Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Long-term outcomes of patients with ventricular arrhythmias and negative programmed ventricular stimulation followed with implantable loop recorders: Impact of delayed-enhancement cardiac magnetic resonance imaging.

BACKGROUND: Programed ventricular stimulation (PVS) is a risk stratification tool in patients at risk for adverse arrhythmia outcomes. Patients with negative PVS may yet be at risk for adverse arrhythmia-related events, particularly in the presence of symptomatic ventricular arrhythmias (VA). OBJECTIVE: To investigate the long-term outcomes of real-world patients with symptomatic VA without indication for device therapy and negative PVS, and to examine the role of cardiac scaring on arrhythmia recurrence. METHODS: Patients with symptomatic VA, and late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR), and negative PVS testing were included. All patients underwent placement of implantable cardiac monitors (ICM). Survival analysis was performed to investigate the impact of LGE-CMR findings on survival free from adverse arrhythmic events. RESULTS: Seventy-eight patients were included (age 60 ± 14 years, women n = 36 (46%), ejection fraction 57 ± 9%, cardiomyopathy n = 26 (33%), mitral valve prolapse [MVP] n = 9 (12%), positive LGE-CMR scar n = 49 (62%), history of syncope n = 23 (29%)) including patients with primarily premature ventricular contractions (n = 21) or nonsustained VA (n = 57). Patients were followed for 1.6 ± 1.5 years during which 14 patients (18%) experienced VA requiring treatment (n = 14) or syncope due to bradycardia (n = 2). Four/9 patients (44%) with MVP experienced VA (n = 3) or syncope (n = 1). Baseline characteristics between those with and without adverse events were similar (p > 0.05); however, the presence of cardiac scar on LGE-CMR was independently associated with an increased risk of adverse events (hazard ratio: 5.6 95% confidence interval: [1.2-27], p = 0.03, log-rank p = 0.03). CONCLUSIONS: In a real-world cohort with long-term follow-up, adverse arrhythmic outcomes occurred in 18% of patients with symptomatic VA despite negative PVS, and this risk was significantly greater in patients with positive DE-CMR scar. Long term-monitoring, including the use of ICM, may be appropriate in these patients.

Three-dimensional-guided and ICE-guided transseptal puncture for cardiac ablations: A propensity score match study.

INTRODUCTION: Transseptal puncture (TSP) is routinely performed for left atrial ablation procedures. The use of a three-dimensional (3D) mapping system or intracardiac echocardiography (ICE) is useful in localizing the fossa ovalis and reducing fluoroscopy use. We aimed to compare the safety and efficacy between 3D mapping system-guided TSP and ICE-guided TSP techniques. METHODS: We conducted a prospective observational study of patients undergoing TSP for left atrial catheter ablation procedures (mostly atrial fibrillation ablation). Propensity scoring was used to match patients undergoing 3D-guided TSP with patients undergoing ICE-guided TSP. Logistic regression was used to compare the clinical data, procedural data, fluoroscopy time, success rate, and complications between the groups. RESULTS: Sixty-five patients underwent 3D-guided TSP, and 151 propensity score-matched patients underwent ICE-guided TSP. The TSP success rate was 100% in both the 3D-guided and ICE-guided groups. Median needle time was 4.00 min (interquartile range [IQR]: 2.57-5.08) in patients with 3D-guided TSP compared to 4.02 min (IQR: 2.83-6.95) in those with ICE-guided TSP (p = .22). Mean fluoroscopy time was 0.2 min (IQR: 0.1-0.4) in patients with 3D-guided TSP compared to 1.2 min (IQR: 0.7-2.2) in those with ICE-guided TSP (p < .001). There were no complications related to TSP in both group. CONCLUSIONS: Three-dimensional mapping-guided TSP is as safe and effective as ICE-guided TSP without additional cost.

Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study.

INTRODUCTION/AIMS: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported. METHODS: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. RESULTS: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. DISCUSSION: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy.

Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Acute flaccid myelitis: cause, diagnosis, and management.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

A comparison of clinical outcomes and cost of radiofrequency catheter ablation for atrial fibrillation with monitored anesthesia care versus general anesthesia.

INTRODUCTION: Monitored anesthesia care (MAC) or general anesthesia (GA) can be used during catheter ablation (CA) of atrial fibrillation (AF). However, each approach may have advantages and disadvantages with variability in operator preferences. The optimal approach has not been well established. The purpose of this study was to compare procedural efficacy, safety, clinical outcomes, and cost of CA for AF performed with MAC versus GA. METHODS: The study population consisted of 810 consecutive patients (mean age: 63 ± 10 years, paroxysmal AF: 48%) who underwent a first CA for AF. All patients completed a preprocedural evaluation by the anesthesiologists. Among the 810 patients, MAC was used in 534 (66%) and GA in 276 (34%). Ten patients (1.5%) had to convert to GA during the CA. RESULTS: Although the total anesthesia care was longer with GA particularly in patients with persistent AF, CA was shorter by 5 min with GA than MAC (p < 0.01). Prevalence of perioperative complications was similar between the two groups (4% vs. 4%, p = 0.89). There was no atrioesophageal fistula with either approach. GA was associated with a small, ~7% increase in total charges due to longer anesthesia care. During 43 ± 17 months of follow-up after a single ablation procedure, 271/534 patients (51%) in the MAC and 129/276 (47%) patients in the GA groups were in sinus rhythm without concomitant antiarrhythmic drug therapy (p = 0.28). CONCLUSION: With the participation of an anesthesiologist, and proper preoperative assessment, CA of AF using GA or MAC has similar efficacy and safety.

A wearable cardioverter defibrillator with a low false alarm rate.

INTRODUCTION: A wearable cardioverter defibrillator (WCD) is indicated in appropriate patients to reduce the risk for sudden cardiac death. Challenges for patients wearing a WCD have been frequent false shock alarms primarily due to electrocardiogram noise and wear discomfort. The objective of this study was to test a contemporary WCD designed for reduced false shock alarms and improved comfort. METHODS: One hundred and thirty patients with left ventricular ejection fraction ≤40% and an active implantable cardioverter defibrillator (ICD) were fitted with the ASSURE WCD (Kestra Medical Technologies) and followed for 30 days. WCD detection was enabled and shock alarm markers recorded, but shocks and shock alarms were disabled. All WCD episodes and ICD ventricular tachycardia/ventricular fibrillation (VT/VF) episodes were adjudicated. The primary endpoint was the false-positive shock alarm rate with a performance goal of 1 every 3.4 days (0.29 per patient-day). RESULTS: Of 163 WCD episodes, 4 were VT/VF and 159 non-VT/VF (121 rhythms with noise, 32 uncertain with noise, 6 atrial flutter without noise). Only three false-positive shock alarm markers were recorded; one false-positive shock alarm every 1333 patient-days (0.00075 per patient-day, 95% confidence interval: 0.00015-0.00361; p < .001). No ICD recorded VT/VF episodes meeting WCD detection criteria (≥170 bpm for ≥20 s) were missed by the WCD during 3501 patient-days of use. Median wear was 31.0 days (interquartile range [IQR] 2.0) and median daily use 23.0 h (IQR 1.7). Adverse events were mostly mild: skin irritation (19.4%) and musculoskeletal discomfort (8.5%). CONCLUSION: The ASSURE WCD demonstrated a low false-positive shock alarm rate, low patient-reported discomfort, and no serious adverse events.

Patients' and family members' views on pacemaker reuse: An international survey.

