Beyond hypoxic-ischemic encephalopathy: genetic insights and precision diagnosis in neonatal encephalopathies

Neonatal encephalopathies are a heterogeneous group of early-onset neurological disorders. While hypoxic-ischemic encephalopathy (HIE) has long been considered the predominant cause, a growing number of genetic, metabolic, immune-mediated, and toxic etiologies may clinically mimic HIE, posing diagnostic challenges. Timely recognition of these alternative causes is essential to initiate targeted therapies and provide appropriate family counseling. This article reviews the main clinical presentations and pathogenetic mechanisms of neonatal encephalopathies and introduces a structured diagnostic algorithm, presented as a flow chart, to guide neonatologists in early differential diagnosis and precision management of affected newborns.