Congenital Titinopathy: Comprehensive characterization and pathogenic insights.

Ann Neurol

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.

RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.

INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Year of Publication
Ann Neurol
Date Published
2018 06
PubMed ID
PubMed Central ID
Grant list
DH_ / Department of Health / United Kingdom
R01 NS029525 / NS / NINDS NIH HHS / United States
R01 HD075802 / HD / NICHD NIH HHS / United States
WT_ / Wellcome Trust / United Kingdom
R01 HL062881 / HL / NHLBI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 HL115988 / HL / NHLBI NIH HHS / United States
R01 AR044345 / AR / NIAMS NIH HHS / United States
MC_UP_1102/20 / MRC_ / Medical Research Council / United Kingdom
107469/Z/15/Z / WT_ / Wellcome Trust / United Kingdom