onset and the pattern of muscle weakness [1,2]. Seven NM-causing genes have been identified hitherto, the caus- ative genes (ACTA1, MIM#161800; NEB, MIM#256030; TPM2, MIM#609285; TPM3, MIM#609284; TNNT1, MIM#605355; KBTBD13, MIM#609273 and CFL2, MIM#610687) encoding proteins of the thin filament of the skeletal muscle sarcomere [3–9]. The mode of inheri- tance can be autosomal recessive or dominant. In NEB, TNNT1 and CFL2, only recessive mutations have been published, while in KBTBD13 only dominant mutations have been described. In ACTA1, TPM2 and TPM3 both dominant and recessive mutations have been reported; many of the dominant mutations arising de novo. The most frequent causes of NM are mutations in NEB and ACTA1. 0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2011.05.012 ⇑ Corresponding author. Fax: +358 9 3155106. E-mail address: Carina.Wallgren@helsinki.fi (C. Wallgren-Pettersson). www.elsevier.com/locate/nmd Available online at www.sciencedirect.com Neuromuscular Disorders 21 (2011) 556–562