Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Abstract

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors.

Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly.

Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF<20% and a grip strength >27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later.

Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones.

Figure 1

CONSORT diagram. Reasons for premature withdrawal included: (A) loss of follow‐up, (B) withdrawal, (C) physician decision to withdraw, (D) enrollment into other clinical trials, (E) death, (F) missed visit, (G) last visit missed, (H) protocol completed, () loss of ambulation.

Figure 2

Longitudinal evolution of clinical outcome measures. Outcomes (A) grip strength as percentage of predicted value, (B) pinch strength as percentage of predicted value, (C) MoviPlate score, (D) MFM total score expressed as percentage, (E) Brooke score (scale from 1 to 6), (F) Walton score, (G) FF expressed as percentage, (H) lCSA expressed as square millimeter of the flexors as a function of age in years for non‐ambulatory (red) and ambulatory (blue) subjects. Each line connects data points for an individual subject.

Figure 3

Relationship between grip strength and MFM total score, FF, and lCSA. Correlations of (A) percentage of predicted grip strength to MFM total score, (B) percentage of predicted grip strength to FF of the flexors, (C) grip strength absolute value (expressed in kg) to lCSA of the flexors (expressed in mm²). Each line connects data points for individual non‐ambulatory (red) or ambulatory (blue) subject.

Figure 4

Correlation between flexor FF and grip strength with clinical parameters. Grip strength (%pred) versus FF in the flexors (% of baseline) for (A) subjects who were ambulatory (blue), non‐ambulatory (red), or changed between baseline and 3 years (blue/red) (n = 25), (B) subjects who were ambulatory (blue), non‐ambulatory (red), or changed between 12 months and 4 years (blue/red) (n = 15 from the cohort baseline 3 years), (C) subjects who were ambulatory (blue), non‐ambulatory (red), or changed between 2 and 5 years (blue/red) (n = 12 from the cohort 1–4 years), (D) subjects who had Brooke score ≤3 (black) or >3 (gray) or who changed (black/gray) between baseline and year 3 (n = 25), (E) subjects who had Brooke score ≤3 (black) or >3 (gray) or who changed (black/gray) between 12 months and year 4 (n = 15 from the cohort baseline 3 years), and (F) subjects who had Brooke score ≤3 (black) or >3 (gray) or who changed (black/gray) between year 2 and year 5 (n = 12 from the cohort 1–4 years).