Structured Patterns of Muscle Involvement in CAV3-Related Myopathy Revealed by Whole-Body CT Imaging

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Abstract
Caveolinopathies caused by CAV3 mutations present with heterogeneous clinical phenotypes ranging from asymptomatic hyperCKemia to limb-girdle–type muscular dystrophy. Although prior imaging studies have described commonly affected muscles, structured modeling of muscle involvement patterns in caveolinopathy has not been established. We analyzed whole-body skeletal muscle computed tomography imaging in eight patients with pathogenic or likely pathogenic CAV3 variants, comprising 14 imaging study samples. Fat infiltration across 43 muscles was graded using modified Mercuri scores. Computational multivariate analysis—including principal component analysis, clustering, and pseudotime modeling—was applied to characterize severity staging and distribution patterns. A statistically supported, stage-dependent continuum of muscle involvement was identified. Most samples demonstrated a distributed limb-girdle–predominant pattern with coordinated progression across muscle clusters. In contrast, one patient (three samples in longitudinal series) exhibited a compartment-restricted thigh-dominant pattern characterized by early posterior and medial thigh involvement. Rectus femoris showed consistent stage-dependent progression, while greater medial gastrocnemius involvement was associated with advanced severity. None of the patients exhibited clinical evidence of rippling muscle disease. These findings suggest that integrating semi-quantitative imaging with computational modeling may provide an objective framework for characterizing muscle involvement patterns in CAV3-related myopathy. Highlights: This is a whole-body muscle imaging analysis of caveolinopathy patients. Multivariate modeling was applied to CT-based modified Mercuri scores. Rectus femoris involvement may be useful as a progression indicator. Two distinct muscle involvement patterns were described. Greater medial gastrocnemius involvement may reflect more advanced disease.
Funding Information
  • Neurological and Psychiatric Disorders of NCNP (Intramural Research Grant (5-6, 5-5))
  • Health, Labour, and Welfare Sciences Research Grants (JPMH23FC1014)

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