A novel missense mutation in the MYH7 gene causes an uncharacteristic phenotype of myosin storage myopathy: a case report.

BACKGROUND: Few manuscripts have reported phenotypes of skeletal muscle myopathies caused by mutations in the head region of slow/cardiac beta-myosin heavy chain (MyHCI). Among the patients, some of them showed the phenotype of skeletal muscle weakness with the obvious clinical features of cardiomyopathy while others showed pure skeletal muscle weakness with no symptoms of cardiac involvement. Genotype-phenotype relationship regarding the effect of a mutation on MyHCI is complex. Questions regarding why some mutations cause cardiomyopathy or skeletal muscle disorders alone or a combination of both still need to be answered. More findings in genetic variation are needed to extend knowledge of mutations in the MYH7 gene linked to skeletal muscle disorders. CASE PRESENTATION: Here we present a female adult patient with a phenotype of childhood onset of muscular disorders and predominant involvement of thigh muscles with biopsy showing intrasarcoplasmic inclusion bodies. Whole exome sequencing showed that variant c.1370 T > G (p.Ile457Arg) in the MYH7 gene is a missense mutation possibly linked to the clinical findings. Our patient likely shows an uncharacteristic myosin storage myopathy associated with respiratory and cardiac involvement linked to a missense mutation in the head of MyHCI. CONCLUSIONS: Given this mutation is located within the motor domain of MyHCI, this might affect the regulation of myosin mechano-chemical activity during the contractile cycle. Consequently, this potentially damaging effect can be easily amplified within the network of ~ 300-myosin molecules forming the thick filament and therefore become cumulatively deleterious, affecting, in turn, the overall organization and performance of sarcomere.

Recurrent post-partum rhombencephalitis associated with anti-centromere antibody: a case report.

BACKGROUND: Rhombencephalitis (RE) is a serious condition of the brain with multiple etiologies. We report a unique case of recurrent, postpartum RE that is associated with positive anti-centromere antibody (ACA). A discussion of the case, current literature on autoimmune RE and related autoantibodies are reviewed. CASE PRESENTATION: A healthy 33-year-old Caucasian patient (gravida 2, para 2) had two episodes of progressive focal neurological deficits during postpartum periods. Signs and symptoms included right-sided dysmetria, adiadochokinesia, weakness, ataxia, and photophobia. MRI revealed rhombencephalitis involving the mesencephalon of the brainstem. Extensive and comprehensive investigations using blood and cerebrospinal fluid (CSF) were consistently positive only for ACA. The first episode was successfully treated with empiric antimicrobial agents and steroid. Given the negative infectious work up with the prior episode and the nearly identical clinical presentations, the second episode was treated with corticosteroid only. This led to complete resolution of her symptoms and reversal of the brain magnetic resonance imaging (MRI) lesions. CONCLUSION: To the author's knowledge, this is the first report of a primary autoimmune RE during postpartum period that is associated with ACA. Immunologic causes should be considered early with any encephalitis. Given the risk of recurrence, relapse, and neurologic deterioration, regular monitoring is recommended, especially for female patients of child-bearing age. Consistent with the current literature on autoimmune RE, steroid seems to be an effective treatment for ACA-associated RE.

Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: The CANOA Randomized Clinical Trial.

