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The long-term impact of ventricular dominance on Fontan outcomes is controversial. We examined this in a 25-year cohort.Patients from October 1998 to February 2022 were reviewed. Primary outcomes were transplant-free survival and Fontan failure (death, transplantation, takedown, protein-losing enteropathy, or plastic bronchitis). Secondary outcomes included hospital and intensive care length of stay. Kaplan-Meier methodology compared outcomes by ventricular dominance. Multiphase parametric risk hazard analysis identified risk factors for primary outcomes.There were 195 patients (104 right ventricular dominant). Baseline characteristics were comparable. Perioperative survival was similar (right ventricular dominant 98%, non-right ventricular dominant 100%, p=0.51). The proportion of patients experiencing death or transplantation was 8.7% and Fontan failure was 11.8% during a median follow-up of 4.5 [0.3 - 9.8] years. Right ventricular dominant patients had reduced transplant-free survival (10-year estimates: 80% (95% CI 70-91%) vs. 92% (83-100%), p=.04) and freedom from Fontan failure (73% (62-86%) vs. 92% (83-100%), p=.04). Multiphase hazard modeling resolved 2 risk phases. The early phase spanned from surgery to approximately 6 months after. The late phase spanned from approximately 6 months after surgery onwards. In multivariable analysis, right ventricular dominance was an independent risk factor for death or transplantation (parameter estimate 1.3±0.6, p=0.04) and Fontan failure (1.1±0.5, p=0.04) during the second phase, with no significant first phase risk factors.Right ventricular dominance was associated with long-term complications after Fontan, including mortality, transplantation, and Fontan failure. This cohort may benefit from heightened surveillance in a multi-disciplinary Fontan clinic after the perioperative period.

The following case report describes a 13-year-old child with alternating hemiplegia of childhood (AHC) who underwent magnetic resonance imaging MRI with general anesthesia and experienced a hemiplegic spell, seizure, apnea, and sudden cardiac arrest with successful resuscitation. AHC is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis affecting one or both sides of the body and multiple other neurologic problems. The challenges associated with this disorder include management of developmental delay, dystonia, hemiplegia, cerebrovascular dysfunction, apnea, and autonomic dysfunction. The current literature is extremely limited in describing the effects of general anesthesia for a patient with AHC. While the neurologic manifestations of AHC are well described, autonomic dysfunction and the potential for sudden cardiac arrest have not been widely reported. To our knowledge, this is the first case report to emphasize anesthetic considerations in a pediatric patient with AHC, specifically the unrecognized potential for cardiac arrhythmia and sudden cardiac arrest.

Background: Cardiac channelopathies such as catecholaminergic polymorphic tachycardia and long QT syndrome predispose patients to fatal arrhythmias and sudden cardiac death. As genetic testing has become common in clinical practice, variants of uncertain significance (VUS) in genes associated with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome are frequently found. The objective of this study was to predict pathogenicity of catecholaminergic polymorphic ventricular tachycardia-associated RYR2 VUS and long QT syndrome-associated VUS in KCNQ1 , KCNH2 , and SCN5A by developing gene-specific machine learning models and assessing them using cross-validation, cellular electrophysiological data, and clinical correlation. Methods: The GENe-specific EnSemble grId Search framework was developed to identify high-performing machine learning models for RYR2 , KCNQ1 , KCNH2 , and SCN5A using variant- and protein-specific inputs. Final models were applied to datasets of VUS identified from ClinVar and exome sequencing. Whole cell patch clamp and clinical correlation of selected VUS was performed. Results: The GENe-specific EnSemble grId Search models outperformed alternative methods, with area under the receiver operating characteristics up to 0.87, average precisions up to 0.83, and calibration slopes as close to 1.0 (perfect) as 1.04. Blinded voltage-clamp analysis of HEK293T cells expressing 2 predicted pathogenic variants in KCNQ1 each revealed an ≈80% reduction of peak Kv7.1 current compared with WT. Normal Kv7.1 function was observed in KCNQ1-V241I HEK cells as predicted. Though predicted benign, loss of Kv7.1 function was observed for KCNQ1-V106D HEK cells. Clinical correlation of 9/10 variants supported model predictions. Conclusions: Gene-specific machine learning models may have a role in post-genetic testing diagnostic analyses by providing high performance prediction of variant pathogenicity.

INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male=21, female=11) and 29 mutation negative controls (male=15, female=14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p< 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction (54%, p=0.048), speech/swallowing dysfunction (96%, p=0.0003); and oral dystonia (88%, p=0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

Background Pathogenic variation in the ATP1A3 ‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status ( P P ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

Background ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. Aim We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. Methods A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. Results Patients (age 2.5–20 years) had symptom onset at an early age (6 days–1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks–4.8 years) with some improvements reported in all five. Conclusions Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure–function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.

Summary Objective Deep brain stimulation (DBS) is a treatment for medically refractory essential tremor (ET), but there is a paucity of literature examining the effects of DBS on voice in patients with ET pre-DBS and post-DBS. This study aimed to report a comprehensive evaluation of voice in patients with ET pre-DBS and 6-months post-DBS. Study Design Case series. Methods Five patients receiving DBS for ET underwent voice evaluations pre-DBS and 6-months post-DBS. One patient had concurrent ET of the vocal tract (ETVT). The evaluation included patient-reported, perceptual, acoustic, and phonatory aerodynamic analyses of voice. Voice Handicap Index-10, Grade, Roughness, Breathiness, Asthenia, Strain Scale, perturbation measures, cepstral spectral index of dysphonia, cepstral peak prominence, and mean phonatory airflow measures were also among the data collected. Results Patients with ET presented with minimal changes in perceptual, acoustic, and phonatory aerodynamic parameters. Perceived vocal roughness significantly increased 6-months post-DBS (P = 0.047). The patient with ETVT presented with clinically significant improvement in almost all collected voice parameters 6-months post-DBS. Conclusion This is the first study to provide data encompassing auditory perceptual voice analysis, voice-specific patient-reported quality of life measures, acoustic, and phonatory aerodynamic outcomes in patients pre-DBS and 6-months post-DBS for ET. The results of our preliminary study have implications for the use of a comprehensive voice assessment to identify and measure change in voice outcomes in patients with ET and ETVT pre- and postsurgery.