“Background: Mutations in the gene that encodes titin (TTN) are linked to multiple skeletal muscle disorders and cardiomyopathies and combinations of these, with autosomal dominant or recessive inheritance. A broad range of clinical phenotypes have been described ranging from congenital to adult onset form.
Methods: Here we describe six unrelated pediatric patients followed in our Neuromuscular Unit carrying TTN mutations and displaying muscle or both muscle and cardiac phenotype.
Results: Onset ranged from prenatal period to infancy. All but one presented delayed motor milestones. Two had arthrogryposis at birth, the remaining developed contractures already in infancy. None had ophthalmoplegia. Four patients presented bulbar involvement. Weakness affected predominantly axial and proximal muscles of both lower and upper limbs. Cardiac involvement was present in three with dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Scoliosis was present in four and started early. Muscle biospy available for 3 patients showed dystrophic changes in two and type 1 fiber predominance, nuclear centralization and minicores in one. Muscle magnetic resonance was performed in three patients and showed predominantly gluteal, hamstring and calf muscle involvement. Genetic analysis using NGS sequencing revealed in five patients compound heterozygous variants in the TTN gene, in one patient array-CGH analysis detected a de novo 2q31.2 microdeletion that involves the region where TTN is located.
Conclusion: Our report contributes to better define clinical, istopathological, imaging features and genetic characteristics of titinopathy and expands the knowledge of the natural history of this disorder.”