IMPORTANCE: The occurrence of new-onset migraine attacks is a complication of transcatheter atrial septal defect (ASD) closure. It has been suggested that clopidogrel may reduce migraine attacks after ASD closure. OBJECTIVE: To assess the efficacy of clopidogrel, used in addition to taking aspirin, for the prevention of migraine attacks following ASD closure. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind clinical trial performed in 6 university hospitals in Canada. Participants were 171 patients with an indication for ASD closure and no history of migraine. INTERVENTIONS: Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin + clopidogrel [the clopidogrel group], n = 84) vs single antiplatelet therapy (aspirin + placebo [the placebo group], n = 87) for 3 months following transcatheter ASD closure. The first patient was enrolled in December 2008, and the last follow-up was completed in February 2015. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the monthly number of migraine days within the 3 months following ASD closure in the entire study population. The incidence and severity of new-onset migraine attacks, as evaluated by the Migraine Disability Assessment questionnaire, were prespecified secondary end points. A zero-inflated Poisson regression model was used for data analysis. RESULTS: The mean (SD) age of the participants was 49 (15) years and 62% (106) were women. Patients in the clopidogrel group had a reduced mean (SD) number of monthly migraine days within the 3 months following the procedure (0.4 [95% CI, 0.07 to 0.69] days) vs the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, -1.02 days [95% CI, -1.94 to -0.10 days]; incident risk ratio [IRR], 0.61 [95% CI, 0.41 to 0.91]; P = .04) and a lower incidence of migraine attacks following ASD closure (9.5% for the clopidogrel group vs 21.8% for the placebo group; difference, -12.3% [95% CI, -23% to -1.6%]; odds ratio [OR], 0.38 [95% CI, 0.15 to 0.89]; P = .03). Among patients with migraines, those in the clopidogrel group had less-severe migraine attacks (zero patients with moderately or severely disabling migraine attacks vs 37% [7 patients] in the placebo group; difference, -36.8% [95% CI, -58.5% to -15.2%]; P = .046). There were no between-group differences in the rate of patients with at least 1 adverse event (16.7% [14 patients] in the clopidogrel group vs 21.8% [19 patients] in the placebo group; difference, -5.2% [95% CI, -17% to 6.6%]; P = .44). CONCLUSIONS AND RELEVANCE: Among patients who underwent transcatheter ASD closure, the use of clopidogrel and aspirin, compared with aspirin alone, resulted in a lower monthly frequency of migraine attacks over 3 months. Further studies are needed to assess generalizability and durability of this effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00799045.

Application of annotation-agnostic RNA sequencing data analysis tools for biomarker discovery in liquid biopsy.

RNA sequencing analysis is an important field in the study of extracellular vesicles (EVs), as these particles contain a variety of RNA species that may have diagnostic, prognostic and predictive value. Many of the bioinformatics tools currently used to analyze EV cargo rely on third-party annotations. Recently, analysis of unannotated expressed RNAs has become of interest, since these may provide complementary information to traditional annotated biomarkers or may help refine biological signatures used in machine learning by including unknown regions. Here we perform a comparative analysis of annotation-free and classical read-summarization tools for the analysis of RNA sequencing data generated for EVs isolated from persons with amyotrophic lateral sclerosis (ALS) and healthy donors. Differential expression analysis and digital-droplet PCR validation of unannotated RNAs also confirmed their existence and demonstrates the usefulness of including such potential biomarkers in transcriptome analysis. We show that find-then-annotate methods perform similarly to standard tools for the analysis of known features, and can also identify unannotated expressed RNAs, two of which were validated as overexpressed in ALS samples. We demonstrate that these tools can therefore be used for a stand-alone analysis or easily integrated into current workflows and may be useful for re-analysis as annotations can be integrated post hoc.

Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: One-Year Results of the CANOA Randomized Clinical Trial.

