Research conference summary from the 2014 International Task Force on ATP1A3 -Related Disorders

Abstract

Objective:ATP1A3-related neurologic disorders encompass a broad range of phenotypes that extend well beyond initial phenotypic criteria associated with alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism.Methods:In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with ATP1A3-related disorders.Results:Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts.Conclusions:This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possible ATP1A3 mutations, providing recommendations for genetic testing, and outlining initial acute management for common recurrent clinical conditions, including epilepsy.

Novel pregnancy‐triggered episodes of CAPOS syndrome

“…Atypical and overlapping features of AHC, RDP, and CAPOS syndrome with intermediate phenotypes have been reported in patients with novel variants p.Arg756His and p.Arg756Cys in ATP1A3 (Jaffer et al, 2017; Kanemasa et al, 2016). While clinical diagnostic criteria for AHC and RDP have been established, supportive features remain the only diagnostic clues for CAPOS syndrome (Rosewich et al, 2017). We propose widening of these criteria to recommend targeted sequencing of ATP1A3 in any patient presenting with cerebellar ataxia triggered by a febrile illness, especially in the presence of any or all of the following: sensorineural hearing loss, optic atrophy, and pes cavus.…”

Phenotypes, genotypes, and the management of paroxysmal movement disorders

“…ATP1A3 mutations also cause rapid‐onset dystonia Parkinsonism (previously called DYT12 , OMIM #128235), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (OMIM #601338). Although rapid‐onset dystonia Parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss themselves do not manifest with paroxysmal dystonia, there is a growing notion that ATP1A3 mutations cause various intermediate phenotypes with clinical overlap …”

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

“…3 Since then, the original criteria were periodically updated, in order to support clinical recognition of this peculiar neurodevelopmental disorder. [4][5][6][7] In 2012, two independent research groupsan international consortium 8 and a German group 9identified de novo heterozygous mutations in the ATP1A3 as the cause of AHC. Soon after, a Japanese study replicated this finding, 10 providing further evidence that ATP1A3 mutations causing AHC.…”