GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/− mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/− males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/− female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/− vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/− mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/− mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE

Facial morphology analysis in osteogenesis imperfecta types I, III and IV using computer vision

Objective Osteogenesis imperfecta (OI) is an autosomal dominant genetic disease that mainly affects the COL1A1/A2 genes. Individuals affected by OI types I, III, and IV have been reported to demonstrate characteristic facial manifestations of the disease. This study aimed to quantitatively assess OI patients' morphological characteristics. Materials and Methods This retrospective case-control study involved 306 individuals (145 male and 161 female). It used automatic facial annotation and statistical shape analysis to compare facial photographs of individuals affected by OI types I, III, and IV with a normocephalic control group. Four facial ratios were used to compare facial proportions. Additionally, we proposed a novel approach to facial analysis using 68 landmarks and statistical shape analysis to compare morphological features. A predictive model (PCALog) was trained to detect whether a subject was affected by OI, based on facial landmarks. Results Our findings correlate with previous reports of OI type III patients' facial characteristics being the most severely affected among the three types studied. Our novel approach facilitated an interpretation and comparison of morphological changes. Moreover, we successfully trained our PCALog model to automatically detect OI based on landmark features. Conclusion We found patients' facial manifestations of OI to be more pronounced at the level of the eyes and temples. Our morphological approach facilitates the comparison of various groups and should be considered for future craniofacial analysis studies. Machine learning models can be trained using facial landmarks to detect the presence of conditions that affect facial morphology