Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy.

Purpose of review: Myofibrillar myopathies (MFMs) are traditionally defined by histopathology, but recent genetic discoveries have broadened the spectrum of causative genes beyond Z-disk components. This review aims to address the resulting terminological inconsistency by proposing a refined, mechanism-based definition of MFM centered on its identity as a "Z-disk-opathy." This re-evaluation is timely and relevant for improving diagnostic clarity and guiding future research.

Recent findings: The literature increasingly reports MFM-like pathology in conditions caused by mutations in genes not directly encoding Z-disk structural proteins or their interacting chaperones. This review highlights the pathogenic mechanisms distinguishing true MFMs, which involve disruption of Z-disk protein structure or Z-disk protein homeostasis, from "myopathies with MFM pathology" that share histological features but stem from different molecular etiologies. Key themes include the dominant nature of mutations in Z-disk structural proteins and the critical role of chaperone dysfunction in MFM pathogenesis.

Summary: A refined definition classifying MFM as a "Z-disk-opathy" offers a clearer framework for diagnosis and mechanistic understanding. This distinction has significant implications for clinical practice, facilitating more accurate diagnosis, and for research, by supporting the development of targeted therapeutic strategies aimed at either restoring Z-disk proteostasis or mitigating the effects of aberrant protein accumulation.