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Neurology. 2016 Jul 26;87(4):401-9. doi: 10.1212/WNL.0000000000002891. Epub 2016 Jun 24.

DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study.

Author information

1
From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.

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.

PMID:
27343068
PMCID:
PMC4977110
DOI:
10.1212/WNL.0000000000002891
[Indexed for MEDLINE]
Free PMC Article

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