Exploring the genetic landscape of neurotransmitter alterations in hypoxic-ischemic encephalopathy: A personalized medicine perspective [version 1; peer review: awaiting peer review]

• Published in: F1000 research 2023, Vol.12, p.1450
• Main Authors: GOMEZ-LONDOÑO, DIEGO MAURICIO, TRUJILLO-ARIAS, NATALIA, CARDONA-RAMIREZ, NATALIA, SERRANO, CAROLINA, RESTREPO-RESTREPO, FELIZA, GARCIA ARIAS, HERNAN FELIPE, Estrada-Alvarez, Jorge Mario, Porras-Hurtado, Gloria Liliana
• Format: Article
• Language: English
• ISSN: 2046-1402; 2046-1402
• DOI: 10.12688/f1000research.133853.1

Background: Hypoxic-ischemic encephalopathy (HIE) is a neurological condition due to perinatal asphyxia, affecting brain areas with high metabolic rates and active myelination processes. The HIE has various origins and can be challenging to diagnose and treat. This study aimed to determine the origin of the clinical phenotype of patients who met the criteria for perinatal asphyxia at birth from personalized medicine. Methods: We evaluated 28 patients classified according to the SARNAT scale (i.e., clinical staging of HIE) and neurological anomalies by MRI scans. We used a next-generation sequencing panel for genes related to neurotransmitters and analyzed the statistical association between sequelae and other clinical variables using Fisher's exact test. We also evaluated odds ratios (OR) with 95% confidence intervals by binary logistic regression analysis adjusted for SARNAT, seizure, MRI scans, and genetic findings. Results: We identified 11 patients with neurotransmitter-related genetic alterations, such as glycine encephalopathy. Three had pathogenic variants (ALDH7A1, AMT, and SLC1A4), and eight had uncertain significance (TH, DBH, MYH2, CGH1, SLC6A5, ABAT, ALDH5A1, GLRB). One patient had 8p11.2 deletion, 14q11.2 deletion, and 10q11.22 duplication. Statistical analyses indicated that the presence or absence of mutations had a statistically significant association with sequelae (p-value = 0.054). Patients with a pathogenetic or uncertain mutation are associated with an increased risk of neurological sequelae (OR: 6.43; 95% CI: 1.2 - 51.5; p-value = 0.044) regardless of clinical conditions such as the presence of seizures, severity of encephalopathy, alterations in the RMI or hypothermia therapy. Conclusions: Our findings suggest that neurotransmitter alterations are a critical factor significantly increasing the risk of HIE-related sequelae. Identifying these genetic alterations could lead to earlier and more precise diagnosis and treatment of HIE patients.