Upper Limb Strength, Function Worsen Over Time in DMD

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by Marta Figueiredo PhD |

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Upper limb strength, function, and muscle fat fraction continuously worsen over time in Duchenne muscular dystrophy (DMD) patients with mutations amenable to exon 53 skipping, according to three-year data from a natural history study.

Notably, this progression of upper limb involvement was assessed reliably with strength, function, and muscle MRI measures in patients who could still walk (ambulatory) and those who had lost such ability (non-ambulatory), supporting their use as outcomes in DMD clinical trials.

In addition, a combination of low grip strength and high forearm muscle fat fraction was able to predict the loss of walking skills in ambulatory patients and the loss of the ability to drink from a glass of water independently in non-ambulatory patients in the next three years.

Future, larger studies are needed to confirm these findings, which may help both in clinical practice and in designing clinical trials, particularly for non-ambulatory DMD patients who often are excluded from trials.

The study, “Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy,” was published in the journal Annals of Clinical and Translational Neurology.

DMD is caused by a deficient production of dystrophin — a protein essential for muscle integrity — due to mutations in the DMD gene. Mostly affecting boys, the disease leads to progressive muscle degradation, inflammation, and the replacement of muscle with fat tissue, all leading to weakness and difficulties with mobility.

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Children with DMD typically lose their ability to walk by age 12, and maintaining the ability to use their arms and hands to perform daily activities has become crucial with the increasing life expectancy of this patient population.

As such, understanding DMD-associated upper limb weakness progression, as well as validating outcomes sensitive to change and able to predict the loss of certain functional abilities are key “in evaluating [therapy] efficacy in patients at risk of losing ambulation or who are already non-ambulatory,” the researchers wrote.

Now, researchers reported three-year results of a natural history study, called PreU7-53 (NCT01385917), which monitored upper limb muscle impairment over time in 40 boys with DMD caused by mutations amenable to exon 53 skipping therapy. The study was sponsored by Généthon.

Clinical assessments of upper limb function (Brooke scale and the motor function measure, or MFM), strength (hand grip with MyoGrip and key pinch with MyoPinch), and coordination and endurance (MoviPlate) were performed every six months. Participants also underwent annual quantitative MRI of fat fraction and lean muscle cross sectional area of the forearm’s flexor and extensor muscles.

The boys’ mean age was 11.7 years, 18 of them were still able to walk, and 22 had already lost this ability at study enrollment. Mean duration of follow-up was 3.5 years, and 72.5% were on glucocorticoids.

Results showed that while patients’ individual trajectories of all outcome measures were highly variable over time, as a group there was a decline in upper limb muscle strength and function, and an increase in muscle fat fraction.

Grip and pinch strength were reduced significantly at all visits for non-ambulatory patients and at one, two, and three years in the overall population, while significant drops in the MFM score (indicating worse function) were detected after two years in all patient populations.

Fat fraction in flexor muscle group was significantly increased from one year onward in the non-ambulatory population and from two years in the overall patient population.

There also were significant associations between functional and strength measures, and between functional and MRI-based measures, with the strongest being found between muscle fat fraction and MFM scores.

This revealed “a continuous decline as well as a strong correlation between upper limb muscle FF [fat fraction], function, and strength over a 3-year period in non-ambulatory and ambulatory DMD patients,” the researchers wrote.

Furthermore, and in contrast to the idea that clinical changes could be more difficult to quantify in non-ambulatory patients, the data showed that clinical and MRI-based measures are as sensitive to changes in upper limb performance in non-ambulatory patients as in those who have not yet lost their walking abilities.

The team then conducted an exploratory analysis to assess whether grip strength and flexor muscle fat fraction could predict important clinical milestones such as loss of walking abilities or loss of the ability to drink a glass of water independently.

They found that neither of these measures, on their own, could significantly predict the loss of these motor milestones within three years. However, a combination of the two was a three-year predictive factor for these functional milestones.

Particularly, patients with a flexor muscle fat fraction greater than 10% and a grip strength of less than 35% at any point of the study had either lost the ability to walk unaided or would lose it in the following three years.

In turn, those who at any point had flexor fat fraction greater than 20% and less than 27% of grip strength lost their ability to bring a glass of water to their mouth within the next three years.

These findings highlighted that a combination of low flexor fat fraction and high grip strength “was a 3-year positive prognosis factor for maintaining ambulation and for the ability to raise a glass to the mouth independently,” the team wrote.

Larger and independent studies are needed to confirm these associations, which may help “the scientific community and industry partners to better stratify patient populations for future clinical trials of the upper limb in non-ambulatory patients with DMD,” the researchers concluded.