ABSTRACT
Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900â¯mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from -7.4% (95% CI: -9.1, -5.8) for the Off-Idebenone periods to -3.8% (95% CI: -4.8, -2.8) for the On-Idebenone periods (Nâ¯=â¯11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was -5.9% (95% CI: -8.0, -3.9) for the Off-Idebenone periods (Nâ¯=â¯9) and reduced to -1.9% (95% CI: -3.2, -0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials.
Subject(s)
Antioxidants/pharmacology , Muscular Dystrophy, Duchenne/drug therapy , Outcome Assessment, Health Care , Respiration Disorders/drug therapy , Respiratory Function Tests , Ubiquinone/analogs & derivatives , Adolescent , Adult , Antioxidants/administration & dosage , Child , Follow-Up Studies , Humans , Male , Muscular Dystrophy, Duchenne/complications , Respiration Disorders/diagnosis , Respiration Disorders/etiology , Retrospective Studies , Ubiquinone/administration & dosage , Ubiquinone/pharmacology , Vital Capacity , Young AdultABSTRACT
Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.
Subject(s)
Inclusion Bodies/pathology , Muscle Fibers, Skeletal/pathology , Muscle Weakness/genetics , Muscular Diseases/genetics , Myocytes, Cardiac/pathology , Myoglobin/genetics , Adult , Female , Heart Failure/etiology , Heme/metabolism , Humans , Male , Middle Aged , Muscle Weakness/physiopathology , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/physiopathology , Muscular Diseases/diagnostic imaging , Muscular Diseases/pathology , Muscular Diseases/physiopathology , Mutation , Oxygen/metabolism , Pedigree , Respiratory Insufficiency/etiology , Superoxides/metabolism , Tomography, X-Ray Computed , White People/geneticsABSTRACT
BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin. DMD is associated with specific learning and behavioural disabilities. In the brain, dystrophin is associated with GABAA receptors and aquaporin-4 in neurons and astrocytes, respectively, but little is known about its function. OBJECTIVE AND METHODS: In this study we aimed to compare the biochemical composition between patients and healthy controls in brain regions that are naturally rich in dystrophin using magnetic resonance spectroscopy. Given previous conflicting results obtained at clinical field strengths, we obtained data using a 7 Tesla system with associated higher signal-to-noise ratio and spectral resolution. RESULTS: Results indicated unchanged biochemical composition in all regions investigated, and increased variance in glutamate in the frontal cortex.
Subject(s)
Brain/diagnostic imaging , Muscular Dystrophy, Duchenne/diagnostic imaging , Adolescent , Aquaporin 4/metabolism , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain/metabolism , Case-Control Studies , Cerebellum/diagnostic imaging , Cerebellum/metabolism , Child , Choline/metabolism , Creatine/metabolism , Frontal Lobe/diagnostic imaging , Frontal Lobe/metabolism , Glutamic Acid/metabolism , Glutamine/metabolism , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Humans , Inositol/metabolism , Male , Muscular Dystrophy, Duchenne/metabolism , Proton Magnetic Resonance Spectroscopy , Receptors, GABA-A/metabolismABSTRACT
Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume.
