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Introduction In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials. Methods Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48‐week changes in ambulatory function were estimated using mixed models. Adjusted differences between corticosteroid groups were pooled in a meta‐analysis. Results In the meta‐analysis, deflazacort‐treated patients vs prednisone/prednisolone‐treated patients experienced, on average, lower declines of 28.3 meters on 6‐minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4‐stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score). Discussion Deflazacort‐treated patients experienced significantly lower functional decline over 48 weeks.

Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] >= 300-= 300-= 300

ObjectiveTo evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD).MethodsWe investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location.ResultsParticipants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63.ConclusionOur data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease.Clinicaltrials.gov identifierNCT02090959.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

We recently identified mutations in the fukutin related protein (FKRP) gene in patients with congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 21 (LGMD21). The sarcolemma of these patients typically displays an immunocytochemical reduction of alpha-dystroglycan. in this report we extend these observations and report a clear correlation between the residual expression of alpha-dystroglycan and the phenotype. Three broad categories were identified. Patients at the severe end of the clinical spectrum (MDC1C) were compound heterozygote between a null allele and a missense mutation or carried two missense mutations and displayed a profound depletion of alpha-dystroglycan. Patients with LGMD with a Duchenne-like severity typically had a moderate reduction in alpha-dystroglycan and were compound heterozygotes; between a common C826A (Lcu276Ileu) FKRP mutation and either a missense or a nonsense mutation. Individuals with the milder form of LGMD21 were almost invariably homozygous for the Leu276Ile FKRP mutation and showed a variable but subtle alteration in alpha-dystroglycan immunolabeling. Our data therefore suggest a correlation between a reduction in alpha-dystroglycan, the mutation and the clinical phenotype in MDC1C and LGMD21 which supports the hypothesis that dystroglycan plays a central role in the pathogenesis of these disorders.

The ENMC Consortium on Congenital muscular dystrophy (CMD) held its 8th meeting in Naarden during the weekend of the 17–19 January 2003. It was attended by 25 participants from nine countries, including Austria, Denmark, France, Germany, Italy, The Netherlands, Turkey, UK, and the USA. The present meeting focused on a group of syndromes characterized by a deficiency in proteins with either a demonstrated or putative enzymatic activity (glycosyltransferases). Five of these conditions have been described so far, of which four affect the human and cause different forms of CMD (Walker–Warburg syndrome, (WWS); Fukuyama CMD, (FCMD); muscle eye brain disease, (MEB); and CMD type 1C, (MDC1C)), and a spontaneously occurring mouse mutant (myd mice) All these five disorders display reduced or absent expression of a-dystroglycan, a highly glycosylated molecule, on immunocytochemistry and Western blot suggesting that the primary defect responsible for each of these disorders may play a role in the processing of a-dystroglycan. In addition, a number of other CMD syndromes in which the primary defect is unknown are also characterized by an abnormal expression of a-dystroglycan, suggesting that abnormal processing of a-dystroglycan plays a significant role in the pathogenesis of a number of CMD syndromes. The first part of the meeting focused on organization of the extracellular matrix, and the role of a-dystroglycan and its binding partners in muscle, while the second part was devoted to syndromes in which abnormal processing or expression of a-dystroglycan has been documented. Sessions were also devoted to pathogenesis of neuronal migration disorders and therapeutic approaches using a novel gene therapy strategy.

Questo è un lavoro del consorzio Internazionale della distrofia muscolare congenita e del gruppo denominato GENRE (Genetic Resolution of Congenital Muscular Dystrophy) che è parte del progetto Myo-Cluster finanziato dalla comunità Europea (QLG1-CT-1999-00870) e di cui lo IOR è il centro di coordinamento e il Dr. Luciano MERLINI dello IOR è il responsabile scientifico dell’intero progetto al quale afferiscono complessivamente 16 centri europei. Nella authorship del lavoro pubblicato a pagina 69-78 vi sono solo 2 nomi per un errore di stampa che è stato corretto nella backcover del numero di maggio 2002 della rivista stessa e riportato anche nell’indice finale pag. 438 (vedi allegati). L’authorship corretta comprende 2 ricercatori 1 dello IORe un del CNR: L. Merlini, P. Sabatelli. Sabatelli in particolare ha riportato i risultati del gruppo Maraldi. Al workshop ha inoltre partecipato un terzo ricercatore dello IOR, B. Talim affiliata al laboratorio di patologia neuromuscolare (vedi lista a pagina 77). Vengono riportati risultati originali che sono stati comunicati e discussi ad un workshop che si è tenuto in Olanda (27-28 Ottobre 2000) sotto l’egida dell’European Neuromuscular Centre (ENMC). In particolare sono riportati nel lavoro i dati originali riferentesi alle distrofie muscolari congenite con ritardo mentale. Merlini riporta i dati clinici e di laboratorio delle famiglie Italiane studiate allo IOR con distrofia muscolare congenita, microcefalia, ritardo mentale e ipertrofia delle sure. Tale malattia viene ora riferita come Italian MEB (Muscle Eye Brain distrofia muscolare congenita). Talim riporta i dati clinici e di laboratorio di una famiglia Italiana di zingari con distrofia muscolare congenita di Walker-Warburg studiata nel centro neuromuscolare dello IOR.

Item does not contain fulltext In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, beta-ureidopropionase (UP) deficiency, are reported. 1D (1)H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D (1)H-(1)H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D (1)H-NMR spectroscopy, UP deficiency can be easily diagnosed. The (1)H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway.