ATP1A3 variants are responsible for rare neurological conditions such as Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP), and Cerebellar Ataxia Areflexia Pes Cavus Optic Atrophy and Sensorineural Hearing Loss (CAPOS). Intermediate phenotypes include Relapsing Encephalopathy with Cerebellar Ataxia (RECA) and Fever‐induced Proximal Weakness and Encephalopathy (FIPWE). Acute encephalopathy as a clinical presentation is unusual. We describe three patients with ATP1A3 variants who presented with initial acute encephalopathy, an unusual presentation, to draw clinicians' attention to this lesser-known clinical presentation.

In all these cases, encephalitis, Guillain-Barré syndrome, or rhombencephalitis with ataxia were initially suspected, despite normal MRI and cerebrospinal fluid (CSF) findings. Ultimately, genetic analyses identified an ATP1A3 variant, including Arg756 variants in 2 cases. The first case is a 11-year-old girl with rapid-onset tetraparesis, facial diplegia, dysarthria, dysphagia, and dystonia, with a final diagnosis of RDP. The second patient is a 21-month-old boy who presented with acute cerebellar ataxia, weakness and areflexia, relapsing two times after viral infections. Final diagnosis was RECA. The third patient is a 3-year-old boy who presented with acute quadriplegia, dysarthria, dysphagia, and seizures. Final diagnosis was AHC.

When patients present with a picture of autoimmune encephalitis or polyradiculoneuritis with normal imaging and CSF analysis, and no response to standard anti-inflammatory treatment, a search for ATP1A3 gene mutations should be considered.