Whole-muscle fat analysis identifies distal muscle end as disease initiation site in facioscapulohumeral muscular dystrophy

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a major muscular dystrophy characterized by asymmetric fatty replacement of muscles. We aimed to determine the initiation site and progression profile of the disease in lower extremity muscles of FSHD patients by assessing fat infiltration along their full proximo-distal axis using quantitative MRI. METHODS: Nine patients underwent MRI of lower extremities to assess end-to-end muscle fat fractions (FFs) and inflammatory lesions. Seven patients underwent the same MRI ~3.5 years later. Individual muscles (n = 396) were semi-automatically segmented to calculate average FFs over all slices covering whole muscles. To assess disease progression we determined FF changes in 5 adjacent muscle segments. RESULTS: We provide evidence that fat replacement commonly starts at the distal end of affected muscles where the highest FFs occur (p < 0.001). It progresses in a wave-like manner in the proximal direction at an increasing rate with the highest value (4.9 ± 2.7%/year) for muscles with baseline FFs of 30–40%. Thereafter it proceeds at a slower pace towards the proximal muscle end. In early phases of disease, inflammatory lesions preferentially occur at the distal muscle end. Compared with whole-muscle analysis, the common FF assessments using only few MR slices centrally placed in muscles are significantly biased (~50% in progression rate). CONCLUSIONS: These findings identify the distal end of leg muscles as a prime location for disease initiation in FSHD and demonstrate a wave-like progression towards the proximal end, consistent with proposed disease mechanisms. End-to-end whole-muscle fat assessment is essential to properly diagnose FSHD and its progression.