INTRODUCTION: The reuse of cardiac implantable electronic devices may help increase access to these therapies in low- and middle-income countries (LMICs). No published data exist regarding the views of patients and family members in LMICs regarding this practice. METHODS AND RESULTS: An article questionnaire eliciting attitudes regarding pacemaker reuse was administered to ambulatory adult patients and patients' family members at outpatient clinics at Centro Nacional Cardiologia in Managua, Nicaragua, Indus Hospital in Karachi, Pakistan, Hospital Carlos Andrade Marín, and Hospital Eugenio Espejo in Quito, Ecuador, and American University of Beirut Medical Center in Beirut, Lebanon. There were 945 responses (Nicaragua - 100; Pakistan - 493; Ecuador - 252; and Lebanon - 100). A majority of respondents agreed or strongly agreed that they would be willing to accept a reused pacemaker if risks were similar to a new device (707, 75%), if there were a higher risk of device failure compared with a new device (584, 70%), or if there were a higher risk of infection compared to a new device (458, 56%). A large majority would be willing to donate their own pacemaker at the time of their death (884, 96%) or the device of a family member (805, 93%). Respondents who were unable to afford a new device were more likely to be willing to accept a reused device (79% vs. 63%, p < .001). CONCLUSIONS: Patients and their family members support the concept of pacemaker reuse for patients who cannot afford new devices.

Quantifying cardiac sympathetic denervation: first studies of 18F-fluorohydroxyphenethylguanidines in cardiomyopathy patients.

PURPOSE: 4-18F-Fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis. The aim of this study was to evaluate their performance in cardiomyopathy patients. METHODS: Eight cardiomyopathy patients were scanned with 18F-4F-MHPG and 18F-3F-PHPG. Also, regional resting perfusion was assessed with 13N-ammonia. 18F-4F-MHPG and 18F-3F-PHPG kinetics were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as measures of regional nerve density. Patlak slope polar maps were used to evaluate the pattern and extent of cardiac denervation. For comparison, "retention index" (RI) values (mL blood/min/mL tissue) were also calculated and used to assess denervation. Perfusion polar maps were used to estimate the extent of hypoperfusion. RESULTS: Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all subjects, ranging from 25 to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion. The two tracers provided comparable metrics of regional nerve density and the extent of left ventricular denervation. 18F-4F-MHPG exhibited faster liver clearance than 18F-3F-PHPG, reducing spillover from the liver into the inferior wall. 18F-4F-MHPG was also metabolized more consistently in plasma, which may allow application of population-averaged metabolite corrections. CONCLUSION: The advantages of 18F-4F-MHPG (more rapid liver clearance, more consistent metabolism in plasma) make it the better imaging agent to carry forward into future clinical studies in patients with cardiomyopathy. TRIAL REGISTRATION: Registered at the ClinicalTrials.gov website (NCT02669563). URL: https://clinicaltrials.gov/ct2/show/NCT02669563.

Hip Pain in Patients With Spinal Muscular Atrophy: Prevalence, Intensity, Interference, and Factors Associated With Moderate to Severe Pain.

BACKGROUND: A subset of patients with spinal muscular atrophy (SMA) develop hip pain. We analyzed (1) the characteristics of hip pain in patients with SMA (prevalence, intensity, interference with activities, and responsiveness to treatment) and (2) factors (patient, clinical, and radiographic) associated with moderate to severe pain. METHODS: We performed a retrospective record review and telephone survey of 104 patients with SMA (77% response rate; 44% female; mean age, 22±13 y) who presented for treatment between 2010 and 2020. Patient, clinical, and radiographic characteristics (when available) were recorded. Patients with current or past hip pain were asked about pain characteristics. Pain intensity and interference were assessed with the Brief Pain Inventory, modified for SMA (scale, 0 to 10 with 0 indicating no pain/interference). We used univariate analysis and ordered logistic regression to determine associations between patient factors and hip pain (α=0.05). RESULTS: Hip pain occurred in 60/104 patients (58%), with 15 (14%) indicating moderate to severe pain. Compared with patients with normal body mass index values, patients who were obese had 5.4 times the odds [95% confidence interval (CI), 1.3-23] of moderate to severe pain. Hip contractures [adjusted odds ratio (aOR), 3.2; 95% CI, 1.2-8.8] and dislocations (aOR, 2.9; 95% CI, 1.1-7.9) were associated with greater odds of pain compared with hips without these presentations. Surgical correction for scoliosis (aOR, 2.6; 95% CI, 1.1-6.5) was also associated with greater odds of moderate to severe pain. Femoral head migration percentage was the only radiographic parameter associated with pain. Mean modified Brief Pain Inventory pain intensity was 2.1±2.3. Prolonged sitting, sleep, and transfers (eg, bed to wheelchair) were the activities most affected by pain. CONCLUSIONS: Hip pain was moderate to severe in 14% of patients with SMA. Obesity, hip contractures, surgical correction of scoliosis, and hip dislocations were independently associated with pain. Although mean pain intensity was low, hip pain interfered with daily activities, including prolonged sitting, sleep, and transfers. LEVEL OF EVIDENCE: Level III.

