Short Report: Clinical Features and Epilepsy Monitoring in an Adult With 22q11.2 Deletion Syndrome.

Background: 22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100 000 live births, and it is a multisystem condition with variable phenotypic presentations. Methods: We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms. Results: Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2 Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome. Conclusion: Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician.

Development of an objective method to quantify hippocampal dentation.

Hippocampal dentation (HD) refers to a series of ridges (dentes) seen on the inferior aspect of the hippocampus. The degree of HD varies dramatically across healthy individuals, and hippocampal pathology may result in loss of HD. Existing studies show associations between HD and memory performance in healthy adults as well as temporal lobe epilepsy (TLE) patients. However, until now studies relied on visual assessment of HD as no objective methods to quantify HD have been described. In this work, we describe a method to objectively quantify HD by transforming the characteristic 3D surface morphology of HD into a simplified 2D plot for which area under the curve (AUC) was calculated. This was applied to T1w scans of 59 TLE subjects, each with one epileptic hippocampus and one normal appearing hippocampus. Results showed that AUC significantly correlated with the number of dentes based on visual inspection (p < .05) and correctly sorted a set of hippocampi from least to most prominently dentated. Intra- and inter-rater reliability was nearly perfect (ICC ≥ 0.99). AUC values were significantly lower in epileptic hippocampi compared to contralateral hippocampi (p = .00019), consistent with previously published findings. In the left TLE group, the AUC values from the contralateral hippocampi showed a positive trend (p = .07) with verbal memory acquisition scores but was not statistically significant. The proposed approach is the first objective, quantitative measurement of dentation described in the literature. The AUC values numerically capture the complex surface contour information of HD and will enable future study of this interesting morphologic feature.

Loss of hippocampal dentation in hippocampal sclerosis and its relationship to memory dysfunction.

OBJECTIVE: Hippocampal dentation (HD) is a "toothlike" morphological feature observed on the inferior aspect of the human hippocampus. It has been found that HD varies dramatically in healthy adults and is positively associated with verbal and visual memory. In this work, we evaluate the loss of HD and its association with memory dysfunction in patients with temporal lobe epilepsy (TLE) who have hippocampal sclerosis (HS). METHODS: Fifty-eight unilateral HS patients with neuropsychological data were identified from a retrospective database. T1-weighted magnetization-prepared rapid acquisition gradient echo images (~1 mm resolution) were upsampled to .25 mm and were processed using ASHS software to obtain ultra-high-resolution segmentations and three-dimensional renderings. Dentes were counted on the epileptic and contralateral sides, and associations were tested between dentation on the epileptic versus contralateral sides and measures of verbal and visuospatial memory with respect to the dominant versus nondominant hemisphere. RESULTS: The median number of dentes in epileptic hippocampi was significantly lower than in contralateral hippocampi (p < .0001). Among cases with HS in the dominant hemisphere, verbal memory was significantly correlated with contralateral nondominant hemisphere dentation (r = .43, p = .04). Similarly, among cases of HS in the nondominant hemisphere, visual memory was significantly correlated with contralateral dominant hemisphere dentation (r = .48, p = .04). All other analyses were not significant. SIGNIFICANCE: This is the first study characterizing dentation in TLE patients with HS and its memory correlates. There is marked loss of dentation in sclerotic hippocampi compared to the unaffected contralateral hippocampi. Material-specific measures of memory performance are paradoxically correlated with dentation contralateral to the side with HS, suggesting that contralateral functional capacity explains some of the variation in memory across TLE patients. HD is an important variable to consider in understanding memory loss in TLE.

Fluorinated Alcohols' Effects on Lipid Bilayer Properties.

Fluorinated alcohols (fluoroalcohols) have physicochemical properties that make them excellent solvents of peptides, proteins, and other compounds. Like other alcohols, fluoroalcohols also alter membrane protein function and lipid bilayer properties and stability. Thus, the questions arise: how potent are fluoroalcohols as lipid-bilayer-perturbing compounds, could small residual amounts that remain after adding compounds dissolved in fluoroalcohols alter lipid bilayer properties sufficiently to affect membranes and membrane protein function, and do they behave like other alcohols? To address these questions, we used a gramicidin-based fluorescence assay to determine the bilayer-modifying potency of selected fluoroalcohols: trifluoroethanol (TFE), HFIP, and perfluoro-tert-butanol (PFTB). These fluoroalcohols alter bilayer properties in the low (PFTB) to high (TFE) mM range. Using the same assay, we determined the bilayer partitioning of the alcohols. When referenced to the aqueous concentrations, the fluoroalcohols are more bilayer perturbing than their nonfluorinated counterparts, with the largest fluoroalcohol, PFTB, being the most potent and the smallest, TFE, the least. When referenced to the mole fractions in the membrane, however, the fluoroalcohols have equal or lesser bilayer-perturbing potency than their nonfluorinated counterparts, with TFE being more bilayer perturbing than PFTB. We compared the fluoroalcohols' molecular level bilayer interactions using atomistic molecular dynamics simulations and showed how, at higher concentrations, they can cause bilayer breakdown using absorbance measurements and 31P nuclear magnetic resonance.

The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.