Eye Movement and Lid Disorders in Patients With Alternating Hemiplegia of Childhood due to ATP1A3 Gene Variants
Abdulaziz Al-Abdulghani1, Claudio DeGusmao2, Michael Brodsky3, David Zee4, Fernando Kok5, Matheus A. A. Castro5, Ganeshwaran H. Mochida6, Janet Rucker1
1NYU Langone Health, 2Mass General Brigham, 3Mayo Clinic, 4Johns Hopkins Hospital, 5University of São Paulo, 6Boston Children's Hospital / Mass General Brigham
Background:
ATP1A3 gene pathogenic variants cause heterogeneous neurological phenotypes, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Paroxysmal neurological episodes—such as hemiplegia, dystonia, ataxia, and seizure-like events— are common; progressive findings include developmental delay and cognitive impairment. Hours-long ocular motor episodes are reported; however, they have not been systematically characterized.
Design/Methods:
Home videos of 29 abnormal eye movement episodes from 11 AHC patients with pathogenic variants in ATP1A3 were analyzed and categorized.
Results:
Monocular deviation/strabismus (MD/S) occurred in 34% of episodes (n=7 exo, 2 eso, 1 hyper), conjugate tonic gaze deviation in 31%, and nystagmus in 17% (n=3 downbeat, 1 upbeat, 1 right beat). Lid findings (all co-existing with abnormal eye movements) included ptosis in 31% of episodes and dynamic lid movements (e.g., excess blinking, lid twitches/flutters) in 31%. In the 7 patients with MD/S and exotropia, all exhibited a unique eye movement, consisting of sudden large abduction of one eye accompanied by dissociated nystagmus/saccadic pulses in the abducting eye. Four additional patients had unidirectional horizontal saccadic pulses without prominent ocular misalignment.
Conclusions:
This study provides detailed analysis of episodic ocular motor and lid abnormalities in ATP1A3-related AHC. The diversity of findings highlights the phenotypic complexity of paroxysms, though most eye movements could be categorized into monocular gaze deviations, conjugate tonic gaze deviations, or classic nystagmus patterns. Several other disorders can also cause paroxysmal conjugate gaze deviations or nystagmus; however, the abrupt onset of monocular abduction accompanied by abducting saccadic pulses is unique, and possibly pathognomonic for AHC. Hypothetical mechanisms for this type of event may include third nerve or medial longitudinal fasciculus hypofunction, sixth nerve activation, or aberrant innervation between the two.
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