Abstract Introduction Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the ...introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. Method A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). Results Detailed information was available on 21 patients. Group one comprises 17 patients; mean age at death was 23.9 (14.4-39.5) years. Group two, comprises 4 patients; mean age at death was 14 (12.7-14.9) years. They died of acute pneumonia, cardio-respiratory arrest following trauma and exercise and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. Conclusions The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death.
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Background Over the last 30 years, there has been little improvement in the age of diagnosis of Duchenne muscular dystrophy (DMD) (mean age of 4.5–4.11 years). Aim To review the diagnostic process ...for DMD in boys without a family history in order to identify where delays occur and suggest areas for improvement. Design A retrospective case note review. Setting A tertiary centre for neuromuscular diseases in England. Patients All boys without family history diagnosed with DMD in the last 10 years (n=20). Outcome measures Mean age at four key steps in the diagnostic pathway of DMD. Results (1) Age at first reported symptoms of DMD was 32.5 (8–72) months (2.7 years). (2) First engagement of a healthcare professional was at 42.9 (10–90) months. (3) Creatine kinase (CK) levels were checked at 50.1 (14–91) months. (4) Diagnosis of DMD was confirmed at 51.7 (16–91) months (4.3 years). The total delay from parental concern to diagnosis was 19.2 (4–50) months (1.6 years). Conclusions Our study shows an improvement in the age of diagnosis of DMD although there continues to be a delay in presentation to a health professional and a delay in obtaining a CK test. To reduce these delays, we propose screening for DMD as part of the Child Health Surveillance Programme, in addition to lowering the threshold for CK testing in primary care by promoting a new DMD mnemonic MUSCLE. An earlier diagnosis of DMD will allow timely access to genetic counselling, standards of care and clinical trials.
1 William Harvey Research Institute, Barts & The London Queen Mary School of Medicine & Dentistry, Charterhouse Square, London; 2 Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford; 3 ...Department of Respiratory Medicine, Northwick Park Hospital, Harrow, United Kingdom; 4 Faculty of Human Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands; 5 Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington; and 6 York Hospitals NHS Foundation Trust, York, United Kingdom
Submitted 9 February 2007
; accepted in final form 21 October 2007
This study examines the potential for a ventilatory drive, independent of mean P CO 2 , but depending instead on changes in P CO 2 that occur during the respiratory cycle. This responsiveness is referred to here as "dynamic ventilatory sensitivity." The normal, spontaneous, respiratory oscillations in alveolar P CO 2 have been modified with inspiratory pulses approximating alveolar P CO 2 concentrations, both at sea level and at high altitude (5,000 m, 16,400 ft.). All tests were conducted with subjects exercising on a cycle ergometer at 60 W. The pulses last about half the inspiratory duration and are timed to arrive in the alveoli during early or late inspiration. Differences in ventilation, which then occur in the face of similar end-tidal P CO 2 values, are taken to result from dynamic ventilatory sensitivity. Highly significant ventilatory responses (early pulse response greater than late) occurred in hypoxia and normoxia at sea level and after more than 4 days at 5,000 m. The response at high altitude was eliminated by normalizing P O 2 and was reduced or eliminated with acetazolamide. No response was present soon after arrival (<4 days) at base camp, 5,000 m, on either of two high-altitude expeditions (BMEME, 1994, and Kanchenjunga, 1998). The largest responses at 5,000 m were obtained in subjects returning from very high altitude (7,100–8,848 m). The present study confirms and extends previous investigations that suggest that alveolar P CO 2 oscillations provide a feedback signal for respiratory control, independent of changes in mean P CO 2 , suggesting that natural P CO 2 oscillations drive breathing in exercise.
normal humans; respiratory control; dynamic CO 2 stimulus; altitude; oxygen supplementation; acetazolamide; P CO 2 ; hypoxia
Address for reprint requests and other correspondence: D. J. Collier, Centre for Clinical Pharmacology, William Harvey Research Institute, Barts & The London Queen Mary School of Medicine & Dentistry, Charterhouse Square, London EC1M 6BQ, UK (e-mail: d.j.collier{at}qmul.ac.uk )
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