Case report Mutations in TPM2 and congenital fibre type disproportion Nigel F. Clarke a,b,⇑ , Leigh B. Waddell a,b , Lilian T.L. Sie c , Bregje W.M. van Bon d , Catriona McLean e , Damian Clark f , Andrew Kornberg f , Martin Lammens g , Kathryn N. North a,b a Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Sydney, Australia b Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia c Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands d Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands e Department of Anatomical Pathology, Bayside Health and the State Neuropathology Service, University of Melbourne, Melbourne, Australia f Department of Neurology, Royal Children’s Hospital, Melbourne, Australia g Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Received 17 March 2012; received in revised form 20 May 2012; accepted 1 June 2012 Abstract The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small ‘caps’ were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis. Ó 2012 Elsevier B.V. All rights reserved. Keywords: Congenital myopathy, Beta-tropomyosin; Cap myopathy; Congenital fibre type disproportion; Electron microscopy 1. Introduction Congenital fibre type disproportion (CFTD) is an uncommon form of congenital myopathy in which consis- tently small type 1 (slow twitch) muscle fibres compared to type 2 (fast twitch) fibres, is the main histological abnor- mality [1]. When a threshold for fibre size disproportion of 35–40% is used, and other forms of congenital myopathy and neuromuscular disease are excluded, a genetic cause can be established in around half of CFTD patients [2]. The most common reported genetic causes are TPM3 [3], RYR1 [4] and ACTA1 [5], and single families have been reported with mutations in MYH7 [6] and TPM2 [7]. Establishing the genetic basis of disease in each family is essential to provide accurate genetic counselling and prena- tal diagnosis but the number of possible genetic causes (some of which likely remain undiscovered) complicates this process. The TPM2 gene codes for beta-tropomyosin, one of three tropomyosin isoforms that are incorporated into sarcomeres in skeletal muscle. Mutations in TPM2 have been associated with two main phenotypes; congenital 0960-8966/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.nmd.2012.06.002 ⇑ Corresponding author. Address: Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Tel.: +61 2 98451453; fax: +61 2 9845 3389. E-mail address: nigel.clarke@health.nsw.gov.au (N.F. Clarke). www.elsevier.com/locate/nmd Available online at www.sciencedirect.com Neuromuscular Disorders 22 (2012) 955–958