The present 7-year-old boy was the third offspring of healthy non-consanguineous parents. He was born at 38 weeks of gestational age, weighing 3376 g. No asphyxia or other perinatal events were noted. He was able to control his head at 5 months, sat independently at 8 months, and walked at 14 months of age. When he was infected with influenza at 1 year and 5 months of age, generalized hypotonia and flaccid paralysis rapidly developed within a few hours on the second day of illness. When he was taken by ambulance to the hospital, his respiratory conditions and heart rate were unaltered, but all of his voluntary movements of the eyes, mouth, limbs, and trunk had disappeared. Both eyes remained open, but no verbal or non-verbal responses were made to external stimuli. Bouncing and rapid oculogyric movements in random directions were also prominent signs on admission. Muscle hypotonia was remarkable, while deep tendon reflexes were absent. Hypoglycemia, acidosis, and unbalanced electrolytes were excluded based on the findings of blood gas analyses, blood cell counts, and serum chemistry. Brain magnetic resonance imaging (MRI) showed no parenchymal lesions or atrophy. Single-photon emission tomography detected laterality in cerebral blood perfusion on the 22nd day of admission. Electroencephalogram (EEG) did not show any high-voltage slow waves, epileptiform discharges, or other signs of encephalopathy. From the third week of admission, he began to show voluntary movements in his mouth and hands. Concurrently, choreoathetotic movements in the upper and lower extremities appeared and subsequently continued for over 6 years, until the present. Accordingly, his muscle strength slowly recovered within 2–3 months after the onset, but it never returned to the prior condition. The rapid and random ocular movements were substantially ameliorated within a month and eventually disappeared at 5 years. No signs of cerebellar ataxia were evident throughout the initial admission and thereafter. He had experienced three episodes of recurrent attacks with flaccid paralysis on febrile illness at 1.9, 3.3, and 5.7 years of age (Additional file: Figure S1). In each episode, the involuntary movements disappeared while generalized paralysis persisted for a few weeks. Electroencephalogram (EEG) and MRI studies did not show signs of encephalopathy or neuro-degeneration (data not shown). He had occasional anuresis without signs of paralysis or fever, but his vesicorectal functions were evaluated as normal. At present, he is unable to stand or walk alone, and his daily activity is limited since he uses a wheelchair. His verbal skill is severely affected by dysarthria, but he can compose sentences and perform single-digit calculations using a touch-panel display and keyboard. As such, his language perception, social skills, and other cognitive functions were considered minimally affected. He has had no arrhythmic episodes or shown any abnormal features on electrocardiography. After filtering the polymorphic variations from the WES dataset, we identified two de novo mutations in the coding regions of ATP1A3 (c.2266C > T:p.R756C) and TOM1L1 (p.Gly4Alafs*16) and one intronic deletion in C3 (c.1976-22_20TCTdel). All of these mutations were validated by the Sanger method. We considered that the de novo missense mutation of ATP1A3 was likely pathogenic in this case, whereas the effects of the other two events remain to be determined. The variant sequence in ATP1A3 encodes the protein with an amino acid substitution of Arg756 with Cys. The amino acid residue is located within a conserved sequence across species and was predicted to be deleterious with the Polyphen-2 (), Sift (), and Mutation Taster () programs (Additional file: Table S5). We further ensured that this mutation was absent in more than 500 healthy individuals. Across the whole protein structure of ATP1A3 (), the Arg756 residue was located close to the junction of the largest cytoplasmic loop and the fifth trans-membrane domain. The p.R756H mutation, previously reported, causes atypical phenotypes of RPD []. Recently, another case carrying a de novo p.R756C mutation was shown to have similar clinical features to the present case []. To compare the phenotypic spectra of ATP1A3-assocaited disorders, we summarized the clinical features of the reported cases and those of AHC, RDP, and CAPOS. The three cases carrying mutations of p.Arg756 to Cys or His all shared the core symptoms of recurrent encephalopathy and acutely developed paralysis followed by prolonged hypotonia, dystonia, and choreoathetosis. We also verified that these cases presented with the mixed phenotypes of AHC, RDP, and CAPOS. Previous studies suggested that RDP-causing mutations were associated with unstable expression of mutant ATP1A3 proteins in cultured cells. We therefore investigated whether or not the p.R756C mutation of ATP1A3 might be expressed at a lower level in HEK293T cells than the wild type and the typical AHC-causing mutant protein (p.D801N). Western blotting showed that the wild type and the two mutant ATP1A3 proteins (p.D801 and p.R756C) were expressed at comparable levels.