Importance: Adding clopidogrel to aspirin for 3 months after transcatheter atrial septal defect (ASD) closure results in a lower incidence of new-onset migraine attacks. However, the outcomes at 6- to 12-month follow-up (after clopidogrel cessation at 3 months) remain largely unknown. Objective: To assess the incidence of migraine attacks at 6- and 12-month follow-up after transcatheter ASD closure. Design, Setting, and Participants: This prespecified analysis of a randomized, double-blind clinical trial included patients with no prior history of migraine undergoing ASD closure from 6 university hospitals in Canada from December 2008 to November 2014. Patients were followed up at 3, 6, and 12 months, and a migraine headache questionnaire was administered at each time. Analysis began June 2019. Interventions: Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin plus clopidogrel; n = 84) vs single antiplatelet therapy (aspirin plus placebo; n = 87) for 3 months following transcatheter ASD closure. After 3 months, only single antiplatelet therapy (aspirin) was pursued. Main Outcomes and Measures: Incidence and severity of migraine attacks at 6- and 12-month follow-up. Results: The mean (SD) age of the study population was 38 (12) years, with 106 women (62%). A total of 27 patients (15.8%) had new-onset migraine attacks within the 3 months following ASD closure (8 of 84 [9.5%] vs 19 of 87 [21.8%] in the initial clopidogrel and placebo groups, respectively; P = .03). After cessation of clopidogrel and aspirin monotherapy, the percentage of patients with migraine attacks decreased over time, with 8 (4.7%) and 4 patients (2.3%) continuing to have migraine attacks at 6 and 12 months, respectively (vs 3 months: P < .001). The severity of migraine attacks progressively decreased over time; no moderate or severe attacks occurred at 6 and 12 months (vs 3 months: P < .001). There were no differences between groups in the rate of migraine attacks at 6 months (initial clopidogrel group: 2 of 84 [2.4%]; initial placebo group: 6 of 87 [6.9%]; P = .28) and 12 months (initial clopidogrel group: 3 of 84 [3.6%]; initial placebo group: 1 of 87 [1.1%]; P = .36) after ASD closure. Only 2 patients (1.2%; 1 patient per group) presented with new-onset migraine attacks after 3 months. Conclusions and Relevance: New-onset migraine attacks after ASD closure improved or resolved spontaneously within 6 to 12 months in most patients. No significant rebound effect was observed after clopidogrel cessation at 3 months. These results demonstrate a low rate of migraine events beyond 3 months following transcatheter ASD closure and support the early discontinuation of clopidogrel therapy if administered. Trial Registration: ClinicalTrials.gov Identifier: NCT00799045.

Atherosclerotic burden findings in young cryptogenic stroke patients with and without a patent foramen ovale.

BACKGROUND AND PURPOSE: To further determine the mechanisms of cryptogenic stroke or transient ischemic attack in young patients, we evaluated indices of atherosclerosis in patients

A new case of spastic paraplegia type 64 due to a missense mutation in the ENTPD1 gene.

Spastic paraplegia type 64 (SPG64; OMIM 615683) is a complicated form of hereditary spastic paraplegia (HSP) recently identified in individuals diagnosed with suspected neurodegenerative disease. Affected patients carry homozygous mutations in the ectonucleoside triphosphate diphosphohydrolase 1 gene (ENTPD1). Although they share common characteristics, affected individuals show slight discrepancies in some clinical aspects. At present, only two different cases of SPG64 have been diagnosed. More findings of genetic variation would be helpful to better understand the effect of mutations in the ENTPD1 gene on the neurological condition of affected individuals. In this study, we examined a family with an individual diagnosed with suspected HSP based on clinical findings. DNA samples from the proband, her affected sister, and both parents were analyzed using next-generation sequencing. We used an in-house automated pipeline to detect potential neuromuscular disease-causing variants. Variants were confirmed by Sanger sequencing. After cosegregation analysis, the variant NM_001776.5:c.401T>G (p.M134R) of the ENTPD1 gene was identified as a novel missense mutation linked to the phenotype of SPG64 in the proband and her sister, who showed similar and distinct clinical features compared with the two cases previously described in the literature.

Cognitive-Postural Interference in Multiple Sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative disease associated with cognition and balance impairments, which can lead to accidental falls. Postural control requires cognitive resources. This interaction is quantifiable by using the dual-task paradigm. The cognitive-postural interference (CPI) is commonly evaluated through an assessment of the dual-task cost (DTC). The aim of this review was to summarize literature related to process, results and effects of CPI in MS patients. The Prisma statement was used to guide this systematic review. Eligible articles had to include participants with MS for whom CPI was assessed using the DTC. A total of 14 articles meeting inclusion criteria were retained. All studies used the double stance with eyes open for the postural task component. Three types of cognitive tasks were used: Stroop Color-Word Test (SCWT), Word List Generation and Backward Counting. However, cognitive task scores in single or dual task were unavailable in 11 studies, which prevented calculating the DTC for that task. Prioritization instructions were provided in seven studies. Mutual interference was shown in three studies, postural interference in nine and postural facilitation in two. This review highlights the presence of CPI among MS patients. Postural interference usually occurred during dual task while cognitive performance during dual task was rarely reported. Postural task performance does not appear to vary based on EDSS level. We advise authors of future studies to use the SCWT in combination with postural task measure (sway area and postural sway) for DT assessment, with explicit prioritization instructions. Further, the cognitive and postural tasks should be performed in ST and DT and all results should be presented.

