Abstract
Objective: To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments. Methods: We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n 186), or small mutations identified by sequencing (n 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers. Results: Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain. Conclusions: As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 401-409 |
| Number of pages | 9 |
| Journal | Neurology |
| Volume | 87 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jul 26 2016 |
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ASJC Scopus subject areas
- Clinical Neurology
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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 M; Cirak, Sebahattin.
In: Neurology, Vol. 87, No. 4, 26.07.2016, p. 401-409.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study
AU - Bello, Luca
AU - Morgenroth, Lauren P.
AU - Gordish-Dressman, Heather
AU - Hoffman, Eric P.
AU - McDonald, Craig M
AU - Cirak, Sebahattin
PY - 2016/7/26
Y1 - 2016/7/26
N2 - Objective: To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments. Methods: We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n 186), or small mutations identified by sequencing (n 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers. Results: Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain. Conclusions: As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
AB - Objective: To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments. Methods: We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n 186), or small mutations identified by sequencing (n 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers. Results: Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain. Conclusions: As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=84980315837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84980315837&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000002891
DO - 10.1212/WNL.0000000000002891
M3 - Article
C2 - 27343068
AN - SCOPUS:84980315837
VL - 87
SP - 401
EP - 409
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 4
ER -