Objective Variations in the ATP1A3 gene are associated with a spectrum of neurological disorders, including fever-induced paroxysmal weakness and encephalopathy (FIPWE). However, genotype-phenotype correlations related to ATP1A3 variants remain incompletely understood. Method This study retrospectively analyzed a family affected by FIPWE, the clinical features and genotype-phenotype correlations of the proband, her elder sister and her mother were reviewed. Results The proband was a girl who first presented at the age of 3 years and 4 months with progressive limb weakness following fever. The weakness rapidly involved bulbar and respiratory functions. Neurological examination revealed flaccid paralysis, absent abdominal reflexes and knee-jerk reflexes, and a Babinski sign on the left side. Whole-exome sequencing identified a missense variant in ATP1A3 in the proband, NM_152296.5:c.2267G>A, p.(Arg756His), in which the nucleotide substitution c.2267G>A results in the replacement of arginine by histidine at residue 756. Both the mother and elder sister presented acute neurological impairment similar to that of the proband after infection at preschool and school age respectively, with residual motor dysfunction and dysarthria of varying severity. Sanger sequencing confirmed that both the mother and elder sister carried the same pathogenic ATP1A3 variant. This family demonstrated infection-triggered onset, familial aggregation and genotype-phenotype co-segregation. Conclusion Clinicians should highly suspect FIPWE syndrome in pediatric patients presenting with acute-onset limb weakness and encephalopathy following fever, combined with signs involving both upper and lower motor neurons. The genotype-phenotype correlation of ATP1A3 related disorders is complicated and warrants further investigation.