Detection of SMN1 to SMN2 gene conversion events and partial SMN1 gene deletions using array digital PCR.

Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutations of survival motor neuron 1 (SMN1) but retention of one or more copies of the paralog SMN2. Within the SMA population, there is substantial variation in SMN2 copy number (CN); in general, those individuals with SMA who have a high SMN2 CN have a milder disease. Because SMN2 functions as a disease modifier, its accurate CN determination may have clinical relevance. In this study, we describe the development of array digital PCR (dPCR) to quantify SMN1 and SMN2 CNs in DNA samples using probes that can distinguish the single nucleotide difference between SMN1 and SMN2 in exon 8. This set of dPCR assays can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 CN and disease severity. We can detect SMN1-SMN2 gene conversion events in DNA samples by comparing CNs at exon 7 and exon 8. Partial deletions of SMN1 can also be detected with dPCR by comparing CNs at exon 7 or exon 8 with those at intron 1. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 CNs from SMA samples as well as identify gene conversion events and partial deletions of SMN1.

Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART).

BACKGROUND: Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. METHODS: Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. DISCUSSION: The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases.

Modifier genes are believed to account for the clinical variability observed in many Mendelian disorders, but their identification remains challenging due to the limited availability of genomics data from large patient cohorts. Here, we present GENDULF (GENetic moDULators identiFication), one of the first methods to facilitate prediction of disease modifiers using healthy and diseased tissue gene expression data. GENDULF is designed for monogenic diseases in which the mechanism is loss of function leading to reduced expression of the mutated gene. When applied to cystic fibrosis, GENDULF successfully identifies multiple, previously established disease modifiers, including EHF, SLC6A14, and CLCA1. It is then utilized in spinal muscular atrophy (SMA) and predicts U2AF1 as a modifier whose low expression correlates with higher SMN2 pre-mRNA exon 7 retention. Indeed, knockdown of U2AF1 in SMA patient-derived cells leads to increased full-length SMN2 transcript and SMN protein expression. Taking advantage of the increasing availability of transcriptomic data, GENDULF is a novel addition to existing strategies for prediction of genetic disease modifiers, providing insights into disease pathogenesis and uncovering novel therapeutic targets.

Efficacy and tolerability of quinidine as salvage therapy for monomorphic ventricular tachycardia in patients with structural heart disease.

INTRODUCTION: Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardia and ventricular fibrillation (VF) syndromes; however, the efficacy of quinidine in scar-related monomorphic ventricular tachycardia (MMVT) is unclear. METHODS AND RESULTS: Between 2009 and 2020 a single VT referral center, a total of 23 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device [LVAD]) were treated with quinidine (14 quinidine gluconate; 996 ± 321 mg, 8 quinidine sulfate; 1062 ± 588 mg). Quinidine was used in combination with other antiarrhythmics (AAD) in 19 (13 also on amiodarone). All patients previously failed >1 AAD (amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and eight had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite AADs (6), inability to tolerate other AADs (4), or recurrent VT(12). Ventricular arrhythmias recurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359 to 434 ms (p = .02). Six (27.3%) patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. The following adverse effects were seen: gastrointestinal side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost. CONCLUSION: Quinidine therapy has limited tolerability and long-term efficacy when used in the management of amiodarone-refractory scar-related MMVT.

