Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome

Purpose: We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. Observations: After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. Conclusions and importance: Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography. Keywords: Helsmoortel-Van der Aa Syndrome, HVDAS, Activity-dependent neuroprotective protein, ADNP, Nystagmus, Retinal degeneration, Electronegative waveform, Optical coherence tomograph

Patterns of decline in upper limb function of boys and men with DMD: an international survey

With increasing life expectancy, upper extremity (UE) function becomes more and more important in boys with Duchenne muscular dystrophy (DMD). Knowledge of UE function in these children is, however, limited. The aim of this study was to gain insight into the changing patterns of UE function during the course of DMD. A Web-based questionnaire on UE function, covering all domains of the International Classification of Functioning Disability and Health, was distributed worldwide. Primary domains of the questionnaire were: participant characteristics, UE pain and stiffness, UE activities, and social participation. Data were described per disease stage and analyzed using descriptive analysis. A total of 213 boys/men with DMD (1-35 years) were included in this study. UE pain, stiffness, and activity limitations increased with disease stage. UE activity limitations already occurred in the early ambulatory stage. Compared to the healthy population, social participation was restricted in DMD patients and about 70 % of the respondents experienced UE limitations when performing social activities. Despite the existence of UE impairments, only 9 % of the respondents used supportive aids. Functional capacities and activities of the UE are limited already in the early ambulatory stage of patients with DMD affecting their social participation. Therefore, clinicians should pay attention to UE limitations before DMD patients lose their capacity to walk. Effective and adequate aids as well as attention for pain and stiffness in the therapeutic management could help to reduce UE activity limitations and related restrictions in social participation

Biallelic CRELD1 variants cause a multisystem syndrome including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

PURPOSE: We sought to delineate a multisystem disorder caused by recessive CRELD1 variants. METHODS: The impact of CRELD1 variants was characterized through an international collaboration utilizing next generation DNA sequencing, gene knockdown and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with one recurrent variant, p.(Cys192Tyr), identified in 10 families. X. tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared to controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X. tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients as compared to healthy donors. CONCLUSION: This patient cohort combined with experimental data provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.Accepted version (6 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Deflazacort vs prednisone treatment for Duchenne muscular dystrophy: A meta‐analysis of disease progression rates in recent multicenter clinical trials

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

Baseline results of the Neuro NEXT

OBJECTIVE: This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA). METHODS: This prospective, multi‐center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. RESULTS: Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high‐frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. INTERPRETATION: By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit

Biallelic CRELD1 variants cause a multisystem syndrome including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

PURPOSE: We sought to delineate a multisystem disorder caused by recessive CRELD1 variants. METHODS: The impact of CRELD1 variants was characterized through an international collaboration utilizing next generation DNA sequencing, gene knockdown and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with one recurrent variant, p.(Cys192Tyr), identified in 10 families. X. tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared to controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X. tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients as compared to healthy donors. CONCLUSION: This patient cohort combined with experimental data provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1