Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De Novo CACNA1A Variant

Abstract

BACKGROUND Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurologic 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. METHODS Case report of 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. RESULTS After failing zonisamide and divalproex sodium, the child had a dramatic response to lamotrigine with a precipitous decrease in seizure frequency and severity. This improvement has persisted over one year. CONCLUSION 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.

Two Missense CACNA1A Variants in a Single Family with Variable Neurobehavioral, Cerebellar, Epileptic, and Oculomotor Features

“…11 Seizure responsiveness to lamotrigine has been reported in a child with CACNA1A-related DEE. 18 Although acetazolamide is a well-established treatment option for CACNA1A-related episodic ataxia and hemiplegic migraines, its use in CACNA1Arelated epilepsy has not been previously reported. [19][20][21] New technologies and increasing availability of commercial genetic testing of medically intractable epilepsies increase the potential for genetic diagnosis of DEE and, in some instances, can inform medical management.…”

Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability

“…There is also literature suggesting that patients with SCN8A gain of function mutations have been shown to respond well to high‐dose phenytoin . In addition, there is literature suggesting that for some patients with a GRIN2A missense mutation, the N ‐methyl‐ d ‐aspartate receptor blocker memantine should be considered and that finding a mutation in the CACNA1A, …”

A novel CACNA1A variant in a child with early stroke and intractable epilepsy

“…However, repeat EEG at 3.5 months after intractable seizures showed multifocal epileptiform discharges and voltage attenuation in the left hemisphere, despite all prior ischemic insults having affected the right side; this may suggest the seizures are not fully attributable to a history of stroke and instead may indicate progression to epileptic encephalopathy. Further, seizures, epilepsy, and epileptic encephalopathy all have been described as part of the phenotypic spectrum of CACNA1A mutations (Byers et al., 2016). In the previously described case of stroke due to CACNA1A mutation, the affected patient also presented with seizures (Knierim et al., 2011).…”

“…The alpha‐1 subunit encoded by CACNA1A contains four repeated domains (I–IV), each consisting of six membrane‐spanning segments (S1–S6) and a P‐loop between S5 and S6 (Currie, 2010); the four S4 segments constitute the voltage sensor of the channel and the S5 and S6 segments along with the P‐loops form the pore lining (Figure 1a). Pathogenic variants in CACNA1A can lead to a variety of neurological symptoms and several well‐described disorders (Byers, Beatty, Hahn, & Gospe, 2016; Luo et al., 2017). Familial hemiplegic migraine type 1 (FHM1, OMIM #141500), caused by gain‐of‐function variants in CACNA1A , is an extreme type of migraine with aura that typically presents in the first or second decade of life with episodes of headaches, sensory loss, visual disturbance, hemiparesis, and cerebellar signs such as nystagmus or ataxia (Byers et al., 2016; Jen, 2001).…”