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

Michio Inoue1, Conrad C Weihl

  • 1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Current Opinion in Neurology
|June 9, 2025
PubMed
Abstract

Insights

Myofibrillar myopathies (MFMs) are redefined as "Z-disk-opathies" based on Z-disk structure or homeostasis disruption. This clarifies diagnosis and guides targeted therapies for these genetic muscle disorders.

Area of Science:

  • Muscle biology
  • Genetics
  • Pathology

Background:

  • Myofibrillar myopathies (MFMs) traditionally diagnosed via histopathology.
  • Recent genetic discoveries expand causative genes beyond Z-disk proteins.
  • This leads to terminological inconsistencies in MFM classification.

Purpose of the Study:

  • To address terminological inconsistencies in MFM definition.
  • To propose a refined, mechanism-based definition of MFM.
  • To re-evaluate MFM as a "Z-disk-opathy" for diagnostic clarity and research guidance.

Main Methods:

  • Literature review of genetic discoveries and pathogenic mechanisms in MFMs.
  • Analysis of MFM-like pathology in conditions with non-Z-disk gene mutations.
  • Identification of key themes in MFM pathogenesis, including dominant mutations and chaperone dysfunction.

Main Results:

  • MFM-like pathology is increasingly reported from mutations in genes not directly encoding Z-disk proteins.
  • True MFMs involve disruption of Z-disk protein structure or homeostasis.
  • Distinguishing true MFMs from those with similar pathology but different molecular origins is crucial.

Conclusions:

  • Classifying MFM as a "Z-disk-opathy" provides a clearer diagnostic and mechanistic framework.
  • This refined definition aids clinical diagnosis and research into targeted therapies.
  • Therapeutic strategies may focus on restoring Z-disk proteostasis or managing aberrant protein accumulation.
Keywords:
chaperonemyofibrillar myopathyz-disk

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