Faculty Bibliography

Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.

BACKGROUND AND OBJECTIVES/OBJECTIVE:-related disorders, although descriptions are limited. We aimed to determine trajectories and outcomes of development and adaptive function. METHODS:-containing 2q24.3 copy number variants (CNVs) were considered separately. We collected medical and developmental history from parents/caregivers and medical records. Adaptive function and behavior were characterized using functional classification system levels and Vineland Adaptive Behavior Scales-3 (VABS-3) Parent/Caregiver Form. We repeated analyses on individuals with variants known to result in gain-of-function (GOF, typically EO phenotypes) or loss-of-function (LOF, typically LO phenotypes). RESULTS:< 0.01). Analyses of individuals with confirmed GOF/LOF variants (n = 57) showed similar results to the EO/LO analyses. DISCUSSION/CONCLUSIONS:-related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.

OBJECTIVES/OBJECTIVE:To investigate the associations between total and individual potato intake and risk of type 2 diabetes (T2D), estimate the effect on T2D risk of replacing potatoes with whole grains and other major carbohydrate sources, and conduct a dose-response and substitution meta-analysis of prospective cohort studies. DESIGN/METHODS:Prospective cohort study and dose-response meta-analysis of prospective cohort studies. SETTING/METHODS:Individual participant data from Nurses' Health Study (1984-2020), Nurses' Health Study II (1991-2021), and Health Professionals Follow-up Study (1986-2018). PARTICIPANTS/METHODS:205 107 men and women free of diabetes, cardiovascular disease, or cancer at baseline. MAIN OUTCOME MEASURE/METHODS:Incident type 2 diabetes. RESULTS:During 5 175 501 person years of follow-up, T2D was documented in 22 299 participants. After adjustment for updated body mass index and other diabetes related risk factors, higher intakes of total potatoes and French fries were associated with increased risk of T2D. For every increment of three servings weekly of total potato, the rate for T2D increased by 5% (hazard ratio 1.05, 95% confidence interval (CI) 1.02 to 1.08) and for every increment of three servings weekly of French fries the rate increased by 20% (1.20, 1.12 to 1.28). Intake of combined baked, boiled, or mashed potatoes was not significantly associated with T2D risk (pooled hazard ratio 1.01, 95% CI 0.98 to 1.05). In substitution analyses, replacing three servings weekly of potatoes with whole grains was estimated to lower T2D rates by 8% (95% CI 5% to 11%) for total potatoes, 4% (1% to 8%) for baked, boiled, or mashed potatoes, and 19% (14% to 25%) for French fries. In contrast, replacing total potatoes or baked, boiled, or mashed potatoes with white rice was associated with an increased risk of T2D. In a meta-analysis of 13 cohorts (587 081 participants and 43 471 diagnoses of T2D), the pooled hazard ratio for risk of T2D with each increment of three servings weekly of total potato was 1.03 (95% CI 1.02 to 1.05) and of fried potatoes was 1.16 (1.09 to 1.23). In substitution meta-analyses, replacing three servings weekly of total, non-fried, and fried potatoes with whole grains was estimated to lower the risk of T2D by 7% (95% CI 5% to 9%), 5% (3% to 7%), and 17% (12% to 22%), respectively. CONCLUSIONS:Higher intake of French fries, but not combined baked, boiled, or mashed potatoes, was associated with a higher risk of T2D. The T2D risk linked to potato intake seemed to depend on the food being replaced: replacing potato with whole grains was associated with lower risk, whereas replacing with white rice was associated with increased risk.

