[Clinical and genetic analysis of a child with Relapsing encephalopathy with cerebellar ataxia due to variant of ATP1A3 gene].

To explore the clinical phenotype, genetic characteristics and etiology of a child with Relapsing encephalopathy with cerebellar ataxia (RECA). A child diagnosed with RECA due to variant of ATP1A3 gene at the Affiliated Women and Children's Hospital of Ningbo University in March 2022 was selected as study subject. Cubital vein blood samples were collected from the child and his parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing. Pathogenicity was classified based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2020-048). The proband, a 4-year-and-1-month-old boy, had the onset of RECA at 2 years and 8 months. His clinical manifestations included altered consciousness, weakness, nystagmus, ataxia and dysarthria following a febrile illness. There was no specific laboratory and neuroimaging findings. Video electroencephalogram (VEEG) showed an abnormal childhood EEG with generalized discharge. WES revealed that the child has harbored a heterozygous c.2267G>A (p.Arg756His) variant of the ATP1A3 gene, which was confirmed by Sanger sequencing to be de novo in origin. Based on the ACMG guidelines, the variant was classified as pathogenic (PS2_VeryStrong+PS4+PM5_Strong+PM2_Supporting+PP1_Moderate+PP2+PP3_Moderate). Using the literature search strategy established in this study, 18 eligible articles were retrieved, involving a total of 44 patients with RECA. Together with the proband from this study, a total of 45 cases of ATP1A3 gene-related RECA were analyzed. The patients included 19 males and 26 females. The age at first onset ranged from 4 months to 5 years and 6 months, and all episodes were triggered by febrile illnesses. The most common clinical manifestations were hypotonia and ataxia, followed by disturbance of consciousness, dysarthria, abnormal eye movements, and choreoathetosis. Genetic testing showed c.2267G>A of the ATP1A3 gene to be the most common variant. The c.2267G>A (p.Arg756His) variant of the ATP1A3 gene probably underlay the pathogenesis of RECA in this proband. Above finding has enriched the variant spectrum of the ATP1A3 gene and the clinical phenotype spectrum of patients with ATP1A3 gene-associated RECA.