Subject(s)
Cerebrovascular Circulation/physiology , Dystrophin/metabolism , Gray Matter/diagnostic imaging , Magnetic Resonance Angiography/methods , Muscular Dystrophy, Duchenne/diagnostic imaging , Adolescent , Child , Female , Gray Matter/pathology , Humans , Male , Muscular Dystrophy, Duchenne/metabolism , Muscular Dystrophy, Duchenne/pathology , Muscular Dystrophy, Duchenne/physiopathologyABSTRACT
Assessment of dynamic inspiratory function may provide valuable information about the degree and progression of pulmonary involvement in patients with Duchenne muscular dystrophy (DMD). The aims of this study were to characterize inspiratory function and to assess the efficacy of idebenone on this pulmonary function outcome in a large and well-characterized cohort of 10-18 year-old DMD patients not taking glucocorticoid steroids (GCs) enrolled in the phase 3 randomized controlled DELOS trial. We evaluated the effect of idebenone on the highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow; V'I,max(FVC)) and the ratio between the largest inspiratory flow during tidal breathing (tidal inspiratory flow; V'I,max(t)) and the V'I,max(FVC). The fraction of the maximum flow that is not used during tidal breathing has been termed inspiratory flow reserve (IFR). DMD patients in both treatment groups of DELOS (idebenone, n = 31; placebo: n = 33) had comparable and abnormally low V'I,max(FVC) at baseline. During the study period, V'I,max(FVC) further declined by -0.29 L/sec in patients on placebo (95%CI: -0.51, -0.08; P = 0.008 at week 52), whereas it remained stable in patients on idebenone (change from baseline to week 52: 0.01 L/sec; 95%CI: -0.22, 0.24; P = 0.950). The between-group difference favoring idebenone was 0.27 L/sec (P = 0.043) at week 26 and 0.30 L/sec (P = 0.061) at week 52. In addition, during the study period, IFR improved by 2.8% in patients receiving idebenone and worsened by -3.0% among patients on placebo (between-group difference 5.8% at week 52; P = 0.040). Although the clinical interpretation of these data is currently limited due to the scarcity of routine clinical practice experience with dynamic inspiratory function outcomes in DMD, these findings from a randomized controlled study nevertheless suggest that idebenone preserved inspiratory muscle function as assessed by V'I,max(FVC) and IFR in patients with DMD. Pediatr Pulmonol. 2017;52:508-515. © 2016 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.
Subject(s)
Antioxidants/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Respiration/drug effects , Ubiquinone/analogs & derivatives , Adolescent , Antioxidants/administration & dosage , Antioxidants/pharmacology , Child , Female , Humans , Inspiratory Reserve Volume/drug effects , Male , Muscular Dystrophy, Duchenne/physiopathology , Respiratory Function Tests , Treatment Outcome , Ubiquinone/administration & dosage , Ubiquinone/pharmacology , Ubiquinone/therapeutic useABSTRACT
In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated "by patient" (HR 0.33, p = 0.0187) and for "all BAEs" (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics.
Subject(s)
Antioxidants/therapeutic use , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/drug therapy , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/etiology , Ubiquinone/analogs & derivatives , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Double-Blind Method , Humans , Incidence , Muscular Dystrophy, Duchenne/epidemiology , Muscular Dystrophy, Duchenne/physiopathology , Proportional Hazards Models , Respiratory Function Tests , Respiratory System/drug effects , Respiratory System/physiopathology , Respiratory Tract Diseases/epidemiology , Respiratory Tract Diseases/physiopathology , Treatment Outcome , Ubiquinone/therapeutic useABSTRACT
INTRODUCTION: The phenotype of Becker muscular dystrophy (BMD) is highly variable, and the disease may be underdiagnosed. We searched for new mutations in the DMD gene in a cohort of previously undiagnosed patients who had been referred in the period 1985-1995. METHODS: All requests for DNA analysis of the DMD gene in probands with suspected BMD were re-evaluated. If the phenotype was compatible with BMD, and no deletions or duplications were detected, DNA samples were screened for small mutations. RESULTS: In 79 of 185 referrals, no mutation was found. Analysis could be performed on 31 DNA samples. Seven different mutations, including 3 novel ones, were found. Long-term clinical follow-up is described. CONCLUSIONS: Refining DNA analysis in previously undiagnosed cases can identify mutations in the DMD gene and provide genetic diagnosis of BMD. A delayed diagnosis can still be valuable for the proband or the relatives of BMD patients.
Subject(s)
DNA Mutational Analysis , Dystrophin/genetics , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/genetics , Mutation/genetics , Anoctamins , Chloride Channels/genetics , Female , Humans , Male , Retrospective StudiesABSTRACT
BACKGROUND: Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. METHODS: In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. FINDINGS: 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). INTERPRETATION: Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. FUNDING: Santhera Pharmaceuticals.
Subject(s)
Antioxidants/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Respiration Disorders/drug therapy , Ubiquinone/analogs & derivatives , Adolescent , Child , Double-Blind Method , Humans , Male , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/physiopathology , Peak Expiratory Flow Rate , Respiration Disorders/etiology , Respiration Disorders/physiopathology , Respiratory Function Tests , Respiratory Muscles/physiopathology , Treatment Outcome , Ubiquinone/therapeutic useABSTRACT
A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening.
