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

Acute Transverse Myelitis Caused by Echovirus 11 in a Pediatric Patient

A 12-year-old boy presented with acute flaccid weakness of the right upper extremity and was found to have acute flaccid myelitis with transverse myelitis involving the cervical cord (C1-T1). An interdisciplinary team-based approach was undertaken, including input from a generalist, an infectious diseases physician, and a pediatric neurologist. Consultation was sought from the Minnesota Department of Health to investigate for a potential etiology and source of the responsible infection. Evaluation for an infectious etiology demonstrated infection with human echovirus 11. The patient recovered with some disability. Echovirus 11 is among the more common etiologies of acute flaccid myelitis and should be considered in the differential diagnosis of this increasingly recognized pediatric infection

Corrigendum to "Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy" [Neuromuscular Disorders, Vol. 30 (6) 2020, 492-502] (Neuromuscular Disorders (2020) 30(6) (492–502), (S0960896620301188), (10.1016/j.nmd.2020.05.002))

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One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

BACKGROUND: The pathogenesis of Duchenne muscular dystrophy starts prior to birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here we report six and twelve month follow-up of two subsets of these boys. PATIENTS: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and six months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, six, and twelve months. RESULTS: Gross motor scores were lower at baseline compared to published controls (6.2 ± 1.7; normal 10 ± 3; p<.0001), and showed a further declining trend to 5.7 ± 1.7 (p =.20) at six months. Repeated measures analysis of the 12 boys followed for 12 months showed that gross motor scores, again low at baseline (6.6 ± 1.7; p<.0001), declined at six months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (p=0.11). Cognitive and language scores were lower at baseline compared to normal children (range p=.002 to p<0.0001) and did not change significantly at 6 or 12 months (range p=.89 to p=.09). Fine motor skills, also low at baseline, improved over one year (p=.05). CONCLUSION: Development can reliably be measured in infants and young boys with DMD across time using the Bayley-III. Power calculations using these data show that motor development may be used as an outcome measure

De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1(-/-)) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p. Arg184Pro, p. Met224Lys, and p. Arg227Pro) or within the homeodomain (p. Arg234Pro, and p. Arg235Gln), whereas p. Ser262Glnfs*2, and p. Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients