Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy.
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ABSTRACT:
SUBMITTER: Kao KT
PROVIDER: S-EPMC6459782 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy.
Kao Kung-Ting KT Joseph Shuko S Capaldi Nadia N Brown Sarah S Di Marco Marina M Dunne Jennifer J Horrocks Iain I Shepherd Sheila S Ahmed Syed Faisal SF Wong Sze Choong SC
European journal of pediatrics 20190214 5
We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI - 6.1, - 0.66; p = 0.016). L ...[more]
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Project description:Background and objectivesDuchenne muscular dystrophy (DMD) is a paediatric neuromuscular disorder caused by mutations in the dystrophin gene. Geneotype-phenotype associations have been examined in glucocorticoid treated boys, but there are few data on the young glucocorticoid-naïve DMD population. A sample of young glucocorticoid-naïve DMD boys is described and genotype-phenotype associations are investigated.MethodsScreening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD)study, an international, multi-centre, randomized, double-blind, clinical trial comparing three glucocorticoid regimens in glucocorticoid-naïve, genetically confirmed boys with DMD between 4 and <8 years of age.ResultsOne hundred and ninety-six boys were recruited. The meanage at randomization (+ standard deviation) was 5.8+ 1.0 years. The predominant mutation type was out of frame deletions 67.4%, (130/193) of which 68.5% (89/130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping 13.0% (25/193). Stop codon mutations accounted for 10.4% (20/193).The mean age at first parental concerns was 29.8 + 18.7 months, the mean age at genetic diagnosis was 53.9 + 21.9 months and the mean diagnostic delay was 25.9 + 18.2 months. The mean diagnostic delay for boys diagnosed following an incidental finding of isolated hyperCKemia (n=19) was 6.4 + 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 + 4.2 and 29.0 + 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with an exon 8 skippable deletions who had better performance on time to walk/run 10 meters (p=0.02)compared to boys with deletions not amenable to skipping.DiscussionThis study describes clinical and genetic characteristics of a sample of young glucocorticoid-naïve boys with DMD. A low threshold for CK testing can lead to an earlier diagnosis. Motor and speech delay were common presenting symptoms.The effects of low, pre-treatment height on growth and adults height requires further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials.
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Project description:To evaluate the safety, tolerability, and efficacy of supported standing in a small sample of boys with Duchenne muscular dystrophy (DMD).Four 12- to 15-year-old boys with DMD engaged in a home-based supported standing program for 6 to 12 months. A single-subject design was employed to examine muscle length. Bone mineral density was assessed at 4-month intervals using dual-energy x-ray absorptiometry.Upright, sustained supported standing was tolerated in 3 of the 4 boys. Mean weekly stand times ranged from 1.3 to 3.3 hours. Improved hip or knee flexor muscle length was seen in 3 of the 4 boys. No boys showed improved plantar flexor muscle length or increased lumbar bone mineral density.Findings offer preliminary empirical evidence addressing the safety, tolerability, and efficacy of standing in boys with DMD. Additional research with an emphasis on better program adherence is indicated.
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Project description:IntroductionIn this study we explored walking activity in a large cohort of boys with Duchenne muscular dystrophy (DMD).MethodsStep activity (monitored for 7 days), functional ability, and strength were quantified in ambulatory boys (5-12.9 years of age) with DMD and unaffected boys. Ambulatory status was determined 2 years later.ResultsTwo to 5 days of activity monitoring predicted weekly step activity (adjusted R2 = 0.80-0.95). Age comparisons revealed significant declines for step activity with increasing age, and relationships were found between step activity with both function and strength (P < .01). Our regression model predicted 36.5% of the variance in step activity. Those who were still ambulatory after 2 years demonstrated baseline step activity nearly double that of those who were no longer walking 2 years later (P < .01).DiscussionStep activity for DMD is related to and predictive of functional declines, which may be useful for clinical trials.
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Project description:ObjectiveTo determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD).MethodsIn 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil.ResultsThe major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD.ConclusionsThese data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD.Classification of evidenceThis study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.
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