P1.6 The incidence of revertant and trace dystrophin expression in muscle biopsies of Duchenne Muscular Dystrophy patients with different exon deletions

Lourbakos, Afrodite; Sipkens, Jessica A.; Beekman, C.; Kreuger, D.; Brasz, L.; Janson, A. A. M.; Campion, G.; Deutekom, J. van; Kipme, S. de

doi:10.1016/j.nmd.2011.06.766

Cited by 9 publications

(11 citation statements)

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“…Furthermore it has also been recently suggested that DMD patients with deletions flanking exon 44 have significantly higher percentage of revertant fibres and traces of low-level dystrophin expression than those with deletions surrounding exon 51 [23], and this could also explain the relatively better baseline values.…”

Section: Discussionmentioning

confidence: 99%

6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes

et al. 2014

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ObjectiveIn the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.MethodsThe 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.ResultsAt baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between −325 and 175 (mean −10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant.Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.Conclusionseven if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.

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Section: Discussionmentioning

confidence: 99%

6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes

et al. 2014

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“…The number of revertant fibers is known to be different between the various sub-groups of patients with genotypes treatable by exon skipping. For instance, patients eligible for exon skipping 44 present more revertant fibers than patients eligible for exon 51 skipping [8]. This is a possible explanation for differences in the age at loss of ambulation in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…Exon skipping naturally occurs in some fibers of patients resulting in the so-called revertant fibers. Their number varies with age and type of deletion [8] and may even result in milder Becker-like phenotype [9]. Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently under evaluation in clinical trials; some agents have progress to Phase III evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, patients with a deletion theoretically treatable by exon 44 skipping present with more revertant fibers than do patients with a deletion theoretically treatable by exon 51 or 53 skipping [8]. There is no published data on these patients’ natural history, and therefore the statistical plans of clinical trials in these specific populations are designed on the basis of data available from the general DMD population.…”

Section: Introductionmentioning

confidence: 99%

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Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype

Servais

Montus

Guiner

et al. 2015

JND

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Background: Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population. Objectives: Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations. Methods: We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53). Results: We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab.Conclusions: These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.

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“…However, exceptions to the reading frame rule exist: for instance, out-of-frame deletions of exons 3-7 sometimes result in a BMD phenotype, while in-frame deletions of exon 3 can exist in patients with a DMD phenotype (Kesari et al, 2008;Koenig et al, 1989;Tuffery-Giraud et al, 2009). 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).…”

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confidence: 99%

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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P1.6 The incidence of revertant and trace dystrophin expression in muscle biopsies of Duchenne Muscular Dystrophy patients with different exon deletions

Cited by 9 publications

References 0 publications

6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes

6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes

Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype

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

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