Nicola Molitierno
Atypical BAG3-related adult-onset clinical presentation
Autori
- NICOLA MOLITIERNO (DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY – SPECIALIZZANDO IN NEUROLOGIA)
- DANIELE VELARDO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – NEUROLOGIA)
- ELENA ABATI (DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY; IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY – NEUROLOGIA)
- SARA ANTOGNOZZI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY – BIOLOGIA)
- MICHELA RIPOLONE (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – BIOLOGIA)
- SIMONA ZANOTTI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – BIOLOGIA)
- LAURA NAPOLI (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – BIOLOGIA)
- PATRIZIA CISCATO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – TECNICO DI LABORATORIO)
- MONICA SCIACCO (IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – NEUROLOGIA)
- STEFANIA PAOLA CORTI (DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY; IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROMUSCULAR AND RARE DISEASE UNIT, MILAN, ITALY – NEUROLOGIA)
- GIACOMO PIETRO COMI (DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY; IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY – NEUROLOGIA)
- DARIO RONCHI (DINO FERRARI CENTER, DEPARTMENT OF PATHOPHYSIOLOGY AND TRANSPLANTATION, UNIVERSITY OF MILAN, MILAN, ITALY; IRCCS FONDAZIONE CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, NEUROLOGY UNIT, MILAN, ITALY – )BIOLOGIA
Presentatore
NICOLA MOLITIERNO
Modalità
Poster Session
Abstract
BAG3 is a multifunctional HSP70 co-chaperone which takes part in intracellular protein quality control by targeting aggregation-prone proteins to autophagic degradation under acute stress and cellular aging. BAG3 seems to play a fundamental role in several disorders, including inherited myopathies.
Pathogenic variants are associated with neuromuscular presentations including skeletal muscle myopathy, dilated cardiomyopathy, adult-onset Charcot-Marie-Tooth neuropathy and, more recently, a dominant form of distal hereditary motor neuronopathy with incomplete penetrance.
BAG3 is strongly expressed in skeletal and heart muscle cells and co-localizes with Z-disks. Mutated patients are characterized by disrupted Z-disks with degeneration or disorganization of myofibrils.
BAG3-related myopathy usually features muscular dystrophy with rapidly progressive limb and axial muscle weakness in early childhood followed by respiratory insufficiency and cardiomyopathy, often resulting in early death.
We describe a 53-year-old male patient who presented with persistent asymptomatic increase of serum creatine kinase levels (from 800 to 1300 U/L). Cardiological evaluation showed mild left atrium dilatation and moderate left ventricular hypertrophy with frequent ventricular and supraventricular ectopic heartbeats on ECG. Electromyography showed no myopathic feature. Histologic findings revealed scattered hypotrophic muscle fibers and small intracytoplasmic accumulation areas made of hypercromic material in some fibers. Ultrastructural analyses revealed some features compatible with myofibrillar myopathy.
By performing clinical exome sequencing, we detected two rare unreported heterozygous BAG3 variants: c.1531C>T p.(Gln511*) and c.776C>T p.(Pro259Leu) classified according ACMG criteria as Likely Pathogenic and Variant of Unknown Significance, respectively.
Our study reports a case of BAG3-related asymptomatic myopathy with mild cardiac involvement and further confirmed the wide phenotypic spectrum of BAG3-related myopathy.