Ophthalmoplegic migraine (OM) may be diagnosed after recurrent episodes of headache, followed by the paresis of one or more ocular cranial nerves (typically oculomotor 1 ). The diagnosis requires all other causes of focal intracranial neuropathy (i.e. vascular, inflammatory, tumor or infectious etiology), to be excluded. Contrast MR imaging typically reveals enhancement of the affected nerve at the site of its exit from the brainstem. 2 Ophthalmoplegic migraine is rare, with an annual incidence estimated at 0.7 per million. 3 However it does account for up to 7% of all isolated cases of childhood oculomotor nerve palsy. 4,5 ABSTRACT: Background: This critical review provides a summary of the clinical presentation, neuroimaging, treatment and prognosis in pediatric ophthalmoplegic migraine (OM). The features of OM are not in keeping with its classification as a migraine-variant. Method: We review 3 new and 37 reported pediatric OM cases. Results: Headache was an inconsistent feature, with 25% patients showing no evidence of pain at the initial OM episode. Patients demonstrated: 1) prolonged time for symptom resolution to occur (median time 3 weeks); 2) tendency for recurrent episodes to have more severe and persistent nerve involvement; 3) evidence of permanent neurological sequelae with recurrent episodes (30% of patients); 4) rapid improvement and shortened duration with corticosteroid therapy and; 5) transient, reversible MRI contrast enhancement of the affected cranial nerve (86% of patients). These features would not be expected in primary migraine headache. Conclusion: A detailed understanding of the natural history of OM is essential for the clinical. This review provides support that OM may result from cranial nerve inflammation with headache a secondary and later feature of this condition. RÉSUMÉ: La migraine ophtalmoplégique : s'agit-il d'une neuropathie inflammatoire avec migraine secondaire?Contexte : Cette revue présente un sommaire du tableau clinique, de la neuroimagerie, du traitement et du pronostic de la migraine ophtalmoplégique (MO) pédiatrique et une analyse critique ce ces données. Bien qu'on classifie la MO comme une forme variante de la migraine, ses manifestations ne cadrent pas avec cette classification. Méthode : Nous rapportons 3 nouvelles observations cliniques pédiatriques de MO et nous révisons 37 observations pédiatriques déjà rapportées. Résultats : La céphalée n'était pas toujours présente et 25% des patients n'avaient pas de douleur au moment du premier épisode de MO. À noter que : 1) les symptômes s'estompaient lentement (temps médian de 3 semaines) ; 2) au moment des rechutes, l'atteinte nerveuse avait tendance à être plus sévère et plus persistante ; 3) les patients ayant présenté plusieurs épisodes pouvaient avoir des signes de séquelles neurologiques permanentes (30% des patients) ; 4) la corticothérapie provoquait une amélioration rapide et des épisodes plus courts et 5) un rehaussement transitoire réversible du nerf crânien atteint était observé à l'IRM avec produit de co...

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 physicianconfirmed 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.RÉSUMÉ: Le RCMN : collaborer pour procurer de nouveaux traitements aux Canadiens. Contexte : Un registre de patients est une façon très avantageuse d'organiser l'information concrète au sujet de patients à des fins cliniques ou de recherche. Les registres peuvent faciliter la planification d'essais cliniques et le recrutement et sont particulièrement utiles à cet égard quand il s'agit de maladies rares. Les maladies neuromusculaires (MNM) considérées individuellement sont des maladies rares mais elles ont une prévalence non négligeable si elles sont regroupées. Au Canada, on manque d'informations sur les MNM. Il existe des obstacles à la réalisation de recherches multicentriques sur les MNM au Canada. Ces obstacles peuvent être surmontés par l'établissement d'un registre détaillé à des fins de collaboration sur les MNM. Méthode : Nous décrivons les objectifs, le plan, la faisabilité et les résultats du recrutement initial du Registre canadien des maladies neuromusculaires. Résultats : Le RCMN est un registre basé sur la clinique qui a été inauguré à travers le Canada en juin 2011. Il inclut des cliniques neuromusculaires pédiatriques et adultes et inclut des patients de Colombie-Britannique, d'Alberta, de l'Ontario, du Québe...

IMPORTANCECorticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life.OBJECTIVE To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD).DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. INTERVENTIONSThe study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. MAIN OUTCOMES AND MEASURESStudy outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test.RESULTS Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo −0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, −1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. CONCLUSIONS AND RELEVANCEIn this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care.

