Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G4A; NP_036192.2:p. (Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.

BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0672-7) contains supplementary material, which is available to authorized users.

Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.

Introduction The COVID‐19 Evidence Support Team (CEST) was a provincial initiative that combined the support of policymakers, researchers, and clinical practitioners to initiate a new learning health cycle (LHS) in response to the pandemic. The primary aim of CEST was to produce and sustain the best available COVID‐19 evidence to facilitate decision‐making in Saskatchewan, Canada. To achieve this objective, four provincial organizations partnered to establish a single, data‐driven system. Methods The CEST partnership was driven by COVID‐19 questions from Emergency Operational Committee (EOC) of the Saskatchewan Health Authority. CEST included three processes: (a) clarifying the nature and priority of COVID‐19 policy and clinical questions; (b) providing Rapid Reviews (RRR) and Evidence Search Reports (ESR); and (c) seeking the requestors' evaluation of the product. A web‐based repository, including a dashboard and database, was designed to house ESRs and RRRs and offered a common platform for clinicians, academics, leaders, and policymakers to find COVID‐19 evidence. Results In CEST's first year, 114 clinical and policy questions have been posed resulting in 135 ESRs and 108 RRRs. While most questions (41.3%) originated with the EOC, several other teams were assembled to address a myriad of questions related to areas such as long‐term care, public health and prevention, infectious diseases, personal protective equipment, vulnerable populations, and Indigenous health. Initial challenges were mobilization of diverse partners and teams, remote work, lack of public access, and quality of emerging COVID‐19 literature. Current challenges indicate the need for institutional commitment for CEST sustainability. Despite these challenges, the CEST provided the Saskatchewan LHS with a template for successful collaboration. Conclusions The urgency of COVID‐19 pandemic and the implementation of the CEST served to catalyze collaboration between different levels of a Saskatchewan LHS.

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.

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISAbased high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.

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Background: In order to combat rising rates of antimicrobial resistant infections, it is vital that antimicrobial stewardship become embedded in primary health care (PHC). Despite the high use of antimicrobials in PHC settings, there is a lack of data regarding the integration of antimicrobial stewardship programs (ASP) in nonhospital settings. Our research aimed to determine which antimicrobial stewardship interventions are optimal to introduce into PHC clinics beginning to engage with an ASP, as well as how to optimize those interventions. This work became focused specifically around management of viral upper respiratory tract infections (URTIs), as these infections are one of the main sources of inappropriate antibiotic use. Methods: This mixed methods study of sequential explanatory design was developed through three research projects over 3 years in Regina, Saskatchewan, Canada. First, a survey of PHC providers was performed to determine their perceived needs from a PHC-based ASP. From this work, a "viral prescription pad" was developed to provide a tool to help PHC providers engage in patient education regarding appropriate antimicrobial use, specifically for URTIs. Next, interviews were performed with family physicians to discuss their perceived utility of this tool. Finally, we performed a public survey to determine preferences for the medium by which information is received regarding symptom management for viral URTIs. Results: The majority of PHC providers responding to the initial survey indicated they were improperly equipped with tools to aid in promoting conversations with patients and providing education about the appropriate use of antimicrobials. Following dissemination of the viral prescription pad and semi-structured interviews with family physicians, the viral prescription pad was deemed to be a useful educational tool. However, about half of the physicians interviewed indicated they did not actually provide a viral prescription to patients when providing advice on symptom management for viral URTIs. When asked about their preferences, 76% of respondents to the public survey indicated they would prefer to receive written or a combination of verbal and written information in this circumstance.