Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family

2021 ◽  
Author(s):  
Wen Wei ◽  
Xiu-fen Zheng ◽  
Dan-dan Ruan ◽  
Yu-mian Gan ◽  
Yan-ping Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Neurological Diseases ◽  
Rapid Onset ◽  
Alternating Hemiplegia Of Childhood

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 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.

Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Phenotypic spectrum of ATP1A3-associated disorders

2013 ◽  
Vol 44 (02) ◽  
Author(s):  
K Brockmann ◽  
H Rosewich ◽  
H Thiele ◽  
U Maschke ◽  
P Huppke ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum

CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood

Cephalalgia ◽  
2008 ◽  
Vol 28 (8) ◽  
pp. 887-891 ◽  
Author(s):  
B de Vries ◽  
AH Stam ◽  
F Beker ◽  
AMJM van den Maagdenberg ◽  
KRJ Vanmolkot ◽  
...  
Keyword(s):  
Clinical Features ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Monozygotic Twin ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Mutation Scanning ◽  
Alternating Hemiplegia Of Childhood ◽  
Neurological Phenotype ◽  
Cacna1a Mutation

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

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 Cardiac phenotype in ATP1A3-related syndromes

Neurology ◽  
2020 ◽  
Vol 95 (21) ◽  
pp. e2866-e2879
Author(s):  
Simona Balestrini ◽  
Mohamad A. Mikati ◽  
Reyes Álvarez-García-Rovés ◽  
Michael Carboni ◽  
Arsen S. Hunanyan ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Rapid Onset ◽  
Conduction Delay ◽  
Conduction Abnormality ◽  
Alternating Hemiplegia Of Childhood ◽  
Cardiac Phenotype ◽  
Sequence Of Events ◽  
Cardiac Assessment ◽  
Life Threatening

ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death.ResultsNinety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.ConclusionsWe found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

scholarly journals Alternating Hemiplegia of Childhood With a de Novo Mutation in ATP1A3 and Changes in SLC2A1 Responsive to a Ketogenic Diet

2014 ◽  
Vol 50 (4) ◽  
pp. 377-379 ◽  
Author(s):  
Adriana Ulate-Campos ◽  
Carmen Fons ◽  
Rafael Artuch ◽  
Esperanza Castejón ◽  
Loreto Martorell ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
De Novo ◽  
De Novo Mutation ◽  
Alternating Hemiplegia Of Childhood

scholarly journals De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Aristides Hadjinicolaou ◽  
Kathie J. Ngo ◽  
Daniel Y. Conway ◽  
John P. Provias ◽  
Steven K. Baker ◽  
...  
Keyword(s):  
Network Analysis ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Neurological Diseases ◽  
Patient Data ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Gene Variation ◽  
Transcriptional Signature ◽  
Pathogenic Variants

AbstractPathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

scholarly journals Deep Learning in Brain MRI: Effect of Data Leakage Due to Slice-level Split Using 2D Convolutional Neural Networks

2021 ◽  
Author(s):  
Ekin Yagis ◽  
Selamawet Workalemahu Atnafu ◽  
Alba García Seco de Herrera ◽  
Chiara Marzi ◽  
Marco Giannelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Neural Networks ◽  
Alzheimer's Disease ◽  
Convolutional Neural Networks ◽  
De Novo ◽  
Neurological Diseases ◽  
Brain Mri ◽  
Progression Markers ◽  
Magnetic Resonance Imaging Mri

Abstract In recent years, 2D convolutional neural networks (CNNs) have been extensively used for the diagnosis of neurological diseases from magnetic resonance imaging (MRI) data due to their potential to discern subtle and intricate patterns. Despite the high performances reported in numerous studies, developing CNN models with good generalization abilities is still a challenging task due to possible data leakage introduced during cross-validation (CV). In this study, we quantitatively assessed the effect of a data leakage caused by 3D MRI data splitting based on a 2D slice-level using three 2D CNN models for the classification of patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our experiments showed that slice-level CV erroneously boosted the average slice level accuracy on the test set by 30% on Open Access Series of Imaging Studies (OASIS), 29% on Alzheimer’s Disease Neuroimaging Initiative (ADNI), 48% on Parkinson's Progression Markers Initiative (PPMI) and 55% on a local de-novo PD Versilia dataset. Further tests on a randomly labeled OASIS-derived dataset produced about 96% of (erroneous) accuracy (slice-level split) and 50% accuracy (subject-level split), as expected from a randomized experiment. Overall, the extent of the effect of an erroneous slice-based CV is severe, especially for small datasets.

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