A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Navigating health care systems for military-connected children with autism spectrum disorder: A qualitative study of military families experiencing mandatory relocation.

BACKGROUND: Most military families experience mandatory relocation, or posting, several times during the military career. For Canadian military families who must access provincial or territorial health care systems, maintaining reasonable continuity of care is a persistent issue. Such challenges may be amplified when a child in a military family has special needs within the health and educational systems. OBJECTIVE: The purpose of this qualitative study was to gain a better understanding of Canadian Armed Forces families' experiences in navigating health care systems on behalf of a child with autism spectrum disorder (ASD) in the context of mandatory relocation. METHODS: Parents of children with ASD, where at least one parent serves in the Canadian Armed Forces and had faced military-related relocation, were recruited. Semi-structured interviews were recorded, transcribed verbatim, and analyzed thematically. RESULTS: Twelve participants represented 12 families and 15 children with ASD. Participants discussed two primary themes. (1) High mobility inherent in the military lifestyle can create disruptions and discontinuities to service, including delays in diagnosis or intervention, losses and gains in available services determined by the direction of posting, and the need to start health care access processes over again when relocating. (2) Navigating health systems for children with ASD creates personal stress and frustration related to relocating, and has career implications for both parents. CONCLUSIONS: Military-related relocation can create significant disruption in access to health and educational services for Canadian military families who have a child with ASD, and take a personal toll on these families.

The Canadian Neuromuscular Disease Registry: Connecting patients to national and international research opportunities.

INTRODUCTION: Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. METHODS: In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry. RESULTS: As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population. DISCUSSION: The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada's visibility as a competitive location for the conduct of clinical trials for NM therapies.

Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development.

The low activity allele of the maternal polymorphism, 5HTTLPR, in the serotonin transporter, SLC6A4, coupled with prenatal stress is reported to increase the risk for children to develop autism spectrum disorder (ASD). Similarly, maternal Slc6a4 knock-out and prenatal stress in rodents results in offspring demonstrating ASD-like characteristics. The present study uses an integrative genomics approach to explore mechanistic changes in early brain development in mouse embryos exposed to this maternal gene-environment phenomenon. Restraint stress was applied to pregnant Slc6a4 +/+ and Slc6a4 +/- mice and post-stress embryonic brains were assessed for whole genome level profiling of methylome, transcriptome and miRNA using Next Generation Sequencing. Embryos of stressed Slc6a4 +/+ dams exhibited significantly altered methylation profiles and differential expression of 157 miRNAs and 1009 genes affecting neuron development and cellular adhesion pathways, which may function as a coping mechanism to prenatal stress. In striking contrast, the response of embryos of stressed Slc6a4 +/- dams was found to be attenuated, shown by significantly reduced numbers of differentially expressed genes (458) and miRNA (0) and genome hypermethylation. This attenuated response may pose increased risks on typical brain development resulting in development of ASD-like characteristics in offspring of mothers with deficits in serotonin related pathways during stressful pregnancies.

The CNDR: collaborating to translate new therapies for Canadians.

BACKGROUND: Patient registries represent an important method of organizing "real world" patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry. METHODS: We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR). RESULTS: The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 "index disease" patients. Another 618 "non-index" patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. "Index disease" patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS. CONCLUSIONS: The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.

Effects of long-term gait training using visual cues in an individual with Parkinson disease.

BACKGROUND AND PURPOSE: In an attempt to improve the gait of people with Parkinson disease (PD), researchers have examined the effect of visual cues placed on the floor. These studies typically have used a single session of training with such cues and have not examined the long-term carryover of such training. In the present study, therefore, gait was analyzed during uncued, cued, and retention phases, each lasting 1 month. SUBJECT: A 78-year-old woman who had been diagnosed with PD 12 years previously (Hoehn and Yahr classification of disability, stage III) volunteered for the study. METHODS: During the initial uncued gait phase, the subject was required to walk a distance of 10 m as many times as she could in 30 minutes, 3 times per week for 4 weeks. During the 4-week cued gait phase, visual cues were placed on the floor along the 10-m walkway. The cues were initially 110% of the uncued step length and were later increased to 120%. Following this cued gait phase, the subject's gait was recorded periodically for 1 month without cues available. Step length, gait speed, and 2-dimensional lower-limb kinematics were compared within and across the 3 experimental phases. Celeration lines were calculated for the initial uncued phase and then extrapolated across the cued training and uncued retention phases. Binomial tests were used to analyze the significance of changes from the initial phase of the experiment. RESULTS: Step length (0.53-0.56 m) and gait speed (0.77-0.82 m x s(-1)) were essentially unchanged during uncued gait training after the first day; however, during the cued gait phase, gait speed improved, from 0.87 m x s(-1) to 1.13 m x s(-1), as step length was increased with visual cues. Improvements in step length (0.68 m) and gait speed (1.08 m x s(-1)) were still evident 1 month following the removal of the cues. Analyses of angle-angle diagrams and phase-plane portraits revealed that training with visual cues increased hip and knee range of motion and engendered more stable motor control of the lower limb. DISCUSSION AND CONCLUSION: In contrast to previous studies in which the benefits of visual cueing were relatively short-lived, in this study, 1 month of gait training with visual cues was successful in establishing a lasting improvement in gait speed and step length while increasing the stability of the underlying motor control system.

Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.

Kv1.3 channels regulate proliferation of normal lymphocytes, but the role of voltage-gated potassium channels in transformed hematopoietic cells is not known. We examined transcripts for Kv1.3, h-erg, h-eag, and BEC1 genes in primary lymphocytes and leukemias and in several hematopoietic cell lines. Surprisingly, BEC1, formerly thought to be brain-specific, was present in all the primary leukemias examined, in resting peripheral blood lymphocytes, and in proliferating activated tonsillar cells, lymphocytes from Sjögren's patients, and Epstein-Barr virus-transformed B-cells. Only h-erg mRNA was up-regulated in the cancer cells, but this was not due to proliferation per se, because it was not elevated in any of the proliferating noncancerous lymphocyte types examined. Nor did h-erg transcript levels correlate with the B-cell subset, because it was elevated in immature neoplastic B-CLL cells (CD5(+)) and in a CD5(-) Burkitt's lymphoma cell line (Raji) but not in Sjögren's syndrome cells (enriched in CD5(+) B-cells) or Epstein-Barr virus-transformed B-cells, which are mature CD5(-) B-cells. The protein and whole cell current levels roughly corresponded with the amount of mRNA expressed in three hematopoietic cell lines: CEM (an acute lymphoblastic leukemic line), K562 (a chronic myelogenous leukemic line), and U937 (an acute promyelocytic leukemic line). The selective HERG channel blocker, E-4031, reduced proliferation of CEM, U937, and K562 cells, and this appears to be the first direct evidence of a functional role for the HERG current in cancer cells. Selective up-regulation of h-erg appears to occur in neoplastic hematopoietic cells, thus providing a marker and potential therapeutic target.