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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.
Biela, M, Rydzanicz, M, Szymanska, K, Pieniawska-Smiech, K, Lewandowicz-Uszynska, A, Chruszcz, J, Benben, L, Kuzior-Plawiak, M, Szyld, P, Jakubiak, A, et al
Molecular genetics & genomic medicine. 2021;(9):e1772
Abstract
BACKGROUND Variants in ATP1A3 cause well-known phenotypes-alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype-phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756-two acronyms are proposed for the moment-FIPWE (fever-induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia). MATERIALS AND METHODS Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty-three cases from literature were analyzed to define and strengthen the genotype-phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu). CONCLUSIONS Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements.
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2.
Long-term follow-up and novel genotype-phenotype analysis of monozygotic twins with ATP1A3 mutation in Alternating Hemiplegia of Childhood-2.
Pavone, P, Pappalardo, XG, Incorpora, G, Falsaperla, R, Marino, SD, Corsello, G, Parano, E, Ruggieri, M
European journal of medical genetics. 2020;(8):103957
Abstract
Alternating Hemiplegia of Childhood (AHC) is a rare disorder characterized by frequent, transient attacks of hemiplegia involving either side of the body or both in association to several other disturbances including dystonic spells, abnormal ocular movements, autonomic manifestations, epileptic seizures and cognitive impairment. The clinical manifestations usually start before the age of 18 months. Two forms of the disorder known as AHC-1 (MIM#104290) and AHC-2 (MIM#614820) depends on mutations in ATP1A2 and ATP1A3 genes respectively, with over 75% of AHC caused by a mutation in the ATP1A3 gene. Herewith, we report serial clinical follow-up data of monozygotic (MZ) twin sisters, who presented in early life bath-induced dystonia, signs of acute encephalopathy at the age of 2 years, hemiplegic spells, and motor dysfunction after the age of 3 years, and in young/adult frequent episodes of headache with drastic reduction of paroxysmal motor attacks. The molecular analysis revealed a known pathogenic variant p.Asn773Ser (rs606231437) in ATP1A3 gene associated with an unusual and moderate AHC-2 phenotype, with mild cognitive impairment and lack of epilepsy. The aim of this study is to analyze the clinical phases of the MZ twins, and to investigate the novel genotype-phenotype correlation.
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Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review.
Du, Y, Li, C, Duan, FJ, Zhao, C, Zhang, W
Neuropediatrics. 2020;(3):215-220
Abstract
Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant inheritance disorder caused by ATP1A2 mutation, and the clinical spectrum is heterogeneous even with acute severe encephalopathy. However, up to now, early treatments against acute and severe attacks in FHM2 are still insufficient. Here, we report a 15-year-old female with intellectual disability due to FHM2 caused by a pathogenic ATP1A2 gene mutation, presenting mild-to-moderate headache at the onset, followed by confusion, complete right hemiparalysis, epileptic partial seizures, and conscious disturbance with rapid progression in acute attack. Brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have revealed left extensive cerebral cortex edema, slightly decreased N-acetylaspartate for neuronal damage, and mildly increased lactate acid for mitochondrial dysfunction throughout the hemispheric swollen cortex. The patient is diagnosed as severe encephalopathy caused by FHM2. Based on literature review about pathophysiologic mechanism described in FHM2 recently, we use early treatments including prevention of glutamatergic excitotoxicity and protection of mitochondria function, as well as traditional antimigraine drug. The symptoms are all greatly improved and recovered within a short time, and follow-up MRI also shows complete disappearance of edema throughout the left hemispheric cortex. Altogether, the approach in our case may reduce the severity and duration of encephalopathy effectively, expend therapeutic options, and provide helpful references for acute severe encephalopathy in FHM2.
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4.
Pediatric sporadic hemiplegic migraine (ATP1A2 gene): a case report and brief literature review.
Schwarz, G, Anzalone, N, Baldoli, C, Impellizzeri, M, Minicucci, F, Comi, G, Colombo, B
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(Suppl 1):69-71
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Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review.
Younes, TB, Benrhouma, H, Klaa, H, Rouissi, A, Chaabouni, M, Kraoua, I, Youssef-Turki, IB
Neuropediatrics. 2018;(5):339-341
Abstract
ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child.
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6.
[A childhood-onset rapid-onset dystonia parkinsonism family with ATP1A3 gene mutation and literatures review].
Zhang, CL, Yin, F, He, F, Gai, N, Shi, ZQ, Peng, J
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2017;(4):288-293
Abstract
Objective: To explore clinical characteristics, treatment, and prognosis of a family with childhood-onset rapid-onset dystonia parkinsonism (RDP) caused by ATP1A3 gene mutation and review literatures. Method: The clinical data of a RDP child, his brother and mother had been analyzed retrospectively. This family was admitted to Xiangya Hospital in January 2016. DNA samples were analyzed by the next-generation sequencing and confirmed by Sanger sequencing. Related literature from PubMed, Online Mendelian Inheritance in Man (OMIM), CNKI and Wanfang databases to date (up to October 2016) with"Rapid-onset dystonia-parkinsonism""RDP""DYT12" as key words was reviewed. Result: The proband boy was three years and four months old (April 2015) when he had the first attack of the disease. After a febricity, he suddenly acquired acute aphasia and limb movement disorder. Rehabilitation therapy and supportive treatment made his speech gradually recovered but still slurred. However, his abnormal walking posture still existed. Nine months later (January 2016, 4 years and one months old), symptoms including aphasia, dysphagia, and weakness with rostrocaudal gradient reoccured after fever. The disease progressed to the critical condition within 24 hours. He"seizured" four times with tonic spasms of limbs but without loss of consciousness. Family history showed his grandparents were consanguineous marriage. His mother and brother also developed abnormal gait and dysarthria after an infection before primary school age. Their symptoms improved gradually without relapsing. However, they did not recover entirely with mild intellectual disability. His mother had a healthy brother and sister. This proband had no other siblings but the brother. Heterozygous missense mutation p. R756H in ATP1A3 gene was detected in this proband, his mother and his brother. This mutation had been reported pathogenically related to RDP, and it located in highly conserved gene region. Benzodiazepine was used for the proband and his brother, with the proband being improved better although not completely. Meanwhile, benzodiazepine had no significant effect on his mother because of poor compliance. This is the first case report of RDP in China. The mutations of ATP1A3 have been previously reported in 51 patients including 6 large families and 16 other unrelated patients. A total of 14 different mutations in ATP1A3 gene with RDP have been reported to date, including 12 missense mutations, a 3-bp in-frame deletion, and a 3-bp in-frame insertion. The sporadic cases all had the typical clinical phenotypes of RDP, such as the abrupt onset of dysarthria, dysphagia, limb dystonia with bradykinesia, and postural instability. The symptoms of bulbar and arms were much more obvious. It was hard to diagnose RDP in a family because some patients had typical symptoms of RDP, while the others might experience from mild symptoms to no symptoms, which might be related to incomplete penetrance of RDP. Two cases carrying the same mutation as our patients also presented some overlapping phenotypes. Conclusion: The p. R756H heterozygous mutation in ATP1A3 gene is the pathogenic mutation of RDP, analysis of genotype-phenotype correlations of RDP will be very important and meaningful.
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The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene.
Maas, RP, Schieving, JH, Schouten, M, Kamsteeg, EJ, van de Warrenburg, BP
Pediatric neurology. 2016;:71-75.e1
Abstract
BACKGROUND The clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) was first described 20 years ago, but it was only recently that whole exome sequencing unveiled the causative mutation in the ATP1A3 gene. We present four patients from the seventh and eighth family identified worldwide, provide a critical review of all patients published thus far, and speculate about the pathophysiologic processes underlying the acute neurological manifestations. CLINICAL OBSERVATIONS The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness. An underlying c.2452G>A mutation in the ATP1A3 gene was found in all four individuals. Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes. After initiation of acetazolamide in two patients, no further episodes occurred. CONCLUSION Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss. Similar to some other types of episodic ataxia, acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study.
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Neuronal Na+/K+ ATPase is an autoantibody target in paraneoplastic neurologic syndrome.
Scharf, M, Miske, R, Heidenreich, F, Giess, R, Landwehr, P, Blöcker, IM, Begemann, N, Denno, Y, Tiede, S, Dähnrich, C, et al
Neurology. 2015;(16):1673-9
Abstract
OBJECTIVES To identify an autoreactivity in a 66-year-old woman who presented with combined brainstem and cerebellar syndrome including vertical gaze palsy, severe progressive ataxia, and spastic tetraparesis, an acute deterioration of vision, dysarthria, and dysphagia with concurrent diagnosis of a colon adenocarcinoma. METHODS Patient's serum and CSF underwent comprehensive autoantibody screening by indirect immunofluorescence assay and immunoblot. For autoantigen purification, a histo-immunoprecipitation technique was developed followed by mass spectrometrical analysis. Recombinant candidate antigens were expressed in HEK293 and used to verify the identification. RESULTS Indirect immunofluorescence assay screening revealed strong immunoglobulin G reactivity with neural tissues in serum and CSF, but not with a panel of 28 recombinantly expressed established neural autoantigens. The hitherto unknown target antigen was identified as the neuronal Na(+)/K(+) ATPase. Epitope mapping and competitive inhibition experiments showed that the autoantibodies were directed against the membrane-spanning alpha 3 subunit (ATP1A3) of the enzyme but did not bind to extracellular epitopes. Immunohistochemical analysis revealed overexpression of this subunit in the patient's tumor. CONCLUSIONS We describe a case of an anti-ATP1A3-associated neurologic disorder. Mutations in the gene encoding this neuronal surface protein have already been recognized as the cause of infantile alternating hemiplegia, rapid-onset dystonia parkinsonism, and CAPOS syndrome. Although the autoantibodies are unlikely to be pathogenic, they are likely to be rare biomarkers for the apparently paraneoplastic neurologic syndrome or for the tumor itself.
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Asystole in alternating hemiplegia with de novo ATP1A3 mutation.
Novy, J, McWilliams, E, Sisodiya, SM
European journal of medical genetics. 2014;(1):37-9
Abstract
Alternating hemiplegia is a rare condition presenting with episodes of hemiplegia, epileptic seizures and, at times, dysautonomic attacks. De novo ATP1A3 (Na(+)/K(+) ATPase subunit) mutations were recently found to be the most common cause. We report a patient with alternating hemiplegia with de novo ATP1A3 mutation who experienced new-onset episodes of collapse in early adulthood unrelated to seizures. An implantable cardiac loop recorder documented episodes of asystole up to 5 s long. Subsequently a permanent pacemaker was implanted. ATP1A3 heart expression may be the explanation for the association of alternating hemiplegia and asystole episodes. Alternating hemiplegia has been associated with an increased risk of sudden death and lethal cardiac arrhythmias may be causative. Patients may need referral for appropriate cardiac investigations, especially if there is a change in symptoms. This case highlights the importance of clinical vigilance in patients with alternating hemiplegia.
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ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.
Brashear, A, Mink, JW, Hill, DF, Boggs, N, McCall, WV, Stacy, MA, Snively, B, Light, LS, Sweadner, KJ, Ozelius, LJ, et al
Developmental medicine and child neurology. 2012;(11):1065-7
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Abstract
We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.