scholarly journals De novo ATP1A3 variants cause polymicrogyria

2021 ◽  
Vol 7 (13) ◽  
pp. eabd2368
Author(s):  
Satoko Miyatake ◽  
Mitsuhiro Kato ◽  
Takuma Kumamoto ◽  
Tomonori Hirose ◽  
Eriko Koshimizu ◽  
...  
Keyword(s):  
De Novo ◽  
Sensorineural Deafness ◽  
Rapid Onset ◽  
Severe Form ◽  
Brain Diseases ◽  
Pes Cavus ◽  
Cortical Malformation ◽  
Alternating Hemiplegia Of Childhood ◽  
Whole Exome ◽  
Malformation Of Cortical Development

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

scholarly journals ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

2021 ◽  
Vol 12 ◽  
Author(s):  
Philippe A. Salles ◽  
Ignacio F. Mata ◽  
Tobias Brünger ◽  
Dennis Lal ◽  
Hubert H. Fernandez
Keyword(s):  
Original Description ◽  
Rapid Onset ◽  
Acute Onset ◽  
Clinical Spectrum ◽  
Pes Cavus ◽  
Sodium Potassium ◽  
Pathogenic Variants ◽  
Alternating Hemiplegia Of Childhood ◽  
The Central Nervous System ◽  
Neurological Features

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.

scholarly journals Expanding Phenotype of ATP1A3 - Related Disorders: A Case Series

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110480
Author(s):  
Jelena De Vrieze ◽  
Ingrid M.B.H. van de Laar ◽  
Johanneke F. de Rijk-van Andel ◽  
Erik-Jan Kamsteeg ◽  
Irene A.W. Kotsopoulos ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Cerebellar Ataxia ◽  
De Novo ◽  
Early Stage ◽  
Case Series ◽  
Rapid Onset ◽  
Sudden Onset ◽  
Intermediate Phenotype ◽  
Alternating Hemiplegia Of Childhood ◽  
Neurologic Disorders

Neurologic disorders caused by mutations in the ATP1A3 gene were originally reported as three distinct rare clinical syndromes: Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Opticus atrophy and Sensorineural hearing loss (CAPOS). In this case series, we describe 3 patients. A mother and her daughter showed an intermediate phenotype different from each other with the same heterozygous missense mutation (p.[R756C]), recently described in literature as Relapsing Encephalopathy With Cerebellar Ataxia (RECA). In addition, a third patient showed an intermediate AHC-RDP phenotype and had a likely pathogenic novel de novo missense mutation (p.[L100 V]). These patients support the growing evidence that AHC, RDP and RECA are part of a continuous ATP1A3 mutation spectrum that is still expanding. Three common features were a sudden onset, asymmetrical neurological symptoms, as well as the presence of triggering factors. When present, the authors argue to perform exome sequencing in an early stage.

scholarly journals Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families

2021 ◽  
Vol 8 ◽  
Author(s):  
Sukun Luo ◽  
Luyi Chen ◽  
Weizhong Wei ◽  
Li Tan ◽  
Meng Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Heart Defects ◽  
Genetic Diagnosis ◽  
Severe Form ◽  
Left Heart ◽  
Whole Exome ◽  
Number Variation ◽  
Cardiovascular Defects ◽  
First Time ◽  
Generation Sequencing

Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive.Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed.Results: All the three couples had no family history, and mid-gestation ultrasound revealed LHH and other variable cardiovascular defects in the fetuses. Trio-WES revealed de novo pathogenic variations in KMT2D (p.Gly3465Aspfs*37) (NM_003482) and WDFY3 (p.Ser117Xfs*) (NM_014991), and CNV-seq identified a deletion of 150 kb encompassing NOTCH1. KMT2D and NOTCH1 previously have been reported to be associated with CHDs, however, WDFY3 is reported for the first time to be possibly related to CHD in human.Conclusion: Our study suggested that genetic component is an important risk factor for the development of LHH, and next generation sequencing is a powerful tool for genetic diagnosis in fetuses with CHDs and genetic counseling, however, more studies and data are need to establish the correlation of fetal phenotypes and genotypes.

Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review

2018 ◽  
Vol 49 (05) ◽  
pp. 339-341 ◽  
Author(s):  
Hanene Benrhouma ◽  
Hedia Klaa ◽  
Aida Rouissi ◽  
Myriam Chaabouni ◽  
Ichraf Kraoua ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Neurological Disorders ◽  
Early Life ◽  
Rapid Onset ◽  
Diverse Group ◽  
Pediatric Case ◽  
Pes Cavus ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum

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.

Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study

2012 ◽  
Vol 11 (9) ◽  
pp. 764-773 ◽  
Author(s):  
Hendrik Rosewich ◽  
Holger Thiele ◽  
Andreas Ohlenbusch ◽  
Ulrike Maschke ◽  
Janine Altmüller ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Gene Identification ◽  
De Novo Mutations ◽  
Alternating Hemiplegia Of Childhood ◽  
Whole Exome

scholarly journals A case report of atypical hemiplegic migraine with nonheadache onset in a Chinese child

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hui Chen ◽  
Xiaolan Sun ◽  
Ruiyan Wang ◽  
Zhaoshi Yi ◽  
Zhixin Huang ◽  
...  
Keyword(s):  
De Novo ◽  
Chinese Child ◽  
Hemiplegic Migraine ◽  
Motor Weakness ◽  
Alternating Hemiplegia Of Childhood ◽  
Whole Exome ◽  
Initial Stage ◽  
Atp1a2 Gene ◽  
Magnetic Resonance Imaging Mri ◽  
Core Symptoms

Abstract Background Hemiplegic migraine (HM) is an uncommon subtype of migraine with aura including motor weakness. The core symptoms of HM are headache and motor weakness. However, we report a rare case of atypical HM with nonheadache onset in a Chinese child who was misdiagnosed several times. Case presentation We report a Chinese boy whose onset was sudden when he was 3 years old. He presented with a variety of phenotypes, including fever, vomiting, alternating hemiplegia, and drowsiness, but no headache in the initial stages. Magnetic resonance imaging (MRI) demonstrated unilateral cerebral oedema during the initial episode of hemiplegia. These symptoms recurred many times. As the disease progressed, the patient developed episodic headache. The patient was misdiagnosed several times with encephalitis, alternating hemiplegia of childhood (AHC) and mitochondrial encephalopathy. Whole-exome next-generation sequencing revealed a de novo heterozygous missense mutation in the ATP1A2 gene(p.Gly715Arg) classified as pathogenic and eventually led to a diagnosis of HM when he was 11 years old. Flunarizine was subsequently administered, and no recurrence was found during follow-up. Conclusions HM in children may be atypical in the initial stage of the disease, which could manifest as fever, alternating hemiplegia and drowsiness but no headache at the onset. This could easily lead to misdiagnosis. With age, it may eventually manifest as typical HM. Therefore, attention should be given to differentiation in clinical practice.When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment.

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