Faculty Bibliography

BACKGROUND:Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder caused by the same intronic TTTTA/TTTCA repeat expansion in seven distinct genes. TTTTA-only expansions are benign, whereas those containing TTTCA insertions are pathogenic. OBJECTIVE:We investigated the genetic basis of dominant cortical myoclonus without seizures in two unrelated families. METHODS:Repeat-primed polymerase chain reaction (PCR), long-range PCR, and nanopore sequencing were used to detect and characterize expansions at known FAME loci. RESULTS:We identified a novel repeat expansion in MARCHF6, comprising 388 to 454 elongated TTTTA repeats and 5 to 11 TTTCA repeats at the 3'-terminus, segregating with cortical myoclonus in 8 affected individuals. This configuration shows meiotic stability but low-level somatic variability in blood. We observed an inverse correlation between the number of TTTCA repeats and the age at myoclonus onset. CONCLUSIONS:These findings indicate that as little as five TTTCA repeats combined with expanded TTTTA repeats can cause cortical myoclonus without epilepsy, highlighting the potential mechanisms underlying FAME pathophysiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

STATEMENT OF THE CLINICAL PROBLEM ADDRESSED BY THE CASE/UNASSIGNED:We report an atypical clinical presentation of a rapidly progressive neurologic emergency that required prompt investigation and treatment of impending respiratory failure. We discuss the differential diagnosis, evaluation, emergency management, and treatment options of patients with atypical variants of this disorder. BRIEF DESCRIPTION OF CASE PRESENTATION/UNASSIGNED:A 56-year-old woman with a history of hypothyroidism, anxiety, and depression presented to the emergency department 3 weeks after an upper respiratory and ear infection with cough, pain with sinus palpation, tingling in her fingers bilaterally and right foot, hives, and an episode of blurry vision on awakening. She was discharged home with antibiotics. That evening, she developed rapidly progressing hoarseness and dysphagia and returned to the emergency department. An initial examination and laryngoscopy revealed complete left vocal cord paralysis, consistent with a left cranial nerve X palsy, which prompted a neurologic evaluation. Her examination progressively worsened over the next day requiring mechanical ventilation and ICU admission. SUMMARY OF THE KEY TEACHING POINT IN THE CASE/UNASSIGNED:New-onset bulbar cranial neuropathies should raise concern for neurologic disorders that can be rapidly progressive and result in respiratory failure. Urgent diagnosis and treatment are warranted.

OBJECTIVE/UNASSIGNED:The authors aimed to characterize the long-term psychiatric outcomes and their predictors among survivors of autoimmune encephalitis (AE). METHODS/UNASSIGNED:In this retrospective cohort study, patients diagnosed as having AE between 2008 and 2023 at two academic medical centers (in New York City and Toronto) completed the Mini International Neuropsychiatric Interview 7.0.2 (MINI) and Profile of Mood States (POMS-2) to assess long-term psychiatric outcomes. Clinical characteristics were assessed for potential predictors of psychiatric outcomes. Bivariate analyses and univariate logistic regressions were conducted to assess the relationship between the predictors and the primary outcome. RESULTS/UNASSIGNED:-methyl-d-aspartate (33%), anti-leucine-rich-glioma-inactivated 1 (24%), anti-glutamic acid decarboxylase 65 (14%), and antibody-negative encephalitis (29%). In total, 71% of participants who completed the MINI met criteria for a DSM-5 diagnosis, and 56% were diagnosed as having a mood disorder. Thirteen participants (31%) reported above-average total mood disturbance on the POMS-2. Mann-Whitney U tests revealed that participants diagnosed as having a mood disorder self-reported significantly higher levels of confusion and bewilderment (z=-2.04, p=0.04) and depression and dejection (z=-2.24, p=0.03) and lower levels of vigor and activity (z=-2.62, p=0.01). CONCLUSIONS/UNASSIGNED:AE survivors have a high prevalence of psychiatric comorbid conditions, with most being diagnosed as having a mood disorder and a significant proportion endorsing ongoing mood disturbance. Patients with a psychiatric history may benefit from closer psychiatric follow-up.

Space occupying cerebral edema is a feared complication after large ischemic stroke, occurring in up to 30% of patients with middle cerebral artery (MCA) occlusion and peaking 2-4 days after injury. Little is known about the factors and outcomes associated with peak edema timing, especially after 96 h. We aimed to characterize differences and compare discharge status between patients who experienced maximum midline shift (MLS) or decompressive hemicraniectomy (DHC) in the acute (< 48 h), average (48-96 h), and subacute (> 96 h) groups. We performed a two-center, retrospective study of patients with ≥ 1/2 MCA territory infarct and MLS. We constructed a multivariable model to test the association of subacute peak edema and favorable discharge status, adjusting for various confounders. Of 321 eligible patients, 32%, 36%, and 32% experienced acute, average, and subacute peak edema. Subacute peak edema was significantly associated with higher odds of favorable discharge than acute peak edema (aOR, 2.05; 95% CI, 1.03-4.11). Subacute peak edema after large MCA stroke is associated with better discharge status compared to acute peak edema courses. Understanding how the timing of cerebral edema affects risk of unfavorable discharge has important implications for treatment decisions and prognostication.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.

