Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. Results: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend mitochondrial cocktails for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. Conclusions: While Canadian physicians\u27 views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Le syndrome de mort subite du nourrisson au Québec : qualité de l’enregistrement des décès et nouvelles estimations

Le syndrome de mort subite du nourrisson (SMSN) étant un diagnostic d'exclusion, plusieurs éléments peuvent influencer le dénombrement exact des cas et, en conséquence, la connaissance des facteurs de risque demeure incertaine. Cet article présente, en premier lieu, une brève revue des études sur le SMSN. Par la suite, une attention spéciale est accordée à l'importance du diagnostic, ainsi qu'au cheminement menant du décès à son inclusion dans les statistiques d'état civil, répertoriées à l'Institut de la statistique du Québec (ISQ). La qualité des données statistiques disponibles sur cette cause de décès est ensuite analysée, au moyen d'une comparaison entre les données de l'ISQ et celles du Bureau du Coroner, qui ont été vérifiées par un groupe de médecins experts. Au cours de la période 1987-1997, les cas de SMSN ont été sous-estimés d'environ. 9 pour cent en moyenne. À l'aide des données corrigées, l'incidence et quelques caractéristiques du phénomène sont présentées pour le Québec. Des comparaisons nationales et internationales montrent que le Québec présente un dossier enviable pour ce qui est de la mortalité par SMSN.Because Sudden Infant Death Syndrome (SIDS) is a diagnosis arrived at when other causes of death have been ruled out, several elements may influence the exact number of these cases, and our understanding of the risk factors is, therefore, still limited. This article first briefly reviews studies on SIDS. Special attention is then given to the importance of the diagnosis, and to the process leading from the death to its inclusion in the vital statistics recorded by the Institut de la statistique du Québec (ISQ). The author then examines the quality of the available statistical data on this cause of death by comparing the ISQ data with data from the Coroner's Office, verified by a group of medical examiners. For the period 1987-1997, cases of SIDS were underestimated by about 9 percent on average. Using the adjusted data, the authors next present the incidence of this phenomenon and some of its characteristics in Quebec. National and international comparisons show that Quebec has an enviable record in terms of SIDS mortality rates

Acute pediatric hyperammonemia: current diagnosis and management strategies

International audienc

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G>T and c.164C>T mutations in the GM2A gene

GM2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the GM2A gene that encodes GM2 ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of GM2 ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of GM2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of GM2-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for GM2 gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in GM2A: a novel nonsense mutation, c.259G>T (p.E87X) and a missense mutation c.164C>T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of GM2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled GM1 ganglioside and by immunohistochemistry with anti-GM2 and anti-GM3 antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to GM2-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells

Use of dexamethasone in acute rhabdomyolysis in LPIN1 deficiency

Introduction: LPIN1 deficiency is an autosomal recessive form of early childhood recurrent severe rhabdomyolysis. Although not completely lucid yet, LPIN1 has been shown to modulate endosomal-related pro-inflammatory responses via peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α). Treatment with anti-inflammatory agents such as dexamethasone has been proposed to improve the outcome. Case: We report a male toddler with recurrent episodes of complicated rhabdomyolysis, requiring prolonged intensive care unit admissions. Whole exome sequencing revealed a common homozygous 1.7 kb intragenic deletion in LPIN1. Despite optimal metabolic cares, the patient presented with an extremely high CK level where he benefited from intravenous dexamethasone (0.6 mg/Kg/day) for a period of 6 days. Results: Dexamethasone administration shortened the course of active rhabdomyolysis, intensive care admission and rehabilitation. It also prevented rhabdomyolysis-related complications such as kidney injury and compartment syndrome. Conclusion: Our patient showed a favorable response to parenteral dexamethasone, in addition to hyperhydration with IV fluids, sufficient calorie intake, and restricted dietary fat. The improvement with corticosteroids suggests an uncontrolled inflammatory response as the pathophysiology of LPIN1 deficiency

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1.Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts.Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1.Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts.Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient