No abstract

Brain insults, including neurotrauma, infection, and perinatal injuries such as hypoxic ischemic encephalopathy, generate inflammation in the brain. These inflammatory cascades induce a wide spectrum of cytokines, which can cause neuron degeneration, have neurotoxic effects on brain tissue, and lead to the development of seizures, even if they are subclinical and occur at birth. Cytokines are secreted by the glial cells of the central nervous system and they function as immune system mediators. Cytokines can be proinflammatory or anti-inflammatory. Interleukin (IL)-1β and IL-8 are proinflammatory cytokines that activate additional cytokine cascades and increase seizure susceptibility and organ damage, whereas IL-1 receptor antagonist and IL-10 act as anti-inflammatory cytokines that have protective and anticonvulsant effects. Therefore, the immune system and its associated inflammatory reactions appear to play an important role in brain damage. Whether cytokine release is relevant for the processes of epileptogenesis and antiepileptogenesis, and whether epileptogenesis could be prevented by immunomodulatory treatment should be addressed in future clinical studies. Furthermore, early detection of brain damage and early intervention are essential for the prevention of disease progression and further neurological complications. Therefore, cytokines might be useful as biomarkers for earlier detection of brain damage in high-risk infants.

Background To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). Methods We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. Results A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. Conclusions Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.