Chronological and Spatial Distribution of Skeletal Muscle Fat Replacement in FHL1‐Related Myopathies

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OBJECTIVES: Variants in the FHL1 gene cause FHL1-related myopathies (FHL1-RMs), a group of neuromuscular disorders with diverse clinical presentations. This study aimed to comprehensively characterize the spatial and temporal patterns of skeletal muscle fat replacement throughout the whole body in FHL1-RMs, to examine disease progression over time, and to evaluate the relationship between imaging findings and clinical symptoms. METHODS: We retrospectively analyzed 21 whole-body imaging studies from 10 patients with genetically confirmed FHL1-RMs. Fatty replacement was scored in 47 muscles using the modified Mercuri score (mMS). Longitudinal data were used to stratify patients into slow, moderate, and rapid progression groups. K-means clustering was applied to classify muscles based on their chronological patterns of fatty infiltration. Hierarchical clustering and violin plots were used to explore inter-muscle and inter-patient variations. RESULTS: Despite notable variability in the rate of disease progression, a consistent pattern of muscle involvement was observed across patients. Muscles were classified into three progression clusters: early-onset and early attainment of the maximal mMS (e.g., paraspinal and posterior thigh muscles), steadily progressive (e.g., trunk and lower leg muscles), and late-onset with slow changes (e.g., shoulder and anterior thigh muscles). These patterns paralleled the clinical symptom progression. In early-stage patients, STIR imaging revealed muscle signal abnormalities preceding fat replacement detectable on T1-weighted images. INTERPRETATION: The rate of fat replacement in FHL1-RMs varies individually, but spatial patterns are conserved and reflect clinical evolution. Serial imaging is a valuable tool to monitor disease progression and may serve as a sensitive biomarker in clinical trials.

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