Duchenne muscular dystrophy (DMD) is caused by a mutation in the DMD gene, coding for dystrophin at Xp21. Inadequate or defective dystrophin protein causes increased muscle membrane fragility, resulting in proximal muscle weakness and marked elevation of serum creatine kinase (CK) levels. Boys with DMD typically present with gait abnormalities (toe-walking, frequent falls, delayed walking, exercise intolerance) between ages 3 -5 years old, with progressive loss of independent ambulation occurring around 7 -12 years-of-age. Most boys live until their late 20's, with death resulting from respiratory or cardiac complications. Corticosteroid therapy ABSTRACT: Background: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Method: To assess the current care of paediatric DMD patients in Canada, a questionnaire was mailed to 17 physicians who were members of the Canadian paediatric neuromuscular group. Areas of enquiry included; 1) multidisciplinary team composition; 2) means of DMD diagnosis; 3) corticosteroid use; surveillance and management for: 4) orthopaedic, 5) respiratory and 6) cardiac complications and 7) health maintenance (nutrition & immunizations). Results: Completed surveys were returned by 14/17 (82%) of physicians. Twelve respondents followed DMD patients. All centres had multidisciplinary teams, including respirology (11/12), child neurology or physiatry (11), physiotherapy (9), occupational therapy (9) and orthopaedic surgery (7). Deflazacort 0.9mg/kg/d was used at all centres, which was continued after loss of independent ambulation (11), along with routine calcium and vitamin D supplementation (10). Night splints were prescribed at all centres. Routine surveillance studies included pulmonary function testing (11), sleep studies (10), EKG/echocardiogram (10), bone density (DEXA) scans (10), spine radiography (9), and dietician referral (4). Conclusion: Paediatric DMD patients are receiving relatively consistent care in multidisciplinary clinics across Canada, in accordance with recommended guidelines for DMD.RÉSUMÉ: Dystrophie musculaire de Duchenne : enquête auprès des pédiatres du Canadian Paediatric Neuromuscular Goup. Contexte : La dystrophie musculaire de Duchenne (DMD) est la forme la plus fréquente de dystrophie musculaire dans l'enfance. Méthode : Nous avons posté un questionnaire à 17 médecins membres du Canadian Paediatric Neuromuscular Group afin d'évaluer les soins actuels donnés aux patients d'âge pédiatrique atteints de DMD au Canada. L'enquête portait sur les aspects suivants : 1) la composition des équipes multidisciplinaires; 2) les moyens diagnostiques utilisés pour poser le diagnostic de DMD; 3) l'utilisation de corticostéroïdes; la surveillance et le traitement des complications 4) orthopédiques, 5) respiratoires et 6) cardiaques et 7) les soins de santé usuels (nutrition et immunisations). Résultats : Quatorze des 17 médecins (82%) ont retourné le questionnaire complété. Douze d'entre eux suivaient des patients atteints de DMD. Tous les ...

Mutations of FBXL4, which encodes an orphan mitochondrial F-box protein, are a recently identified cause of encephalomyopathic mtDNA depletion. Here, we describe the detailed clinical and biochemical phenotype of a neonate presenting with hyperlactatemia, leukoencephalopathy, arrhythmias, pulmonary hypertension, dysmorphic features, and lymphopenia. Next-generation sequencing in the proband identified a homozygous frameshift, c.1641_1642delTG, in FBXL4, with a surrounding block of SNP marker homozygosity identified by microarray. Muscle biopsy showed a paucity of mitochondria with ultrastructural abnormalities, mitochondrial DNA depletion, and profound deficiency of all respiratory chain complexes. Cell-based mitochondrial phenotyping in fibroblasts showed mitochondrial fragmentation, decreased basal and maximal respiration, absence of ATP-linked respiratory and leak capacity, impaired survival under obligate aerobic respiration, and reduced mitochondrial inner membrane potential, with relative sparing of mitochondrial mass. Cultured fibroblasts from the patient exhibited a more oxidized glutathione ratio, consistent with altered cellular redox poise. High-resolution respirometry of permeabilized muscle fibers showed marked deficiency of oxidative phosphorylation using a variety of mitochondrial energy substrates and inhibitors. This constitutes the fourth and most detailed report of FBXL4 deficiency to date. In light of our patient's clinical findings and genotype (homozygous frameshift), this phenotype likely represents the severe end of the FBXL4 clinical spectrum.

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Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.

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