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

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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ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

Frontiers in Neurology ◽

10.3389/fneur.2021.637890 ◽

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.

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Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity

Neurobiology of Disease ◽

10.1016/j.nbd.2020.105012 ◽

2020 ◽

Vol 143 ◽

pp. 105012 ◽

Cited By ~ 1

Author(s):

Elinor Lazarov ◽

Merle Hillebrand ◽

Simone Schröder ◽

Katharina Ternka ◽

Julia Hofhuis ◽

...

Keyword(s):

Comparative Analysis ◽

Disease Severity ◽

Rapid Onset ◽

Functional Deficits ◽

Alternating Hemiplegia Of Childhood

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Cardiac phenotype in ATP1A3-related syndromes

Neurology ◽

10.1212/wnl.0000000000010794 ◽

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.

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Alternating Hemiplegia of Childhood in a Child Harboring a Novel TBC1D24 Mutation: Case Report and Literature Review

Neuropediatrics ◽

10.1055/s-0041-1739132 ◽

2021 ◽

Author(s):

Ramona Cordani ◽

Livia Pisciotta ◽

Maria Margherita Mancardi ◽

Michela Stagnaro ◽

Giulia Prato ◽

...

Keyword(s):

Case Report ◽

Neurological Disease ◽

Neurological Deficits ◽

Loss Of Consciousness ◽

Gene Variants ◽

Alternating Hemiplegia Of Childhood ◽

Phenotypic Spectrum ◽

Genetics And Genomics ◽

Epilepsy Gene ◽

Main Clinical Manifestation

AbstractAlternating Hemiplegia of Childhood (AHC) is a rare neurological disease characterized by early-onset recurrent paroxysmal events and persistent neurological deficits. TBC1D24 gene variants have been associated with a phenotypic spectrum having epilepsy as the main clinical manifestation. Herein, we report the case of a child affected by developmental delay, polymorphic seizures, and nonepileptic episodes characterized by hemiplegia or bilateral plegia, pallor, hypotonia, and dystonic postures without loss of consciousness that resolved with sleep. Noteworthy, the patient fulfills all the diagnostic criteria for AHC. An epilepsy gene panel revealed a novel TBC1D24 mutation. This variant may be considered a PM5, according to the American College of Medical Genetics and Genomics guidelines. TBC1D24 gene variants are associated with various clinical features, and increasing data confirms the association with permanent and paroxysmal movement disorders. Our report suggests that the TBC1D24 molecular analysis could be considered in the diagnostic workup of AHC patients.

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Expanding Phenotype of ATP1A3 - Related Disorders: A Case Series

Child Neurology Open ◽

10.1177/2329048x211048068 ◽

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.

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