Subject(s)
Chloride Channels/genetics , Distal Myopathies/genetics , Muscle Proteins/genetics , Muscular Atrophy/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Mutation/genetics , Adult , Aged , Anoctamins , Cohort Studies , Distal Myopathies/diagnosis , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Muscular Atrophy/diagnosis , Muscular Dystrophies, Limb-Girdle/diagnosis , Netherlands , Pedigree , Young AdultSubject(s)
Genetic Therapy/methods , Muscular Dystrophy, Duchenne/therapy , Adrenal Cortex Hormones/therapeutic use , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Codon, Terminator , Disease Progression , Drug Design , Exons , Humans , Oligonucleotides, Antisense/therapeutic useABSTRACT
Corticosteroids are effective in improving motor function in Duchenne muscular dystrophy (DMD) patients within 6 months-2 years of treatment initiation, but there is as yet no consensus on which treatment scheme is the best. We retrospectively analyzed data of 35 DMD patients who were treated with prednisone 0.75 mg/kg per day intermittently 10 days on/10 days off. Prednisone was started during the ambulant phase at age 3.5-9.7 years (median 6.5 years). The median period of treatment was 27 months (range 3-123 months). The median age at which ambulation was lost was 10.8 years (mean 10.9 years; 95% confidence interval 10.0-11.8 years). Nine patients (26%) had excessive weight gain. Eight boys (21%) had a bone fracture, which was when four of these eight children lost the ability to walk. Treatment was stopped in two obese patients, two hyperactive boys and one patient following a fracture. Our data suggest that prednisone 10 on/10 off has relatively few side effects and extends the ambulant phase by 1 year compared to historical controls.
Subject(s)
Muscle Weakness/drug therapy , Muscle, Skeletal/drug effects , Muscular Dystrophy, Duchenne/drug therapy , Prednisone/administration & dosage , Adolescent , Age Factors , Age of Onset , Akathisia, Drug-Induced , Anti-Inflammatory Agents/administration & dosage , Child , Child, Preschool , Disease Progression , Drug Administration Schedule , Fractures, Bone/chemically induced , Glucocorticoids/administration & dosage , Humans , Male , Mobility Limitation , Muscle Weakness/etiology , Muscle Weakness/prevention & control , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Duchenne/physiopathology , Obesity/chemically induced , Obesity/physiopathology , Osteoporosis/chemically induced , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) represents noninvasive management of urolithiasis. Since the first HM3 model, technological progress has improved the efficacy and safety of this treatment. The current study aimed to evaluate the role of ESWL as a first-line emergency therapy of renal colic due to ureteral stone with impaired renal function. METHODS: This prospective study enrolled all the patients admitted from the emergency room with acute renal colic meeting the following criteria: serum creatinine level ranging from 1.5 to 2.5 mg/dl, hydronephrosis, ureteral stones 6 to 15 mm in size, body mass index less than 30, normal renal function at baseline, and no evidence of urinary tract infection. The patients were submitted to a single-session emergency treatment using Dornier Litothripter S. Follow-up assessment, performed at 24 and 72 h, included radiologic and ultrasound examinations with renal function serum assessment. The end points were a decrease in creatinine level and a stone-free condition. RESULTS: A total of 40 patients were eligible for the study. The mean creatinine level at admission was 1.93 +/- 0.26 mg/dl. After the treatment, renal function recovery occurred for 34 subjects (85%), with a significant global decrease in creatinine levels (p = 0.00). The global stone-free rate 72 h after SWL was 67.5% (27/40). The patients with residual fragments were managed using re-SWL (n = 7) and endoscopic technique (n = 6). CONCLUSIONS: Emergency SWL represents an effective tool in the treatment of ureteral stones with hydronephrosis and slight renal impairment. Although complete stone clearance after one treatment still remains a difficult target, the actual role of SWL in the management of acute obstruction is to obtain ureteral canalization and renal function recovery.