70P Defining the landscape of TIA1 and SQSTM1 digenic myopathy

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Fernández-Eulate, G., Panos-Basterra, P., Theuriet, J., Nadaj-Pakleza, A., Magot, A., Lannes, B., Marcorelles, P., Behin, A., Masingue, M., Caillon, F., Malek, Y., Fenouil, T., Bas, J., Menassa, R., Michel-Calemard, L., Streichenberger, N., Simon, J., Bouhour, F., Evangelista, T., Métay, C., Pegat, A., Stojkovic, T.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.433

TIA1/SQSTM1 myopathy is one of the few myopathies with a true digenic inheritance. Our goal was to define the phenotype presentation of the disease, genotype-phenotype correlations, and to study the prevalence of the TIA1-N357S variant in distal myopathy. We describe four new adult male patients carrying the TIA1-N357S and SQSTM1-P392L variant and review the literature to include 20 additional cases. We reviewed the results of the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort for the TIA1-N357S variant. Twenty-four patients (75% males) were included, with late-onset (52,6±10,1years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and EMG myopathic changes. Two of the four French patients also had a sensorimotor axonal polyneuropathy and an additional one had neurogenic features in tibialis anterior biopsy. Most commonly, muscle histopathology showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1-N357S variant was present in all patients and the SQSTM1-P392L was the most frequent (68%) of the four reported SQSTM1 variants. The TIA1-N357S variant was carried by 11/414=2.7% of distal myopathy patients and two had an alternative diagnosis (TTN and MYH7) with atypical phenotypes. TIA1/SQSTM1 myopathy has a homogenous and characteristic phenotype reinforcing the pathogenicity of its digenic variants. Furthermore, sensorimotor axonal polyneuropathy may be an additional feature of the disease. Finally, we confirm an increased burden of the TIA1-N357S variant in distal myopathy patients which could act as a genetic modifier.