Variants of <i>ATP1A3</i> in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)—Report of two cases and literature review

Biela, Mateusz; Rydzanicz, Małgorzata; Sztefko, Krystyna; Pieniawska-Śmiech, Karolina; Lewandowicz-Uszyńska, Aleksandra; Chruszcz, Joanna; Benben, Lucyna; Kuzior-Plawiak, Malgorzata; Szyld, Pawel; Jakubiak, Aleksandra; Szenborn, Leszek; Płoski, Rafał; Śmigiel, Robert

doi:10.1002/mgg3.1772

Cited by 12 publications

(11 citation statements)

References 20 publications

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“…In our study, most patients had their first fever‐induced episode before 3 years of age. All of the patients had encephalopathy, which was significantly higher than the proportion of such patients in a previous report (50%) 11 . This is presumably because our hospital is a national children's medical center; thus, all referred patients are in critical condition.…”

Section: Discussioncontrasting

confidence: 53%

“…Three genotypes of Arg756 mutations have been reported: c.2267G > T (p.R756L), c.2266C > T (p.R756C), and c.2267G > A (p.R756H)-most of these mutations are de novo. 2,3,6,[11][12][13][14][15][16][17][18][19][20][21][22][23] Kanemasa et al 6 showed that the expression level was similar between the p.R756C mutant protein and the wild-type protein in transfected HEK293T cells; this implied that the mutation modulates the activity of the Na + /K + -ATPase pump. Arg756 is located within a sequence conserved across species.…”

Section: Discussionmentioning

confidence: 99%

“…All of the patients had encephalopathy, which was significantly higher than the proportion of such patients in a previous report (50%). 11 This is presumably because our hospital is a national children's medical center; thus, all referred patients are in critical condition. Other clinical features varied among our patients.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Zhuo

et al. 2022

Pediatric Investigation

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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.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Zhuo

et al. 2022

Pediatric Investigation

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“…Mutations in the ATPA1A3 gene clinically present with multiple phenotypes including alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome and early-infantile epileptic encephalopathy. Specific ATPA1A3 variants may cause acute encephalopathy: relapsing encephalopathy with cerebellar ataxia ( Dard et al, 2015 ; Biela et al, 2021 ).…”

Section: Susceptibility Genesmentioning

confidence: 99%

Genetic and environmental risk factors of acute infection-triggered encephalopathy

et al. 2023

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Acute encephalopathy is a constellation of syndromes in which immune response, metabolism and neuronal excitation are affected in a variable fashion. Most of the syndromes are complex disorders, caused or aggravated by multiple, genetic and environmental risk factors. Environmental factors include pathogenic microorganisms of the antecedent infection such as influenza virus, human herpesvirus-6 and enterohemorrhagic Escherichia coli, and drugs such as non-steroidal anti-inflammatory drugs, valproate and theophylline. Genetic factors include mutations such as rare variants of the SCN1A and RANBP2 genes, and polymorphisms such as thermolabile CPT2 variants and HLA genotypes. By altering immune response, metabolism or neuronal excitation, these factors complicate the pathologic process. On the other hand, some of them could provide promising targets to prevent or treat acute encephalopathy.

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“…It encodes a neuron-specific P-type Na+/K+ ATPase that is closely related to the sodium-coupled transport of a variety of organic and inorganic molecules, osmoregulation, and electrical excitability of nerves and muscles (Heinzen et al, 2014 ). ATP1A3 variation is also the primary cause of alternating hemiplegia of childhood (AHC), Relapsing encephalopathy with cerebellar ataxia (RECA) (Dard et al, 2015 ; Biela et al, 2021 ), early onset epileptic encephalopathy (Paciorkowski et al, 2015 ; Schirinzi et al, 2018 ), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) (Heinzen et al, 2012 ). The clinical phenotype of AHC is characterized by recurrent episodes of hemiplegia and dystonia alternating in laterality, and the onset age is usually before 18 months (Rosewich et al, 2012 ), which is quite different from RDP.…”

Section: Introductionmentioning

confidence: 99%

ATP1A3 mutation in rapid-onset dystonia parkinsonism: New data and genotype-phenotype correlation analysis

Peng

Yuan

et al. 2022

Front. Aging Neurosci.

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BackgroundRapid-onset dystonia parkinsonism (RDP) is a rare disease caused by ATP1A3 mutation with considerable clinical heterogeneity. Increased knowledge of RDP could be beneficial in its early diagnosis and treatment.ObjectiveThis study aimed to summarize the gene mutation spectrum of ATP1A3 associated with RDP, and to explore the correlation of ATP1A3 variants with RDP clinical phenotypes.MethodsIn this study, we reported two RDP patients from a family with a novel inherited ATP1A3 variant. Then, we reviewed and analyzed the available literature in English focused on ATP1A3-causative RDP. A total of 35 articles covering 15 families (59 patients) and 36 sporadic RDP cases were included in our analysis.ResultsThe variant A813V (2438C>T) in ATP1A3 found in our cases was a novel mutant. Delays in diagnosis were common, with a mean delay time of 14 years. ATP1A3 had distinct RDP-related mutation hotspots, which consisted of exon8, 14, 17, and 18, and the most frequently occurring variants were T613M and I578S. Approximately 74.5% of patients have specific triggers before disease onset, and 82.1% of RDPs have stable symptoms within 1 month. The incidence rates of dystonia and bradykinesia are 100 and 88.1%, respectively. The onset site varied and exhibited a rostrocaudal gradient distribution pattern in 45% of patients with RDP. Approximately 63.6% of patients had mild improvement after receiving comprehensive interventions, especially in gait disturbance amelioration.ConclusionIn patients with acute and unexplained dystonia or bradykinesia, gene screening on ATP1A3 should be timely performed. When a diagnosis has been made, treatments that may be effective are to be attempted. Our study would be helpful for the early diagnosis and treatment of ATP1T3-related RDP.

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Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)—Report of two cases and literature review

Cited by 12 publications

References 20 publications

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

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

Genetic and environmental risk factors of acute infection-triggered encephalopathy

ATP1A3 mutation in rapid-onset dystonia parkinsonism: New data and genotype-phenotype correlation analysis

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