Genetic causes of acute encephalopathy in adults: beyond inherited metabolic and epileptic disorders

Acute encephalopathy is a widely used term, implying a rapidly progressive multifocal or diffuse brain dysfunction, caused by acute structural disturbance or a myriad of metabolic, toxic, epileptic, or infection-related factors. Apart from the more common acquired causes, a broad range of rare inherited disorders may produce spells of encephalopathy in adulthood, posing diagnostic challenges to clinicians. Among the latter, neurometabolic disorders and epileptic syndromes constitute typical examples. Interestingly, certain genetic entities have the potential to provoke episodic changes of cognition, via alternative, neither metabolic nor epileptic, mechanisms. Our aim is to provide a short and focused overview of their clinicoradiological features and potential pathophysiology. As the neurogenetic landscape is rapidly evolving, it is important to be familiar with these chameleons, in order to provide swift diagnosis and proper genetic counselling. Highlights Approaching a patient with episodic impairment of consciousness is one of the most demanding tasks in the field of clinical neurology. After excluding common and uncommon acquired causes of acute encephalopathy, one should always think of the genetic variants. Among the latter, encephalopathies of metabolic origin due to enzymatic deficiency or mitochondrial dysfunction are commonly analyzed in the literature. Certain genetic diseases without evidence of metabolic alteration or epileptic component should also be considered in differential diagnosis, principally in terms of genetic counselling and preventing, or treating disabling attacks.