• Gerald Pfeffer, Rita Barresi, Ian J Wilson, Steven A Hardy, Helen Griffin, Judith Hudson, Hannah R Elliott, Aravind V Ramesh, Aleksandar Radunovic, John B Winer, Sujit Vaidya, Ashok Raman, Mark Busby, Maria E Farrugia, Alec Ming, Chris Everett, Hedley C A Emsley, Rita Horvath, Volker Straub, Kate Bushby, Hanns Lochmüller, Patrick F Chinnery, and Anna Sarkozy.
• Institute of Genetic Medicine, International Centre for Life, Newcastle University, , Newcastle upon Tyne, UK.
• J. Neurol. Neurosurg. Psychiatr.. 2014 Mar 1;85(3):331-8.

ObjectiveTitin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement.MethodsWe studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology.ResultsWe identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450.ConclusionsMutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

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