Background: Sarcoglycanopathies are the most severe autosomal recessive limb-girdle muscular dystrophies (LGMDs), with onset typically between 6–10yrs. LGMDR3/R5 comprise over half of sarcoglycanopathies, featuring proximal weakness, elevated creatine kinase, and cardiorespiratory involvement.
Objectives: MRI studies in sarcoglycanopathy remain scarce and predominantly qualitative. We characterized LGMDR3/R5 using quantitative water T2 (wT2) and fat fraction (FF) by MRS and whole-body MRI (WBI), and cardiac MRI with myocardial circumferential strain and native T1 mapping, to identify sensitive imaging biomarkers.
Results: Fourteen research participants (5 LGMDR3, 9 LGMDR5; age range 6–17yrs, mean 10.4±2.7yrs) underwent baseline MRI/MRS. Skeletal muscle wT2 was elevated in 12/14 (86%) and was significantly elevated compared to controls (SOL: 31.4±1.4 vs. 28.3±0.8ms; VL: 32.1±1.9 vs. 28.5±1.2ms; both p<0.001). Among LGMDR5 participants with normal FF, all (5/5) showed elevated wT2, indicating disease activity prior to fat replacement. Baseline FF was higher in older (≥10yrs) versus younger participants (SOL: 11.7±7.1 vs. 2.6±0.9%, p=0.01; VL: 26.2±25.7 vs. 5.2±6.3%, p=0.03). WBI in 3 participants prior to gene therapy (mean follow-up 9.0mo) revealed annualized lower limb FF progression of +9.2%/yr with a proximodistal gradient (glutei +13–16%/yr, distal leg +3–4%/yr), and accelerated trunk and shoulder girdle progression (+18–20%/yr) in the most advanced participant.
Cardiac MRI revealed preserved LVEF (67.6±5.2%) and GCS (−20.9±2.8%), except in the oldest participant (LGMDR5; LVEF 53%, GCS −13.6%). Regional T1 elevation was present in 5/14 (36%), predominantly LGMDR5 (4/9 vs 1/5 LGMDR3).
Conclusions: Quantitative MRI demonstrated elevated skeletal muscle wT2 in nearly all participants including all with normal FF, and rapid FF progression with a characteristic proximodistal gradient. Elevated T1 in a subset warrants further investigation as an early marker of myocardial involvement. These biomarkers show potential for detecting early disease activity and monitoring therapeutic efficacy in sarcoglycanopathy.