DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Bello, Luca; Morgenroth, Lauren P.; Gordish‐Dressman, Heather; Hoffman, Eric P.; McDonald, Craig; Çırak, Sebahattin

doi:10.1016/j.nmd.2016.06.124

Cited by 46 publications

(114 citation statements)

References 27 publications

(27 reference statements)

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“…HRs for deflazacort and prednisone were 0.31 and 0.62, which is consistent with our previous finding that deflazacort tends to have a stronger effect at delaying age at LOA than prednisone (Wang et al, 2014). This is similar to Bello et al (2016), who estimated HR for exon 44 skippable mutations to be 0.34. Their data also showed deflazacort to be more beneficial in delaying age at LOA compared to prednisone (0.34 vs.…”

Section: Discussionsupporting

confidence: 90%

“…This is similar to Bello et al. (), who estimated HR for exon 44 skippable mutations to be 0.34. Their data also showed deflazacort to be more beneficial in delaying age at LOA compared to prednisone (0.34 vs. 0.22) and that the genetic effect was similar to corticosteroid treatment.…”

Section: Discussionsupporting

confidence: 90%

“…The availability of these multiple data types and the ability of participants to update data make the Duchenne Registry a robust data set for exploratory studies and natural history comparison because it is larger than all reported studies investigating DMD age at LOA combined (Bello et al, 2016;Pane et al, 2014;Servais et al, 2015;van den Bergen, et al, 2014). (Bello et al, 2016;van den Bergen et al, 2014). Consistent with the results presented here, both strongly support a delay in age at LOA among individuals amenable to targeted skipping of exon 44.…”

Section: Discussionsupporting

confidence: 82%

“…Recently, some DMD individuals with mutations amenable to exon 44 skipping were observed to have a higher rate of revertant fibers and a larger number of trace dystrophin positive fibers relative to muscles from exon 51 amenable DMD boys (Lourbakos et al, 2011). Consistent with this description, several studies have indicated that exon 44 skip amenable DMD boys have an overall better functional outcome with higher age at LOA relative to typical DMD (Bello et al, 2016;Pane et al, 2014;van den Bergen, Ginjaar, Niks, Aartsma-Rus, & Verschuuren, 2014).…”

mentioning

confidence: 71%

“…In the available data from the Duchenne Registry, we were able to retain a substantial number (N = 765) of males with an exonic duplication, nonsense mutation, or deletion mutation correctable by skipping exon 8, 44, 45, 50, 51, 52, 53, or 55 alongside their steroid usage and age at LOA. The availability of these multiple data types and the ability of participants to update data make the Duchenne Registry a robust data set for exploratory studies and natural history comparison because it is larger than all reported studies investigating DMD age at LOA combined (Bello et al, 2016;Pane et al, 2014;Servais et al, 2015;van den Bergen, et al, 2014). (Bello et al, 2016;van den Bergen et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype

et al. 2018

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Antisense oligonucleotide (AON)‐mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in‐frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in the Duchenne Registry, a large database of phenotypic and genetic data for DMD (N = 765). Males amenable to exon 44 (N = 74) and exon 8 skipping (N = 18) showed prolonged ambulation compared to other exon skip groups and nonsense mutations (P = 0.035 and P < 0.01, respectively). In particular, exon 45 deletions were associated with prolonged age at loss of ambulation relative to the rest of the exon 44 skip amenable cohort and other DMD mutations. Exon 3–7 deletions also showed prolonged ambulation relative to all other exon 8 skippable mutations. Cultured myotubes from DMD patients with deletions of exons 3–7 or exon 45 showed higher endogenous skipping than other mutations, providing a potential biological rationale for our observations. These results highlight the utility of aggregating phenotypic and genotypic data for rare pediatric diseases to reveal progression differences, identify potentially confounding factors, and probe molecular mechanisms that may affect disease severity.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype

et al. 2018

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Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Bello

D'Angelo

Villa

et al. 2020

Ann Clin Transl Neurol

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Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, 786 estimated that forced vital capacity (FVC) declined yearly by À4.2%, forced expiratory volume in 1 sec by À5.0%, and peak expiratory flow (PEF) by À2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately À6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

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Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study

Komaki

Takeshima

Matsumura

et al. 2020

Ann Clin Transl Neurol

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Objective The novel morpholino antisense oligonucleotide viltolarsen targets exon 53 of the dystrophin gene, and could be an effective treatment for patients with Duchenne muscular dystrophy (DMD). We investigated viltolarsen’s ability to induce dystrophin expression and examined its safety in DMD patients. Methods In this open‐label, multicenter, parallel‐group, phase 1/2, exploratory study, 16 ambulant and nonambulant males aged 5–12 years with DMD received viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary endpoints were dystrophin expression and exon 53 skipping levels. Results In western blot analysis, mean changes in dystrophin expression (% normal) from baseline to Weeks 12 and 24 were − 1.21 ( P = 0.5136) and 1.46 ( P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 ( P = 0.2367) and 4.81 ( P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group (2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53 skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events were judged to be mild or moderate in intensity and none led to study discontinuation. Interpretation Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing trend in dystrophin expression and exon 53 skipping levels, and was safe and well tolerated. The decline in motor function appeared less marked in patients with higher dystrophin levels; this may warrant further investigation. This study supports the potential clinical benefit of viltolarsen.

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DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Cited by 46 publications

References 27 publications

DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype

DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study

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