title: Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De NovoCACNA1A Variant.
abstract: Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurological disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. CACNA1A encodes the principal pore-forming subunit of the voltage-gated P/Q-type calcium channel, alpha1. Patients with epileptic encephalopathy due to pathogenic variants in CACNA1A have been previously described and are challenging to treat.
  
  
  
  We describe a child with epileptic encephalopathy, ataxia, cognitive impairment, and significant social-behavioral abnormalities due to a de novo pathogenic variant, p.S1373L in the CACNA1A gene. After failing zonisamide and divalproex sodium, she had a dramatic response to lamotrigine with a precipitous decrease in seizure frequency and severity. This improvement has persisted over one year.
  
  
  
  While classically thought to act at sodium channels, lamotrigine also modulates the activity of the P/Q-type calcium channel, making it a candidate for precision therapy for patients with epileptic encephalopathy due to CACNA1A pathogenic variants. The rarity and clinical heterogeneity of epilepsy due to variants in CACNA1A presents challenges to clinical diagnosis. However, genetic analysis for patients with epilepsy continues to expand; additional patients are likely to be identified molecularly. Lamotrigine should be considered as a first-line treatment in patients with epileptic encephalopathy due to pathogenic variants in CACNA1A.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Byers
authors.affiliation: Department of Neurology, University of Washington, Division of Neurology, Seattle Children's Hospital, Seattle Washington.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Beatty
authors.affiliation: Department of Pediatrics and Division of Medical Genetics, University of Washington, Division of Biochemical Genetics, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Si Houn
authors.initials: SH
authors.lastname: Hahn
authors.affiliation: Departments of Neurology and Pediatrics, University of Washington, Division of Neurology, Seattle Children's Hospital, Seattle Washington.
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Gospe
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D000077213:Lamotrigine; D014227:Triazines / Q000627:therapeutic use*; D020864:Calcium Channels, N-Type
chemical_list: D000927:Anticonvulsants; D015220:Calcium Channels; D000077213:Lamotrigine; D014227:Triazines; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type
keywords: CACNA1A; calcium; channelopathy; epilepsy; epileptic encephalopathy; genetic; lamotrigine