Objective
To continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy ...(DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).
Methods
Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.
Results
At 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.
Interpretation
Over 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271
Galactosemia type 1 is an autosomal recessive disorder of galactose metabolism, determined by a deficiency in the enzyme galactose‐1‐phosphate uridyltransferase (GALT). GALT deficiency is classified ...as severe or variant depending on biochemical phenotype, genotype and potential to develop acute and long‐term complications. Neonatal symptoms usually resolve after galactose‐restricted diet; however, some patients, despite the diet, can develop long‐term complications, in particular when the GALT enzyme activity results absent or severely decreased. The mechanisms of acute and long‐term complications are still discussed and several hypotheses are presented in the literature like enzymatic inhibition, osmotic stress, endoplasmic reticulum stress, oxidative stress, defects of glycosylation or epigenetic modification. This review summarizes the current knowledge of galactosemia, in particular the putative mechanisms of neonatal and long‐term complications and the molecular genetics of GALT deficiency.
Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5–7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of ...dystrophin, probably because of skewed patterns of X‐chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non‐manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation‐based assay. The results showed that DMD‐manifesting carriers had a preferential inactivation of the X‐chromosome carrying the normal allele, while non‐manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother–daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non‐random patterns of X inactivation.
Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or ...in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.
Myotonic dystrophy type 1 (MD1) is characterized by cardiac involvement, in about 80% of case, that predominantly affects the conduction system. Aim of our study was to evaluate the P-wave duration ...and dispersion (PD) in MD1 patients underwent pacemaker implantation with conserved systolic and diastolic function.
We enrolled 60 MD1 patients (age 51.3 ± 5 years; 11 females) underwent dual chamber pacemaker implantation for various grade of atrioventricular (AV) block. Sixty sex-and age matched non-MD1 subjects were recruited as controls. P-wave duration and dispersion were carefully measured using 12-lead electrocardiogram.
Compared with healthy control group, MD1 patients presented increased maximum P wave duration (106.4 ± 20.9 vs 65.9 ± 8.2 ms, p = 0.03) and PD values (40.1 ± 11 vs 27.1 ± 4.2 ms, p = 0.003). No statistically significant difference was found in minimum P wave duration (69.7 ± 11.8 vs 65.4 ± 8.1 ms, p = 0.4). The MD1 patients with paroxysmal atrial fibrillation, compared with MD1 patients without evidence of atrial fibrillation, presented increased maximum P wave duration (108.1 ± 10.4 vs 78.1 ± 7.9 ms, p = 0.001) and PD values (41.1 ± 8.5 vs 33.2 ± 4.2 ms, p = 0.003). Minimum P wave duration (68.4 ± 8.2 vs 67.1 ± 4.9 ms, p = 0.5) didn't differ between the two groups.
Our data showed a significantly increased P wave duration and dispersion in MD1 patients compared with age and sex-matched healthy controls. We showed a statistically significant increase in PD and P max in MD1 patients subgroup with AF compared to MD1 patients with no arrhythmias.
PDF
