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Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2.
To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result.
An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management.
Ontario’s pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.
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.
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.
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.
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.
To summarize the evidence for neurologic uses of immunoglobulin, intravenous (IGIV) in light of present-day clinical usage. This summary guided the development of practice recommendations for the effective and efficient use of IGIV in Neurology.
MEDLINE was searched to identify pertinent English-language review articles and original reports (n = 231) on the use of IGIV in neurology (excluding editorials, letters, and comments) published before March 1998. Evidence on alternative therapies was only included as compared to IGIV. The relevant original reports and review articles and older classic studies (n = 92) were synthesized into an information foundation. Extracted data included laboratory and clinical findings, objective measures, and clinical impressions. Clinical recommendations were based on evidence quality, graded by study design, clinical experiences of IGIV in Neurology Advisory Board members, and the conditions of IGIV use in therapy.
Results and Conclusions:
In neurology, many disorders are poorly understood, and the mechanisms behind beneficial regimens even less so. As a result, it is fairly common for best-practice decisions to rest on weaker evidence. The usefulness of IGIV in neurology can be described by a “combined score” based on evidence quality and strength of impact. Combined scores ranged from A+ (strongly recommended) to C (recommended as a last resort). The following clinical recommendations are made: IGIV is: strongly recommended for the treatment of Guillain-Barré syndrome (A+); favorably recommended for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy, dermatomyositis, and multifocal motor neuropathy (A); recommended as a second resort for the treatment of multiple scerosis and myasthenia gravis (B); and recommended as a last resort for the treatment of polymyositis, inclusion-body myositis, intractable epilepsies, and stiff-man syndrome (C).
Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. Based on neurophysiological and neuropathological criteria CMT has been sub-classified into two main types: demyelinating and axonal. Furthermore, it is genetically heterogeneous with autosomal dominant, autosomal recessive (AR) and X-linked modes of inheritance. Thus far, seven genes have been identified in association with the demyelinating AR-CMT disease. We hereby report our clinical and molecular genetic findings in a consanguineous family with AR-CMT.
Two young sisters with AR-CMT and other non-affected family members were clinically and electrophysiologically evaluated and then molecular genetic investigation was carried out in order to identify the pathogenic mutation.
Following an initial indication for linkage of the family to the CMT4A locus on chromosome 8, we sequenced the Ganglioside-induced differentiation-associated protein 1 (GDAP1) gene and identified a single nucleotide deletion in exon 3 that is associated with AR-CMT in the family.
We identified a novel GDAP1 439delA mutation that is associated with AR-CMT in a consanguineous family of Iranian descent with two affected young girls and a history in other members of the family.
The aim of this study was to evaluate anaerobic muscle performance in children after long-term recovery from Guillain-Barré syndrome (GBS). Participants were recruited from all children and adolescents with GBS admitted to The Hospital for Sick Children, University of Toronto, Canada, between 1988 and 1995. We assessed 17 children (nine males, eight females; mean age at GBS diagnosis 7 years 11 months, SD 4 years 2 months; mean age at testing 14 years 1 month) more than two years after acute GBS. Participants completed the Wingate anaerobic test to evaluate mean and peak muscle power. For mean arm muscle power (mean 47.5% [SD 17.4%] of normal), only two participants were in the normal range. For mean leg muscle power (mean 83% [SD 28.3%] of normal), 15 participants were in the normal range. For arm peak power (mean 92.6% [SD 20.7%] of normal), 12 participants were in the normal range. For leg peak power (mean 116.3% of normal, SD 15.8%), all participants were in the normal range. Detailed manual muscle testing with the modified Medical Research Council scale was done on 34 muscle groups. Data were pooled to give a mean arm and leg muscle strength score (9.7, SD 0.30 and 9.4, SD 0.50 respectively). Pearson's correlations of muscle endurance with arm and leg strength were not significant. Children with GBS have excellent long-term recovery of peak muscle power. Muscle endurance, measured by mean muscle power, was normal in the legs but markedly low in the arms. Pediatric rehabilitation programs after GBS should specifically target endurance of arm muscles.
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