Lead damage after cardiac implantable device replacement procedure: Comparison between electrical plasma tool and electrocautery.

BACKGROUND: Lead damage is a complication caused by lead manipulation or heating damage from conventional electrocautery (EC) after cardiovascular implantable electronic device (CIED) replacement. Application of electrical plasma (PEAK PlasmaBlade) is a new technology that reportedly reduces this risk. OBJECTIVES: This study was designed to compare the effect of EC versus PEAK PlasmaBlade on lead parameters and complications after generator replacement procedures. METHODS: We retrospectively studied 410 consecutive patients (840 leads) who underwent CIED replacement using EC (EC group) and 410 consecutive patients (824 leads) using PEAK PlasmaBlade (PlamaBlade group). Pacing lead impedance, incidence of lead damage, and complications were compared between both groups. RESULTS: Lead impedance increased in 393 leads (46.8%) in the EC group versus 282 leads (34.2%) in the PlasmaBlade group (p < .01) with average percent changes of 6.7% and 4.0% (p < .01), respectively. Lead impedance decreased in 438 leads (52.1%) in the EC group versus 507 leads (61.5%) in the PlasmaBlade group (p < .01) with average percent changes of -5.7% and -7.1% (p < .01), respectively. Lead damage requiring lead revision occurred in five leads (0.6%) or after five procedures (1.2%) in the EC group compared to three leads (0.4%, p = .50) or after three procedures (0.7%, p = .48) in the PlasmaBlade group. There were no significant differences in the procedural-related complications between the EC group (nine patients, 2.2%) and the PlasmaBlade group (five patients, 1.2%, p = .28). CONCLUSION: Conventional electrocautery can potentially damage lead insulations. However, this study shows that when used carefully electrocautery is as safe as the PEAK PlasmaBlade™.

Effect of metformin on outcomes of catheter ablation for atrial fibrillation.

BACKGROUND: Diabetes mellitus (DM) is a risk factor for atrial fibrillation (AF). The effect of antidiabetic medications on AF or the outcomes of catheter ablation (CA) has not been well described. We sought to determine whether metformin treatment is associated with a lower risk of atrial arrhythmias after CA in patients with DM and AF. METHODS AND RESULTS: A first CA was performed in 271 consecutive patients with DM and AF (age: 65 ± 9 years, women: 34%; and paroxysmal AF: 51%). At a median of 13 months after CA (interquartile range: 6-30), 100/182 patients (55%) treated with metformin remained in sinus rhythm without antiarrhythmic drug therapy, compared with 36/89 patients (40%) not receiving metformin (p = .03). There was a significant association between metformin therapy and freedom from recurrent atrial arrhythmias after CA in multivariable Cox hazards models (hazard ratio [HR]: 0.66; ±95% confidence interval [CI]: 0.44-0.98; p = .04) that adjusted for age, sex, body mass index, AF type (paroxysmal vs. nonparoxysmal), antiarrhythmic medication, obstructive sleep apnea, chronic kidney disease, coronary artery disease, left ventricular ejection fraction, and left atrial diameter. A Cox model that also incorporated other antidiabetic agents and fasting blood glucose demonstrated a similar reduction in the risk of recurrent atrial arrhythmias with metformin treatment (HR: 0.63; ±95% CI: 0.42-0.96; p = .03). CONCLUSIONS: In patients with DM, treatment with metformin appears to be independently associated with a significant reduction in the risk of recurrent atrial arrhythmias after CA for AF. Whether this effect is due to glycemic control or pleiotropic effects on electroanatomical mechanisms of AF remains to be determined.

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases.

BACKGROUND: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres. METHODS: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays. RESULTS: Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients. CONCLUSIONS: Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.