G.P.35 Identical TTN gene A-band mutation causing HMERF occurs in different European populations

Abstract Hereditary myopathy with early respiratory failure (HMERF) is characterized by proximal–distal weakness and respiratory insufficiency in ambulant patients. The clinical onset of the disease is variable, ranging from early to late adulthood. Muscle weakness is typical in neck flexors, limb girdle, and in some cases also in distal lower limb muscles. A prominent early finding is respiratory muscle weakness presenting with an acute respiratory failure in many patients. A dominant mutation in the TTN kinase domain leading to HMERF has been described in a few families from Sweden. Very recently, two reports (in press) revealed a novel dominant A-band mutation in titin gene, TTN. This mutation (g.274375T>C; p.Cys30071Arg) was found in eight HMERF patients from three Swedish families and in 31 patients from three families. In our collaborative study we have identified the identical mutation in one Finnish family with four affected HMERF patients. In addition, the mutation was identified in one British patient, in one Italian patient and in one additional Swedish family. The patients had the same phenotype with progressive muscle weakness in the lower limbs and respiratory muscles, cytoplasmic bodies and rimmed vacuolar myopathy in muscle biopsy. Muscle MRI findings are pathognomonic with fatty degenerative changes in semitendinosus, obturatorius, sartorius, gracilis and iliopsoas muscles with variable involvement of anterior and lateral compartment and tibialis posterior on the lower legs. All patients carried the same haplotype including markers D2S2173 and D2S385 at the mutational locus. The shared genomic region is less than 3.3 Mb in size suggesting an ancestral founder, and indicating the existence of many undiagnosed families with this mutation.