Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De NovoCACNA1A Variant.
- 1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
- 2Department of Neurology, University of Washington, Seattle, Washington; Division of Neurology, Seattle Children’s Hospital, Seattle, Washington.
- 3Division of Medical Genetics, Department of Pediatrics, University of Washington, Seattle, Washington; Division of Biochemical Genetics, Seattle Children’s Hospital, Seattle, Washington.
- 4Department of Neurology, University of Washington, Seattle, Washington; Division of Neurology, Seattle Children’s Hospital, Seattle, Washington; Department of Pediatrics, University of Washington, Seattle, Washington. Electronic address: firstname.lastname@example.org.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
CACNA1A; calcium; channelopathy; epilepsy; epileptic encephalopathy; genetic; lamotrigine
- PMID: 27212419
This paper, ‘Dramatic Response After Lamotrigine in a Patient with Epileptic Encephalopathy and a De Novo CACNA1A Variant’ describes the clinical presentation and response of a young girl with epileptic encephalopathy due to a channelopathy and her impressive response to lamotrigine and valproic acid. The patient had been trialed on several anti-epileptic drugs with minimal sustained improvement. However, once lamotrigine was added to her regimen of valproic acid, she had a remarkable and persistent clinical response with improvement in both seizure burden and encephalopathy. Lamotrigine partially acts on the P/Q-type calcium channels, which were predicted to be altered by the patient’s pathogenic variant in CACNA1A. Utilizing precision medicine to identify this patient’s genetic alteration offered an opportunity for more targeted, effective care of this child’s epileptic encephalopathy. Additional reports are needed to characterize this medication response in other patients with CACNA1A pathogenic variants and epileptic encephalopathy.