Identification of a circulating miRNA signature in extracellular vesicles collected from amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with the progressive death of motor neurons. Mean survival for a patient diagnosed with ALS is between 2 and 5 years. Early and efficient diagnosis of the various forms of ALS remains a significant challenge, resulting in a need to identify clinically-relevant biomarkers in readily accessible body fluids. microRNAs (miRNAs) are short, evolutionarily conserved non-coding RNA molecules involved in post-transcriptional regulation of gene expression that have received interest as disease biomarkers. This study was undertaken to identify an ALS-associated miRNA signature in extracellular vesicles (EVs), which can cross the blood-brain barrier and enter the circulatory system, obtained from plasma samples of persons diagnosed and living with ALS (PALS). Next-generation sequencing was used to identify differentially expressed miRNAs recovered from EVs of PALS and healthy controls. High-throughput sequencing data for select miRNA targets was subsequently validated by droplet digital PCR (ddPCR). This approach revealed elevated levels of 5 miRNAs and reduced levels of 22 miRNAs in EVs collected from PALS as compared with healthy controls subjects. miRNAs with relevance to ALS were found to be deregulated, including miR-9-5p, miR-183-5p, miR-338-3p and miR-1246. MiR-15a-5p and miR-193a-5p were identified for their diagnostic potential of ALS and association with disability progression, respectively. Functional assessment of transcripts targeted by select ALS-associated miRNAs revealed processes such as transcriptional regulation and protein ubiquitination. These data identify an ALS-associated miRNAs signature in EVs of PALS and further strengthen the potential diagnostic relevance of these small molecules for this condition.

Incidence, timing, and predictive factors of new-onset migraine headache attack after transcatheter closure of atrial septal defect or patent foramen ovale.

The objectives of this study were to evaluate the incidence, predictive factors, and duration of migraine headache attack (MHA) after transcatheter atrial septal defect (ASD) or patent foramen ovale (PFO) closure. A total of 260 consecutive patients who underwent ASD or PFO closure in our center answered a structured headache questionnaire focused in 3 period times, including (1) at baseline (just before closure), (2) within the 3 months after ASD-PFO closure, and (3) at the last (median 27 months, range 6 to 80 months) follow-up. All questionnaires were evaluated by a neurologist who established the diagnosis of MHA with or without aura, according to International Headache Society criteria. The Amplatzer ASD or PFO device was used in 95% of the patients, and aspirin, for at least 6 months, was the antithrombotic treatment in 91% of the cases. A total of 185 patients (71%) had no history of MHA before ASD-PFO closure, and these constituted the study population (mean age 39 +/- 21 years). MHA occurred in 13 patients (7%) after ASD-PFO closure, with aura in 9 of them. MHA appeared after a median of 10 days (range 0.3 to 30 days) after the procedure and were still present at the last follow-up (23 +/- 17 months) in 9 patients (69%). The median number of MHA within the 3 months after the procedure was 4 per month (interquartile range 1 to 23), and decreased to 1 per month (interquartile range 0.3 to 1) at the latest follow-up (p = 0.03). Compared with the patients who did not develop MHA, patients with MHA after ASD-PFO closure were younger (26 +/- 16 vs 39 +/- 21 years; p = 0.02) and were more likely to have undergone ASD closure (100% vs 58%; p = 0.001). In the multivariate analysis, ASD closure was the only predictor of MHA occurrence after the procedure (odds ratio 7.7; 95% confidence interval 1.5 to 22; p = 0.01). In conclusion, MHA, mostly with aura, occurred in 7% of patients after transcatheter ASD-PFO closure and persisted in most of them after a mean follow-up of 2 years. ASD closure was the only independent predictor of MHA occurrence after the procedure. These results suggest that mechanisms other than device composition are involved in the occurrence of MHA in these cases.

