An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain.

OBJECTIVE: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD. METHODS: A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays. RESULTS: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF-associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation. INTERPRETATION: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138-153.

Validation and diagnostic utility of the dementia rating scale in a mixed dementia population.

The Dementia Severity Rating Scale (DSRS), a previously validated caregiver-based measure assessing dementia severity, was recently revised to improve clarity. Our study aims included: (1) identifying the DSRS factor structure, (2) examining the relation between neuropsychological measures, the Mini-Mental State Examination, and clinical diagnoses with the DSRS, and (3) determining the clinical utility of the DSRS in a mixed clinical sample. A total of 270 veterans were referred to a cognitive disorders clinic at a VA medical center and completed neuropsychological, affective, and cognitive screening measures. Caregivers completed the DSRS. Principal components analysis identified a 2-factor solution. After controlling for age and education, memory and language were related to the Cognitive factor, whereas attention, processing speed, visuospatial processing, and executive functioning were related to both Cognitive and Self-Care factors. Neither factors correlated with depression. The total DSRS score was able to differentiate patients by the Mini-Mental State Examination scores and diagnoses of mild cognitive impairment and dementia (mixed vascular Alzheimer, vascular dementia, and Alzheimer disease). A cut-score >15 was optimal for detecting dementia in a mixed clinical sample (sensitivity=0.41, specificity=0.79), with a posttest probability of 74%. This study suggests that the DSRS improves detection of dementia and requires minimal effort to implement.

Induction of psychogenic nonepileptic events: success rate influenced by prior induction exposure, ictal semiology, and psychological profiles.

PURPOSE: To evaluate whether certain preinduction clinical characteristics may influence the success rate of induction. METHODS: We prospectively enrolled and attempted inductions on 51 patients who were suspected to have psychogenic nonepileptic events based on clinical grounds. In addition to careful examination of the reported ictal semiology, we administered a battery of four psychological instruments to our enrolled patients. KEY FINDINGS: We found that among 42 cases of successful induction, 92.9% (n=39) of these cases were successfully induced on the first attempt (i.e., without prior induction exposure). We observed that induction showed significantly higher rate of success in cases that demonstrate: (1) hypermotor ictal semiology (p=0.029); (2) more prevalent self-reporting of uncommon cognitive and affective symptoms (p=0.035); or (3) higher tendency to rely on coping strategies of "instrumental support" (p=0.013) and "active coping" (p=0.027), when compared to noninducible cases. SIGNIFICANCE: Singular administration of placebo induction on preselected patients with these clinical characteristics may reduce costs by shortening video electroencephalography-(EEG) monitoring sessions and improve the diagnostic yield of video-EEG even for patients with very infrequent events.