The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Sweney, Matthew; Newcomb, Tara; Swoboda, Kathryn J.

doi:10.1016/j.pediatrneurol.2014.09.015

Cited by 133 publications

(122 citation statements)

References 73 publications

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“…Although the three syndromes were originally identified as phenotypically distinct, it has become clear that many patients do not strictly fall into one category or the other, but may have symptoms that fall on a continuous spectrum as well as unique symptoms for individual mutations (Rosewich et al, 2014; Paciorkowski et al, 2015; Sweney et al, 2015; Kanemasa et al, 2016; Liu et al, 2016; Smedemark-Margulies et al, 2016; Sweadner et al, 2016). …”

Section: Disease-causing Mutations In Nak-atpase Alpha Isoformsmentioning

confidence: 99%

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

2017

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The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.

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Section: Disease-causing Mutations In Nak-atpase Alpha Isoformsmentioning

confidence: 99%

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

2017

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“…68 Other paroxysmal movement disorders include hemiplegic migraine and the episodic ataxias. 35,176 A DIAGNOSTIC APPROACH Approaching the epilepsy-dyskinesia spectrum from a diagnostic perspective can be challenging in view of the clinical and genetic heterogeneity, non-specific or atypical presentations, and lack of clinical awareness of rarer entities. 34,175 Finally, ATP1A3 mutations manifest in a broad clinical spectrum encompassing alternating hemiplegia of childhood, rapidonset dystonia-parkinsonism, and epilepsy.…”

Section: Paroxysmal Dyskinesias and Epilepsymentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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“…Pathogenic variants in ATP1A3 have been implicated in a phenotypic spectrum of autosomal dominant disorders including Alternating Hemiplegia of Childhood (AHC, OMIM 614820), Rapid-onset Dystonia-Parkinsonism (RDP, OMIM 128235) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss syndrome (CAPOS syndrome, OMIM 601338) (de Carvalho Aguiar et al, 2004; Demos et al, 2014; Heinzen et al, 2014; Paciorkowski et al, 2015; Rosewich et al, 2012; Sweney, Newcomb, & Swoboda, 2015). Marked genetic heterogeneity exists for AHC and RDP, including possible genotype-phenotype correlation (Yang et al, 2014) and mosaicism (Hully et al, 2017).…”

Section: | Introductionmentioning

confidence: 99%

Novel pregnancy‐triggered episodes of CAPOS syndrome

Chang

Adam

Jayadev

et al. 2017

American J of Med Genetics Pt A

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Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever-induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na /K ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.

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The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Cited by 133 publications

References 73 publications

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

The expanding spectrum of movement disorders in genetic epilepsies

Novel pregnancy‐triggered episodes of CAPOS syndrome

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