BACKGROUND:Childhood environmental factors back to the prenatal environment can contribute to MS risk. Childhood adversity, which causes biological, behavioral, and epigenetic changes that can be passed down through families, has been understudied in MS. Here, we emphasize the need to understand the role that intergenerational adversity may play among families affected by MS. OBJECTIVE:To evaluate the frequency and types of adverse childhood experiences among parents of children with MS. METHODS:Individuals with pediatric MS (n = 68) were enrolled in a longitudinal study of cognition. At enrollment, the patient and one caregiver or parent completed questionnaires. As the pediatric participants were under age 18 at time of enrollment, one parent completed the Adverse Childhood Experiences (ACEs, a 10-item self-report measure) about the parents' own childhood. Results from the ACE questionnaire among parents of pediatric healthy controls (n = 96) and adults in a national cohort are also reported for comparison. RESULTS:Over half of pediatric MS parents reported at least one ACE exposure. Of parents that did have ACE exposures, the exposures were broad in terms of abuse, neglect, and household dysfunction. Over 10 % of parents reported total ACE scores of 7 or above. CONCLUSION/CONCLUSIONS:Over half of pediatric MS parents experienced some degree of childhood adversity. The impact of intergenerational adversity on the development of pediatric onset MS warrants further study.

IMPORTANCE/UNASSIGNED:It remains unclear whether children and adolescents with SARS-CoV-2 infection are at heightened risk for long-term kidney complications. OBJECTIVE/UNASSIGNED:To investigate whether SARS-CoV-2 infection is associated with an increased risk of postacute kidney outcomes among pediatric patients, including those with preexisting kidney disease or acute kidney injury (AKI). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from 19 health institutions in the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) initiative from March 1, 2020, to May 1, 2023 (follow-up ≤2 years completed December 1, 2024; index date cutoff, December 1, 2022). Participants included children and adolescents (aged <21 years) with at least 1 baseline visit (24 months to 7 days before the index date) and at least 1 follow-up visit (28 to 179 days after the index date). EXPOSURES/UNASSIGNED:SARS-CoV-2 infection, determined by positive laboratory test results (polymerase chain reaction, antigen, or serologic) or relevant clinical diagnoses. A comparison group included children with documented negative test results and no history of SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Outcomes included new-onset chronic kidney disease (CKD) stage 2 or higher or CKD stage 3 or higher among those without preexisting CKD; composite kidney events (≥50% decline in estimated glomerular filtration rate [eGFR], eGFR ≤15 mL/min/1.73 m2, dialysis, transplant, or end-stage kidney disease diagnosis), and at least 30%, 40%, or 50% eGFR decline among those with preexisting CKD or acute-phase AKI. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models with propensity score stratification. RESULTS/UNASSIGNED:Among 1 900 146 pediatric patients (487 378 with and 1 412 768 without COVID-19), 969 937 (51.0%) were male, the mean (SD) age was 8.2 (6.2) years, and a range of comorbidities was represented. SARS-CoV-2 infection was associated with higher risk of new-onset CKD stage 2 or higher (HR, 1.17; 95% CI, 1.12-1.22) and CKD stage 3 or higher (HR, 1.35; 95% CI, 1.13-1.62). In those with preexisting CKD, COVID-19 was associated with an increased risk of composite kidney events (HR, 1.15; 95% CI, 1.04-1.27) at 28 to 179 days. Children with acute-phase AKI had elevated HRs (1.29; 95% CI, 1.21-1.38) at 90 to 179 days for composite outcomes. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this large US cohort study of children and adolescents, SARS-CoV-2 infection was associated with a higher risk of adverse postacute kidney outcomes, particularly among those with preexisting CKD or AKI, suggesting the need for vigilant long-term monitoring.

INTRODUCTION/UNASSIGNED:Seizures are common in autoimmune encephalitis (AE), but identifying patients at risk of chronic epilepsy in the post-acute phase remains challenging. This study aims to identify risk factors of treatment-resistant postencephalitic epilepsy. METHODS/UNASSIGNED:This retrospective cohort study included patients with AE who experienced new-onset seizures within one year of symptom onset from two tertiary care centers in New York. EEG findings were analyzed separately based on whether the EEG recording was obtained in the acute (<3 months from symptom onset) or subacute phase. A multivariate logistic regression model was used to identify independent predictors of postencephalitic epilepsy. RESULTS/UNASSIGNED:Eighty-nine patients were included (median age: 33 years). Neural antibodies were present in 73% of patients (NMDAR: 35, LGI1: 19, GAD65: 9, Hu: 1, AGNA-1: 1). Over a median follow-up of 4.9 years, 29.2% developed treatment-resistant postencephalitic epilepsy. Independent predictors of postencephalitic epilepsy included focal slowing on acute EEG (OR 0.15, CI 0.02-0.90), interictal epileptiform discharges (IEDs) or periodic discharges (PDs) on subacute EEG (OR 20.01, CI 1.94-206.44), and cell surface antibodies (OR 0.21, CI 0.05-0.89). Immunotherapy within three months of onset was associated with decreased epilepsy development in patients with neural antibodies (OR 4.16, CI 1.11-16.30). CONCLUSIONS/UNASSIGNED:Nearly one-third of patients with AE and acute seizures developed treatment-resistant postencephalitic epilepsy, with significant predictors including absence of focal slowing on acute EEG, presence of IEDs and PDs on subacute EEG, absence of cell surface antibodies, and absence of early immunotherapy treatment of patients with positive neural antibodies.