ClinicalATP1A2 Benefit of NMDA Receptor AntagonistsKeisuke Ueda, MD, Fatema Serajee, MD, in Ahm M. a Huq, Patient MD, PhD With Geneabstract Mutation ATP1A2 Mutations in the gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation.‍ These symptoms are likely related to glutamatergic hyperexcitability.‍ Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty.‍ During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy.‍ His seizures did not respond to several antiepileptic medications but stopped after Division of Neurology, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, he received valproate.‍ His intermittent episodes of hemiplegia persisted.‍ Detroit, Michigan Additionally, he had pronounced bilateral fine motor impairmentATP1A2 and Dr Ueda acquired, analyzed, and interpreted data; significant executive deficitsPOLG that gradually worsened.‍ The whole exome Dr Serajee acquired, analyzed, and interpreted data sequencing revealed a de novo missense mutation in the ATP1A2 gene and a and critically revised the manuscript for intellectual maternally inherited gene mutation of unknown clinical significance.‍ content; Dr Huq acquired, analyzed, and interpreted ’ data and contributed to the study concept and We hypothesized that glutamatergic excitotoxicity due to the design, the critical revision of manuscript for mutation contributed to the pathogenesis of our patient s condition.‍ He was intellectual content, and study supervision; and all started on N-methyl-D-aspartate receptor antagonists (memantine and authors approved the final manuscript as submitted 10 and agree to be accountable for all aspects of the dextromethorphan), as well as coenzyme Q .‍ One year later, he showed work. significant improvement in sustained attention, learning efficiency, general DOI: https:// doi. org/ 10. 1542/ peds. 2017- 0852 cognitive efficiency, and fine motor dexterityATP1A2.‍ We postulate that N-methyl-D- Accepted for publication May 18, 2017 aspartate receptor antagonists were effective for behavioral, cognitive, and Address correspondence to Ahm M. Huq, MD, cerebellar symptoms in our patient with gene mutation.‍ Department of Child Neurology, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201. ATP1A2 E-mail: [email protected] Mutations in the gene are involving alternating body sides; PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). associated with familial hemiplegic episodes of bilateral hemiplegia migraine type 2 (FHM2) and or quadriplegia; generalization of Copyright © 2018 by the American Academy of Pediatrics alternating hemiplegia of childhood a hemiplegic episode or bilateral (AHC), as well as cerebellar function from the beginning of attack; FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships deficits, epilepsy,1, 2 and mental disappearance or relief of symptoms relevant to this article to disclose. retardation.‍ AHC is distinguished on sleeping; other paroxysmal events, FUNDING: No external funding. from familial hemiplegic migraine including dystonia, oculomotor by infantile onset of symptoms and abnormalities, or autonomic POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of a high prevalence of associated3 dysfunction occurring during interest to disclose. evolving neurologic deficits.‍ Families hemiplegic spells or independently; with overlapping features of both and evidence of developmental To cite: Ueda K, Serajee F, Huq AM. Clinical Benefit AHC and FHM2 have been reported, delay or neurologic abnormalities, of NMDA Receptor Antagonists in a Patient With suggesting a possible common 3 including choreoathetosis,4 ataxia, or ATP1A2 Gene Mutation. Pediatrics. 2018;141(s5): pathogenesis in a subset of such cases.‍ cognitive disability.‍ AHC has also e20170852 Diagnostic criteria for AHC include been reported to cause significant onset before the age of 18 months; deficits in intellectual, academic, repeated episodes of hemiplegia memory, attention, and executive Downloaded from www.aappublications.org/news by guest on October 2, 2021 CASE REPORT PEDIATRICS Volume 141, number s5, April 2018:e20170852 functioning, as well as deficits in arising from the left hemisphere.‍ His reading, comprehension, and language,ATP1A2 psychomotor abilities,5 No significant abnormalities were memory performance declined to and psychosocial functioning.‍ found on the computed tomography the point at which he was at least α The gene on chromosome or MRI, but positron emission 2 grades behind in his academic 1q23 encodes the -2 subunit of tomography revealed left posterior performance.‍ A metabolic disease the sodium-potassium+ +adenosine quadrant hypometabolism.