Mutations in the ATP1A2 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 he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient’s condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10. One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation.

Mutations in the ATP1A2 gene are associated with familial hemiplegic migraine type 2 (FHM2) and alternating hemiplegia of childhood (AHC), as well as cerebellar function deficits, epilepsy, and mental retardation.1,2 AHC is distinguished from familial hemiplegic migraine by infantile onset of symptoms and a high prevalence of associated evolving neurologic deficits.3 Families with overlapping features of both AHC and FHM2 have been reported, suggesting a possible common pathogenesis in a subset of such cases.3 Diagnostic criteria for AHC include onset before the age of 18 months; repeated episodes of hemiplegia involving alternating body sides; episodes of bilateral hemiplegia or quadriplegia; generalization of a hemiplegic episode or bilateral from the beginning of attack; disappearance or relief of symptoms on sleeping; other paroxysmal events, including dystonia, oculomotor abnormalities, or autonomic dysfunction occurring during hemiplegic spells or independently; and evidence of developmental delay or neurologic abnormalities, including choreoathetosis, ataxia, or cognitive disability.4 AHC has also been reported to cause significant deficits in intellectual, academic, memory, attention, and executive functioning, as well as deficits in language, psychomotor abilities, and psychosocial functioning.5 The ATP1A2 gene on chromosome 1q23 encodes the α-2 subunit of the sodium-potassium adenosine triphosphatase (Na+/K+ ATPase) pump that is expressed in glial cells and is involved in maintaining sodium ion (Na+) and potassium ion (K+) gradients across the synaptic cleft. In glial cells, the Na+/K+ ATPase pump is colocalized with the excitatory amino acid transporter (EAAT)-1, a glial glutamate transporter, and EAAT-2 in the astrocytic plasma membrane.6 The Na+ and K+ gradients enable the EAATs to reuptake glutamate from the synaptic cleft into neurons and astrocytes.6 Decreased glutamate reuptake due to impaired function of the EAATs results in cortical glutamatergic hyperexcitability, causing epilepsy, episodic ataxia, and hemiplegia.7 Our hypothesis is that the N-methyl-D-aspartate (NMDA) receptor antagonists can be therapeutic for symptoms of ATP1A2 gene mutation. We report a case in which NMDA receptor antagonists had clinical benefit in a patient with an ATP1A2 gene mutation manifesting hemiplegia, focal epilepsy, and problems in cognition, behavior, and fine motor function.

Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. Family history is unremarkable with no consanguinity. At the age of 12 months, he had several episodes of a self-resolving right-sided hemiparesis. At the age of 18 months, he had 6 seizures consisting of muscle twitches in the right arm and a horizontal conjugate eye deviation to the right, followed by right hemiparesis. An EEG revealed spike and wave discharges arising from the left hemisphere. No significant abnormalities were found on the computed tomography or MRI, but positron emission tomography revealed left posterior quadrant hypometabolism. He was diagnosed with focal epilepsy. Initially, oxcarbazepine was started with no significant improvement. Then, topiramate was started, which decreased the frequency of his seizures. Topiramate was later switched to levetiracetam and valproate at the same time, resulting in seizure cessation. Six months later, levetiracetam was discontinued because of mood changes; the patient remained seizure-free. However, he continued to have the intermittent, self-limited episodes of getting uncoordinated and flaccid on the right side of the body. These events were reported to improve after sleep. At the age of 6 years, he was successfully weaned off valproate. Developmentally, pronounced bilateral fine motor impairment was noted. His hand started to shake, especially when he held a pen or fastened with buttons. A neuropsychological evaluation revealed significant executive deficits, such as poor sustained attention and impulse control. He was started on stimulants and a selective α2 adrenergic receptor agonist with mild improvement in his attention and impulsiveness, but he continued to have difficulties in reading and writing. His motor coordination and visual-spatial and visual-motor processing skills were borderline or impaired. Occupational, physical, and speech therapy were started. At the age of 8 years, he had an episode of a headache associated with weakness in the right upper and lower extremities. The headache and weakness resolved within a few hours and did not recur. At the age of 11 years, his handwriting was no longer legible (Fig 1A). He had anxiety with trichotillomania, for which sertraline was started with no improvement. His reading, comprehension, and memory performance declined to the point at which he was at least 2 grades behind in his academic performance. A metabolic disease evaluation including lactate, plasma acylcarnitine profile, serum amino acids, urine organic acids, fatty acid, and phytanic acid did not have significant results. A chromosomal microarray did not reveal any abnormality. Whole exome sequencing and bioinformatic analysis based on various inheritance models of the proband, mother, and father revealed a heterozygous, missense mutation (c.879C>G; p.I293M) in exon 8 of the ATP1A2 gene (Ensembl Transcript identifier: ENST00000361216.7) on chromosome 1q21-q23 (Fig 2A). Cosegregation analysis of the mutation in this family revealed that the unaffected mother, father, and brother did not carry this alteration, indicating a de novo mutation (Fig 2B). The alteration is not present in healthy cohorts including those from the National Heart, Lung, and Blood Institute Exome Sequencing Project (http://evs.gs.washington.edu/EVS), 1000 Genomes Project (http://www.internationalgenome.org), Exome Aggregation Consortium (http://exac.broadinstitute.org), and the Database of Single Nucleotide Polymorphism (https://www.ncbi.nlm.nih.gov/projects/SNP). The alteration is predicted to be deleterious by in silico analysis. On the basis of the available evidence, the ATP1A2 mutation of the patient was considered as a pathogenic mutation. The p.I293 amino acid is located in the third transmembrane segment of the α-2 subunit of the Na+/K+ ATPase pump and is within the E1-E2 adenosine triphosphatase domain, which is a functionally important protein domain. No mutation was identified in the ATP1A3 gene, which is also associated with AHC. The ATP1A3 gene exons were sequenced to an average coverage of 234-fold, with every base sequenced to a coverage of >50-fold. The whole-exome sequencing, however, identified a maternally inherited heterozygous POLG gene alteration (POLG c.2217_2230dupCAACGACGTGGACA [p.I744Tfs*59]) of unknown clinical significance (Ensembl Transcript identifier: ENST00000268124.9). His mother, who is healthy, had the same POLG gene alteration. Mitochondrial respiratory chain enzyme assays from a muscle biopsy sample revealed reductions of complex II (42%) and complex IV (38%) activities, which were not sufficiently low to meet the minor modified Walker criteria for respiratory chain disorders. Our hypothesis was that the glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient. He was started on memantine at a dose of 2 mg twice daily, and the dose was gradually increased to the target dose of 10 mg twice daily. He was also started on dextromethorphan at a dose of 30 mg twice daily, as well as being started on coenzyme Q10 at a dose of 300 mg daily. Four months later, the neuropsychological evaluation revealed that he was more alert and active with significant improvement in sustained attention, fine motor dexterity (Fig 1B), general cognitive efficiency, and learning efficiency. He was doing well, with rare mild headaches until recently (age 12 years), when he had a concussion precipitated by falling on ice, hitting the back of his head on the ice, and having a few seconds of “blackout.” Since then, he has complained of moderate to severe intermittent headaches in the frontal and occipital areas, which have been associated with nausea, photophobia, and intermittent left-sided weakness. Results from MRIs of the brain and spine were unremarkable. He was also noted to have occasional periodic dystonic posturing in hands with the headaches. EEG results were normal.

FIGURE 1

The patient’s handwriting. A, Pretreatment with NMDA receptor antagonists. B, Four months after starting the treatment with NMDA receptor antagonists.

FIGURE 1

The patient’s handwriting. A, Pretreatment with NMDA receptor antagonists. B, Four months after starting the treatment with NMDA receptor antagonists.

