CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.242Neonatal presentations of recessive TTN-related myopathy: an emerging distinct clinical phenotype

Abstract

With the increasing availability of next generation-based sequencing, the phenotypic spectrum associated with TTN-related myopathies is ever-expanding. Early clinical recognition is essential to facilitate accurate genetic testing methodologies, to aid in pathogenicity interpretation of the large number of TTN variants identified, and to direct proper medical care and management. Here we report four unrelated patients, aged 2 to 12 years, with genetically confirmed biallelic TTN mutations who display a consistent, recurrent phenotype that is recognizable at birth. Retrospective review of the neonatal presentations of these four patients revealed characteristic clinical features, the most prominent of which is striking positioning of the hands and feet, namely bilateral wrist extension with ulnar deviation of the hands and extreme ankle dorsiflexion of the feet with associated Achilles tendon hyperlaxity. Additional salient features include reduced fetal movements and oligohydramnios, along with bulbar weakness clinically manifesting as dysphagia and feeding difficulties, generalized hypotonia and joint hypermobility. Bilateral hip dysplasia and respiratory distress or apnea was also seen in three out of four neonates. This cohort delineates a distinct and recognizable neonatal clinical phenotype associated with recessive TTN-related myopathy and may aid in the recognition of titinopathy in neonates presenting with features of a congenital myopathy. It can be added as a ``titin-compatible'' phenotype that will also help in interpreting TTN genotypes ``of uncertain significance.'' Additional neonatal titinopathy cases will surely expand on this phenotype. Longitudinal data are needed to further characterize this phenotype and increase our understanding of the natural history of titinopathy as well as expand genotype-phenotype correlations.