Chinese patients with p.Arg756 mutations of ATP1A3: Clinical manifestations, treatment, and follow‐up

Abstract

Importance The phenotypes of ATP1A3 gene mutations are diverse. Relapsing encephalopathy with cerebellar ataxia and fever‐induced paroxysmal weakness and encephalopathy (FIPWE) are considered non‐classical phenotypes caused by p.Arg756 mutations of ATP1A3. Objective To summarize the clinical manifestations, treatment, and follow‐up of Chinese patients with p.Arg756 mutations of ATP1A3. Methods We analyzed the clinical features, treatment, and genotypes of eight children with p.Arg756 mutations of ATP1A3 who were treated in Beijing Children's Hospital from January 2014 to December 2019. Results Eight patients (six boys and two girls) were included; seven had been misdiagnosed with encephalitis. The age of onset ranged from 0.8 to 4.5 years. All patients had encephalopathy and had at least one episode of FIPWE. Cerebellar ataxia was present in nine episodes. Reversible splenial lesions of the corpus callosum were found in two patients in the acute phase. Three types of heterozygous ATP1A3 mutations were found: c.2267G > T (p.R756L) (patient 3 [P3]), c.2266C > T (p.R756C) (P2 and P4), and c.2267G > A (p.R756H) (P1, P5, P6, P7, and P8). Six mutations were de novo; two mutations were inherited. Both patients with p.R756C and one patient (P7) with p.R756H had four episodes of severe ataxia as the main manifestations. However, in the other three episodes, limb weakness was more prominent than ataxia. P5 with p.R756H exhibited overlap with FIPWE and rapid‐onset dystonia‐parkinsonism. Interpretation Acute encephalopathy followed by febrile disease was characteristic of the disease in patients with p.Arg756 mutations of ATP1A3. However, the weakness and ataxia were variable. Phenotypic crossover and overlap were observed among these patients.

Temperature instability of a mutation at a multidomain junction in Na,K-ATPase isoform ATP1A3 (p.Arg756His) produces a fever-induced neurological syndrome

“…When histidine is substituted for arginine in the crystal structure, three out of six rotamers clash with the carbonyl of G358, and the other three clash with the side chain of I821. When cysteine is substituted, one of three rotamers produces a hydrogen bond between the sulfur group and the carbonyl of G358, as also noted in a recent case report ( 19 ), and the other two rotamers do not clash. When leucine is substituted, one of four rotamers clashes with the carbonyl of V752, which also normally forms a backbone α-helical hydrogen bond with it.…”

ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever

“…This syndrome has displayed a strong genotype-phenotype correlation with p.R756H, p.R756C, or p.R756L variants in more than 10 independent reports to date from our group and others. 14 , 35 – 51 Remarkably, fever consistently precedes encephalopathic episodes among all these patients, suggesting that hyperthermia or infection/inflammation could be specific triggers. p.R756H was recently discovered to induce misfolding of ATP1A3 at elevated temperatures, providing a biochemical explanation for intermittent hyperthermia-triggered symptoms in these patients.…”