Titin is a muscle protein that gets its name from its “titanic” size. Coded by the TTN gene, it forms the essential backbone of the contractile apparatus of the muscle fiber and interacts with many other proteins in this cell compartment. It is only relatively recently that neuromuscular pathologies, that is titinopathies, have been associated with abnormalities in the TTN gene. This very large gene was in fact not very accessible for molecular diagnosis until the advent of high-throughput sequencing (NGS for next-generation sequencing). Titinopathies are associated with a wide variety of clinical pictures, ranging from congenital forms to forms with later onset.
In an article published in August 2020, the international consortium dedicated to titinopathies compiled the clinical and biological data of a cohort of 123 people with TTN gene abnormalities, 100 of which had already been published. Half of the cases involved hypotonic newborns or infants with delayed motor acquisitions. In them, the mutations found were present throughout the TTN gene. The remaining cases often had more atypical presentations with motor deficit in the extremities (distal myopathies) or prominent respiratory failure (as in HMERF syndrome for Hereditary Myopathy with Early Respiratory Failure). In these latter forms, most of the mutations were found in the last exons of the gene. The authors also noted a greater severity of the clinical picture in the event of a so-called “stop” mutation in the region corresponding to the M band of the sarcomere. These genotype-phenotype correlations, however imperfect they may be, are useful for a better understanding of this heterogeneous set of neuromuscular pathologies.