FIGURE 2

A, I (Isoleucine) at amino acid position 293 is evolutionarily conserved from fish to human, whereas it has been mutated to M (methinine) in our patient. This alteration results from a C to G substitution at nucleotide position 879. I, isoleucine; M, methionine; MYA, million years ago. a Common name: African clawed frog. b Common name: Zebrafish. B, Family pedigree. ■, affected; □, unaffected. a Exome sequencing was performed.

FIGURE 2

A, I (Isoleucine) at amino acid position 293 is evolutionarily conserved from fish to human, whereas it has been mutated to M (methinine) in our patient. This alteration results from a C to G substitution at nucleotide position 879. I, isoleucine; M, methionine; MYA, million years ago. a Common name: African clawed frog. b Common name: Zebrafish. B, Family pedigree. ■, affected; □, unaffected. a Exome sequencing was performed.

This patient had a missense ATP1A2 gene and a heterozygous POLG mutation. He had a mild reduction of mitochondrial complex II and complex IV activities. Glutamate excitotoxicity can produce secondary mitochondrial dysfunction.8 Therefore, it is not obvious if the mitochondrial dysfunction is related to the ATP1A2 or POLG mutation. Although ATP1A2 mutation is commonly associated with FHM2, our patient’s clinical course is more consistent with a diagnosis of AHC. Treated with NMDA receptor antagonists and Coenzyme Q10, he showed significant improvement in his behavior, cognitive function, and fine motor difficulties.

Memantine is a noncompetitive NMDA receptor antagonist and has been used for symptomatic treatment of neurodegenerative disease such as Alzheimer disease. In children, memantine can be helpful for behavioral problems in attention-deficit/hyperactivity disorder or autism spectrum disorder.9 Memantine binds to the NMDA receptors and is relatively ineffective at blocking the low levels of receptor activity associated with physiologic synaptic function, but during prolonged activation of the receptors under excitotoxic conditions, memantine becomes a highly effective blocker.10,11 NMDA receptor antagonists including memantine improved behavioral problems in a knock-in mouse model of ATP1A2 mutation with FMH2, supporting our hypothesis.12 Whether NMDA receptor antagonists can be effective for other symptoms, such as AHC and hemiplegic migraine, is unclear from our experience. Our patient suffered from prolonged episodes of hemiplegic migraine after trauma while receiving target doses of memantine and dextromethorphan.

Dextromethorphan is well known as an antitussive but also has effects such as blocking NMDA receptors and inhibiting glutamate excitotoxicity via additional mechanisms, including σ-1 receptor agonist and voltage-gated calcium channel antagonist actions.13 Such effects of dextromethorphan may also have contributed to the improvement of this patient. Flunarizine, a calcium channel blocker, has been reported to decrease the frequency and severity of attacks of headaches and hemiplegia of ATP1A2- and ATP1A3-mutated AHC.14,16 

Behavioral, cognitive, and cerebellar symptoms associated with ATP1A2 gene mutation in a single patient improved with NMDA receptor antagonists. Our patient had worsening headaches while receiving memantine and dextromethorphan. However, his recent episodes of headaches may have been related more closely to concussion rather than to a symptom of his underlying alternating hemiplegia. Further study is needed to better understand the role of NMDA receptor antagonists in the treatment of patients with ATP1A2 mutations. We also speculate that NMDA receptor antagonists may be helpful in the treatment of patients with other Na+/K+ ATPase gene mutations.

     
  • AHC

    alternating hemiplegia of childhood

  •  
  • EAAT

    excitatory amino acid transporter

  •  
  • FHM2

    familial hemiplegic migraine type 2

  •  
  • Na+/K+ ATPase

    sodium-potassium adenosine triphosphatase

  •  
  • NMDA

    N-methyl-D-aspartate

Dr Ueda acquired, analyzed, and interpreted data; Dr Serajee acquired, analyzed, and interpreted data and critically revised the manuscript for intellectual content; Dr Huq acquired, analyzed, and interpreted data and contributed to the study concept and design, the critical revision of manuscript for intellectual content, and study supervision; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.