Francesca Magri
Pathogenic TNNI1 variants cause muscle disease manifesting as either a hypo- (recessively inherited) or a hyper- (dominantly inherited) contractile phenotype.
Autori
- FRANCESCA MAGRI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY. – NEUROLOGO)
- SIMONA ZANOTTI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – BIOLOGO)
- DANIELE VELARDO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – NEUROLOGO)
- SARA ANTOGNOZZI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY. – BIOTECNOLOGO)
- MICHELA RIPOLONE (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – BIOLOGO)
- MOSE’ PARISI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY. – NEUROLOGO)
- LAURA NAPOLI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – BIOLOGO)
- PATRIZIA CISCATO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – BIOLOGO)
- MONICA SCIACCO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY. – NEUROLOGO)
- STEFANIA CORTI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY; DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY. – NEUROLOGO)
- GIACOMO PIETRO COMI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY; DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY. – NEUROLOGO)
- DARIO RONCHI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY; DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY. – BIOTECNOLOGO)
Presentatore
FRANCESCA MAGRI
Modalità
Oral Communication
Abstract
“Troponin I is the inhibitory subunit of the troponin complex. Among the 3 Troponin I genes (TNNI1, TNNI2 and TNNI3), defects in TNNI2 (fast twitch myofibers) and TNNI3 (cardiac myofibers) were associated with distal arthrogryposis and cardiomyopathy, respectively.
We investigated two patients, a mother (P1) and her son (P2), presenting with adult-onset muscle cramping, myalgias, stiffness and fatigue, often following physical activity. Creatine kinase levels were increased. Cardiac screening in P1 demonstrated mild left ventricular enlargement. P2 developed a myocarditis followed by cardiac arrest requiring implantation of a pacemaker device. Muscle MRI revealed selective (gastrocnemius, P1) or diffuse (P2) fatty infiltration. Muscle biopsies showed myofiber size variation, with internalized nuclei increase and type 1 hypertrophy on oxidative stains. Eosinophilic granular inclusions were observed in type 1 fibers. Electron microscopy confirmed the presence of several rods and core-like regions with rare streaming of Z-lines. WES analysis revealed the c.527_529delAGA deletion in TNNI1, encoding the Troponin I, expressed in slow twitch myofibers. This variant likely results in the in-frame deletion of the conserved Lys176 residue.
Gene Matcher connections were established with a second family displaying dominantly acting heterozygous TNNI1 variant and two families with biallelic loss-of-function TNNI1 variants resulting in a hypocontractile phenotype and manifesting with early-onset progressive muscle weakness. A rod-myopathy predominantly affecting type 1 slow-twitch fibers was confirmed.
We provide clinical and histological characterization of patients with pathogenic TNNI1 variants, disclosing a novel genetic cause underlining opposite clinical phenotypes.”