Enhanced thrombogenesis but not platelet activation is associated with transcatheter closure of patent foramen ovale in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: No studies have yet determined whether antiplatelet or anticoagulant therapy is the more appropriate treatment after transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. The objective of this study was to prospectively evaluate the presence, degree, and timing of activation of the platelet and coagulation systems after transcatheter closure of PFO in patients with cryptogenic stroke. METHODS: Twenty-four consecutive patients (mean age, 44+/-10 years; 11 men) with previous cryptogenic stroke who had undergone successful transcatheter closure of PFO were included in the study. Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin III (TAT) were used as markers of coagulation activation, and soluble P-selectin and soluble CD40 ligand were used as markers of platelet activation. Measurements of all hemostatic markers were taken at baseline just before the procedure and at 7, 30, and 90 days after device implantation. RESULTS: F1+2 and TAT levels increased from 0.41+/-0.16 nmol/L and 2.34+/-1.81 ng/mL, respectively, at baseline to a maximal value of 0.61+/-0.16 nmol/L and 4.34+/-1.83 ng/mL, respectively, at 7 days, gradually returning to baseline levels at 90 days (P<0.001 for both markers). F1+2 and TAT levels at 7 days after PFO closure were higher than those obtained in a group of 25 healthy controls (P<0.001 for both markers). Levels of soluble P-selectin and soluble CD40 ligand did not change at any time after PFO closure. CONCLUSIONS: Transcatheter closure of PFO is associated with significant activation of the coagulation system, with no increase in platelet activation markers. These findings raise the question of whether optimal antithrombotic treatment after PFO closure should be short-term anticoagulant rather than antiplatelet therapy.

Canadian Stroke Best Practice Recommendations: Telestroke Best Practice Guidelines Update 2017.

Every year, approximately 62,000 people with stroke and transient ischemic attack are treated in Canadian hospitals. The 2016 update of the Canadian Stroke Best Practice Recommendations Telestroke guideline is a comprehensive summary of current evidence-based and consensus-based recommendations appropriate for use by all healthcare providers and system planners who organize and provide care to patients following stroke across a broad range of settings. These recommendations focus on the use of telemedicine technologies to rapidly identify and treat appropriate patients with acute thrombolytic therapies in hospitals without stroke specialized expertise; select patients who require to immediate transfer to stroke centers for Endovascular Therapy; and for the patients who remain in community hospitals to facilitate their care on a stroke unit and provide remote access to stroke prevention and rehabilitation services. While these latter areas of Telestroke application are newer, they are rapidly developing, with new opportunities that are yet unrealized. Virtual rehabilitation therapies offer patients the opportunity to participate in rehabilitation therapies, supervised by physical and occupational therapists. While not without its limitations (e.g., access to telecommunications in remote areas, fragmentation of care), the evidence-to-date sets the foundation for improving access to care and management for patients during both the acute phase and now through post stroke recovery.

