Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy

Abstract

Background Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. Methods We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. Results There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. Conclusions Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Orofacial Muscle Weakening in Facioscapulohumeral Muscular Dystrophy (FSHD) Patients

“…The further elucidation of the genetic involvement in the growth and function of the dentofacial complex and musculature will contribute to better patient care aimed at enhanced function, facial aesthetics and well-being. Finally, monitoring the correlation between D4Z4 fragment size and the severity of orofacial muscle weakness in prospective longitudinal observational studies of subjects diagnosed with FSHD, even by implementing contemporary imaging techniques such as magnetic resonance (MRI), could provide essential information regarding the onset, progression and the manifestations of FSHD in the orofacial complex [ 51 ].…”

Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

“…[101,120,121] MRI provides an objective measure of disease progression and can be a helpful endpoint in follow-up and trials in patients with FSHD. [101,122,123] Nevertheless, the current diagnostic approach rests on modalities other than radiological evidence, as shown in Figure 2, and finding a compatible pattern on MRI may serve as corroborative evidence for the diagnosis of FSHD2 in cases of diagnostic uncertainty or an atypical phenotype despite results from investigations highlighted in the algorithm. [124]…”

Identification of candidate miRNA biomarkers for facioscapulohumeral muscular dystrophy using DUX4-based mouse models

“…As an alternative to circulating protein biomarkers, a global gene expression analysis was performed using blood from two well-controlled patient cohorts, but failed to find gene expression profiles differentially expressed in FSHD patients ( Signoelli et al, 2020 ). Additional non-invasive approaches such as MRI and ultrasound techniques have been developed as imaging biomarkers of disease progression, and display the sensitivity to define disease severity and motor function ( Mul et al, 2018a , 2017 ; Wang et al, 2019 , 2021b ). Importantly MRI measurements have shown a correlation with both pathological changes and expression of DUX4 target genes ( Wang et al, 2019 ), but not with immunosuppressive treatments for FSHD ( Wang et al, 2021a ).…”