‍ He evaluation including lactate, triphosphatase (Na /K ATPase) was diagnosed with focal epilepsy.‍ plasma acylcarnitine profile, pump that is expressed in glial Initially, oxcarbazepine was started serum amino acids, urine organic cells and is involved+ in maintaining with no significant improvement.‍ acids, fatty acid, and phytanic acid sodium+ ion (Na ) and potassium Then, topiramate was started, did not have significant results.‍ ion (K ) gradients across the which decreased the frequency A chromosomal microarray did synaptic+ + cleft.‍ In glial cells, the of his seizures.‍ Topiramate was not reveal any abnormality.‍ Na /K ATPase pump is colocalized later switched to levetiracetam Whole exome sequencing and with the excitatory amino acid and valproate at the same time, bioinformatic analysis based on transporter (EAAT)-1, a glial resulting in seizure cessation.‍ Six various inheritance models of the glutamate transporter, and EAAT-2 6 months later, levetiracetam was proband, mother, and father revealed in the astrocytic+ + plasma membrane.‍ discontinued because of mood ATP1A2a heterozygous, missense mutation The Na and K gradients enable the changes; the patient remained (c.‍879C>G; p.‍I293M) in exon 8 of the EAATs to reuptake glutamate from seizure-free.‍ However, he continued gene (Ensembl Transcript the synaptic6 cleft into neurons and to have the intermittent, self-limited identifier: ENST00000361216.‍7) on astrocytes.‍ Decreased glutamate episodes of getting uncoordinated chromosome 1q21-q23 (Fig 2A).‍ reuptake due to impaired function and flaccid on the right side of the Cosegregation analysis of the of the EAATs results in cortical body.‍ These events were reported mutation in this family revealed that glutamatergic hyperexcitability, to improve after sleep.‍ At the age of the unaffected mother, father, and causing epilepsy,7 episodic ataxia, 6 years, he was successfully weaned brother did not carry this alteration, and hemiplegia.‍ Our hypothesis off valproate.‍ Developmentally, indicating a de novo mutation (Fig 2B).‍ is that the N-methyl-D-aspartateATP1A2 pronounced bilateral fine motor The alteration is not present in (NMDA) receptor antagonists can be impairment was noted.‍ His hand healthy cohorts including those therapeutic for symptoms of started to shake, especially when he from the National Heart, Lung, and gene mutation.‍ We report a case in held a pen or fastened with buttons.‍ Blood Institute Exome Sequencing which NMDAATP1A2 receptor antagonists A neuropsychological evaluation Project (http:// evs.‍gs .‍washington .‍ had clinical benefit in a patient revealed significant executive edu/EVS), 1000 Genomes Project with an gene mutation deficits, such as poor sustained (http:// www.‍internationalgeno me.‍ manifesting hemiplegia, focal attention and impulse control.‍ He org), Exome Aggregation Consortium α epilepsy, and problems in cognition, was started on stimulants and a (http:// exac.‍broadinstitute .‍org), and behavior, and fine motor function.‍ selective 2 adrenergic receptor the Database of Single Nucleotide agonist with mild improvement in Polymorphism (https:// www.‍ CASE REPORT his attention and impulsiveness, ncbi.‍nlm .‍nih .‍gov/ projects/ SNP).‍ but he continued to have difficulties The alteration is predicted to be in reading and writing.‍ His motor deleterious byATP1A2 in silico analysis.‍ Our patient is a 12-year-old boy with coordination and visual-spatial and On the basis of the available a history of complex partial seizures, visual-motor processing skills were evidence, the mutation of attention-deficit/hyperactivity borderline or impaired.‍ Occupational, the patient was considered as a pathogenic mutation.‍ The p.‍I293 disorder, and fine motor difficulty.‍ physical, and speech therapy were α Family history is unremarkable started.‍ At the age of 8 years, he amino acid is located in the third with no consanguinity.‍ At the had an episode of a headache transmembrane segment+ + of the -2 age of 12 months, he had several associated with weakness in the right subunit of the Na /K ATPase pump episodes of a self-resolving right- upper and lower extremities.‍ The and is within the E1-E2 adenosine sided hemiparesis.‍ At the age of 18 headache and weakness resolved triphosphatase domain, which is months, he had 6 seizures consisting within a few hours and did not a functionallyATP1A3 important protein of muscle twitches in the right arm recur.‍ At the age of 11 years, his domain.‍ No mutation was ATP1A3identified and a horizontal conjugate eye handwriting was no longer legible