Application for primary endpoint qualification of the 95th centile of stride velocity (SV95C) in Duchenne muscular dystrophy

peer reviewe

DMD and West syndrome

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients

Non-ambulant duchenne patients theoretically treatable by exon 53 skipping have severe phenotype

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