Colin Wilbur1, Sarah E Buerki1, Ilaria Guella2, Eric B Toyota1, Daniel M Evans2, Marna B McKenzie2, Anita Datta1, Aspasia Michoulas1, Shelin Adam3, Margot I Van Allen3, Tanya N Nelson4, Matthew J Farrer2, Mary B Connolly1, Michelle Demos5. 1. Division of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada. 2. Department of Medical Genetics, Centre for Applied Neurogenetics (CAN), University of British Columbia, Vancouver, British Columbia, Canada. 3. Department of Medical Genetics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada. 4. Department of Pathology, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada; Department of Laboratory Medicine, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada. 5. Division of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada. Electronic address: mdemos@cw.bc.ca.
Abstract
BACKGROUND: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described. PATIENT DESCRIPTION: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis. RESULTS: Whole-exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred. CONCLUSIONS: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management.
BACKGROUND: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described. PATIENT DESCRIPTION: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis. RESULTS: Whole-exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred. CONCLUSIONS: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management.
Authors: Juan L García-Hernández; Luis A Corchete; Íñigo Marcos-Alcalde; Paulino Gómez-Puertas; Carmen Fons; Pedro A Lazo Journal: Hum Genomics Date: 2021-02-08 Impact factor: 4.639
Authors: Hadley Stevens Smith; J Michael Swint; Seema R Lalani; Jose-Miguel Yamal; Marcia C de Oliveira Otto; Stephan Castellanos; Amy Taylor; Brendan H Lee; Heidi V Russell Journal: Genet Med Date: 2018-05-14 Impact factor: 8.822