Serial Changes in Cognitive Function Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Data regarding the mid- to long-term cognitive trajectory of transcatheter aortic valve (TAVR) recipients are scarce. OBJECTIVES: Changes in global cognition and specific cognitive domains up to 1 year post-TAVR were evaluated. METHODS: Fifty-one patients (median age 80.0 [interquartile range: 72.0 to 85.0] years; 37% women) underwent TAVR and prospective assessment of cognitive function using the Montreal Cognitive Assessment (MoCA) at baseline, short-term (30 days), and 1 year post-TAVR. Processing speed and executive cognitive functions were further evaluated with the digit-symbol substitution test (DSST), Trail Making Tests (TMT), and verbal fluency tests at the same time points. Cognitive decline (CD) was determined by changes in mean scores and as a rate using practice-corrected reliable change index (RCI). RESULTS: The baseline mean total MoCA score was 22.71 ± 3.84. Twenty patients (39.2%) were considered cognitively impaired using a cutoff of <23 of 30 points. Mean total MoCA score improved at short-term post-TAVR and remained stable at 1 year (p = 0.022). On the basis of the RCI of total MoCA score, 4 patients (7.8%) presented with short-term CD, which persisted at 1 year in 1 patient (2.0%). Four patients (7.8%) exhibited cognitive improvement at 1 year, increasing to 15% among those with baseline cognitive impairment. No significant changes were observed over time in the mean DSST, TMT, and verbal fluency test scores. On the basis of the RCI, 10 of 40 patients (25%) presented with a reduction in performance of at least 1 test at 30 days that persisted at 1 year in 4 patients (10%). CONCLUSIONS: TAVR was associated with global improvement in cognitive status, more pronounced among those with cognitive impairment pre-TAVR. However, early decline in some complex cognitive functions was observed in one-quarter of TAVR recipients, persisting at 1 year in 10% of patients.

MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a condition primarily characterized by the selective loss of upper and lower motor neurons. Motor neuron loss gives rise to muscle tissue malfunctions, including weakness, spasticity, atrophy, and ultimately paralysis, with death typically due to respiratory failure within 2 to 5 years of symptoms' onset. The mean delay in time from presentation to diagnosis remains at over 1 year. Biomarkers are urgently needed to facilitate ALS diagnosis and prognosis as well as to act as indicators of therapeutic response in clinical trials. MicroRNAs (miRNAs) are small molecules that can influence posttranscriptional gene expression of a variety of transcript targets. Interestingly, miRNAs can be released into the circulation by pathologically affected tissues. This review presents therapeutic and diagnostic challenges associated with ALS, highlights the potential role of miRNAs in ALS, and discusses the diagnostic potential of these molecules in identifying ALS-specific miRNAs or in distinguishing between the various genotypic and phenotypic forms of ALS.

Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches.

OBJECTIVES: The objective of this study was to compare the incidence of cerebral embolism (CE) as evaluated by diffusion-weighted magnetic resonance imaging (DW-MRI) following transapical (TA) transcatheter aortic valve implantation (TAVI) versus transfemoral (TF) TAVI. BACKGROUND: The TA-TAVI approach avoids both the manipulation of large catheters in the aortic arch/ascending aorta and the retrograde crossing of the aortic valve, and this avoidance might lead to a lower rate of CE. METHODS: This was a prospective multicenter study including 60 patients who underwent cerebral DW-MRI the day before and within the 6 days following TAVI (TF approach: 29 patients; TA approach: 31 patients). Neurologic and cognitive function assessments were performed at DW-MRI time points. RESULTS: The TAVI procedure was performed with the Edwards valve and was successful in all cases but one (98%). A total of 41 patients (68%) had 251 new cerebral ischemic lesions at the DW-MRI performed 4 ± 1 days after the procedure, 19 patients in the TF group (66%) and 22 patients in the TA group (71%; p = 0.78). Most patients (76%) with new ischemic lesions had multiple lesions (median number of lesions per patient: 3, range 1 to 31). There were no differences in lesion number and size between the TF and TA groups. No baseline or procedural factors were found to be predictors of new ischemic lesions. The occurrence of CE was not associated with a measurable impairment in cognitive function, but 2 patients (3.3%) had a clinically apparent stroke within the 24 h following the procedure (1 patient in each group). CONCLUSIONS: TAVI is associated with a high rate of silent cerebral ischemic lesions as evaluated by DW-MRI, with no differences between the TF and TA approaches. These results provide important novel insight into the mechanisms of CE associated with TAVI and support the need for further research to both reduce the incidence of CE during these procedures and better determine their clinical relevance.