BACKGROUND:Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk. METHODS:Genetic data from people who had succumbed to SUDEP was compared to data from people with epilepsy who had not succumbed to SUDEP and from healthy controls. Polygenic risk scores (PRSs) for longevity, intelligence and epilepsy were compared across cohorts. Reactome pathways and gene ontology terms implicated by the contributing single nucleotide polymorphisms (SNPs) were explored. In the subset of SUDEP cases with the necessary data available, a risk score was calculated using an existing risk prediction tool (SUDEP-3); the added value to this prediction of SNP-based genomic information was evaluated. FINDINGS/RESULTS:Only European-ancestry participants were included. 161 SUDEP cases were compared to 768 cases with epilepsy and 1153 healthy controls. PRS for longevity was significantly reduced in SUDEP cases compared to disease (P = 0·0096) and healthy controls (P = 0·0016), as was PRS for intelligence (SUDEP cases compared to disease (P = 0·0073) and healthy controls (P = 0·00024)). The PRS for epilepsy did not differ between SUDEP cases and disease controls (P = 0·76). SNP-determined pathway and gene ontology analysis highlighted those related to inter-neuronal communication as amongst the most enriched in SUDEP. Addition of PRS for longevity and intelligence to SUDEP-3 scores improved risk prediction in a subset of cases (38) and controls (703), raising the area-under-the-curve in a receiver-operator characteristic from 0·699 using SUDEP-3 alone to 0·913 when PRSs were added. INTERPRETATION/CONCLUSIONS:Common genetic variation contributes to SUDEP risk, offering new approaches to improve risk prediction and to understand underlying mechanisms. FUNDING/BACKGROUND:The Amelia Roberts Fund; CURE Epilepsy; Epilepsy Society, UK; Finding A Cure for Epilepsy and Seizures (FACES).

Naturalistic electrocorticography (ECoG) data are a rare but essential resource for studying the brain's linguistic capabilities. ECoG offers high temporal resolution suitable for investigating processes at multiple temporal timescales and frequency bands. It also provides broad spatial coverage, often along critical language areas. Here, we share a dataset of nine ECoG participants with 1,330 electrodes listening to a 30-minute audio podcast. The richness of this naturalistic stimulus can be used for various research questions, from auditory perception to narrative integration. In addition to the neural data, we extracted linguistic features of the stimulus ranging from phonetic information to large language model word embeddings. We use these linguistic features in encoding models that relate stimulus properties to neural activity. Finally, we provide detailed tutorials for preprocessing raw data, extracting stimulus features, and running encoding analyses that can serve as a pedagogical resource or a springboard for new research.

BACKGROUND:Haploinsufficiency of the bromodomain PHD finger transcription factor (BPTF) gene, essential in chromatin remodeling, leads to a neurodevelopmental disorder characterized by dysmorphic facies, distal limb anomalies, neurological disturbances, epilepsy, and gastrointestinal symptoms. METHODS:Families with BPTF-related neurodevelopmental disorders, with or without gastrointestinal symptoms, were recruited through an international collaboration. Data were collected via questionnaires on demographics, clinical features, genetics, and comorbidities, focusing on cyclical vomiting syndrome (CVS). CVS was diagnosed using criteria from the International Classification of Headache Disorders, 3rd edition (ICHD-3). Genetic variants were analyzed for pathogenicity, and effectiveness of therapies was assessed. RESULTS:We enrolled 15 individuals with likely pathogenic/pathogenic BPTF variants (median age: 8.8 years). Three individuals (20%) were diagnosed with CVS, and an additional four individuals (26.7%) met at least three of the ICHD-3 criteria for CVS. Among these seven individuals, the median age at onset of recurrent vomiting episodes was 3 years. In all seven individuals, recurrent vomiting episodes, typically lasting under an hour, were triggered by poor sleep (50%) and fever (66.7%). Acute therapy (ondansetron or domperidone) was administered in 42.8% of cases, and prophylactic therapy was provided in 57.1% of cases with cyproheptadine, levetiracetam combined with lamotrigine, and domperidone; all therapies were associated with clinical benefit. Episodes disrupted families' daily lives, causing emotional stress (85.7%) and routine disruptions (85.7%). CONCLUSIONS:This study broadens the syndromic phenotype associated with BPTF haploinsufficiency, highlighting CVS as a core feature. The findings raise clinician awareness, guide management, and enhance understanding of this rare condition.

Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across the occipital cortex and are usually largest when the cortex is inactive. However, recent studies measuring visual receptive fields have reported that local alpha power increases when cortex is excited by visual stimulation. This contrasts with the expectation that alpha oscillations are associated with cortical inactivity. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We hypothesized that stimulus-driven local increases in alpha power result from a mixture of two effects: a reduction in alpha oscillatory power and a simultaneous increase in broadband power. To test this, we implemented a model to separate these components. The two components were then independently fit by population receptive field (pRF) models. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power but are several times larger and exhibit the opposite effect: alpha oscillatory power decreases in response to stimuli within the receptive field, reinforcing the link between alpha oscillations and cortical inactivity, whereas broadband power increases. The results demonstrate that alpha suppression in the human visual cortex can be precisely tuned, but that to measure these effects, it is essential to separate the oscillatory signal from broadband power changes. Finally, we show how the large size and the negative valence of alpha pRFs can explain key features of exogenous visual attention.

BACKGROUND:Febrile seizures occur in 3%-4% of US children aged six months to five years and are considered benign. However, sudden unexplained death in childhood is associated with 10 times increase in febrile seizures. We assessed the characteristics of children with febrile seizure and sudden death to identify factors that confer increased sudden death risk. METHODS:We conducted a case-control analysis of children with febrile seizure and subsequent sudden death versus living controls from December 2021 to June 2023 through an ∼10-minute anonymous online survey. We enrolled parents of children, living or deceased, whose child had experienced a febrile seizure from age six months to six years. Subjects were excluded if the child had an afebrile seizure or parents had not witnessed a febrile seizure. Demographic characteristics, parasomnias, and febrile seizure features were analyzed. RESULTS:A total of 381 completed surveys were received; 53 (14%) cases of febrile seizure with sudden death and 328 (86%) living controls. Cases reported febrile seizure onset >2 months earlier (P = 0.013) and reported developmental concerns (odds ratio [OR] = 2.32, 95% confidence interval [CI] [1.14, 4.71], P = 0.03), less frequent night awakenings (OR = 0.34, 95% CI [0.18, 0.65], P = 0.001), and less restless sleep (OR = 0.37, 95% CI [0.16, 0.85], P = 0.02). Cases were also less likely to drool (OR = 0.442, 95% CI [0.218, 0.900], P = 0.032) or be unresponsive for more than one minute (OR = 0.45, 95% CI [0.238, 0.854], P = 0.021). CONCLUSIONS:We report novel associations of febrile seizure and sudden death related to age, development, sleep, and observed ictal features. Anonymous survey methodology cannot exclude ascertainment bias and any related potential effect on results. Our findings suggest that impaired arousal mechanisms may increase risk of death in subjects with febrile seizure.

Sentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. It remains a largely untested assumption that the principles of word production generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where ten patients produced six words in isolation (picture naming) and in sentences (scene description). We trained machine learning classifiers to identify the unique brain activity patterns for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings confirm that words share cortical representations across tasks, but reveal a division of labor within the language network. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in prefrontal cortex, the order in which words were processed depended on the syntactic structure of the sentence. In non-canonical sentences (passives), we further observed a spatial code for syntactic roles, with subjects selectively encoded in inferior frontal gyrus (IFG) and objects selectively encoded in middle frontal gyrus (MFG). We suggest that these complex dynamics of prefrontal cortex may impose a subtle pressure on language evolution, potentially explaining why nearly all the world's languages position subjects before objects.

OBJECTIVE:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs). METHODS:This cross-sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss-Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder. RESULTS:A total of 92 patients were enrolled (age range = 18-51 years, mean = 27.93 ± 8.59 years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty-three percent screened positive for social communication deficits. SIGNIFICANCE/CONCLUSIONS:This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.