Recurrent Stroke Due to a Novel Voltage Sensor Mutation in Ca _v 2.1 Responds to Verapamil

Abstract

Background and Purpose— Familial hemiplegic migraine is characterized by recurrent migraine, hemiparesis, and ataxia. Causes may be mutations in calcium and sodium channels or in a subunit of the Na/K-ATPse. Migraine treatment with calcium channel blockers was only successful in some patients. Summary of Case— We describe a 6-year-old girl with recurrent ischemic strokes after minor head trauma associated with seizures, hemiparesis, fever, and altered consciousness. Genetic analysis revealed a spontaneous, novel dominant CACNA1A mutation (c.4046G→A, p.R1349Q) that removed a highly conserved arginine of the voltage sensing region of the P/Q-type Ca v 2.1 channel. Because a homologous mutation in the tottering-5J mouse increased open probability of the channel as well as calcium influx, we treated the patient with the calcium channel blocker verapamil during characteristic prodromi after head trauma. Treatment was instantly effective and prevented a new stroke. Conclusion— CACNA1A mutations should be considered in the diagnostic workup of childhood stroke, especially if associated with ataxia and migraine.

Acute Intravenous Calcium Antagonist for Suspected Hemiplegic Migraine – A Case Story

“…However, this is the third reported case of suspected hemiplegic migraine where the patient regained full motor function during verapamil infusion [6, 7]. At the time of verapamil infusion, 1 h 32 min had elapsed since the end of rtPA infusion – with no remarkable gain of motor function.…”

“…Of the 3 previous reports, 2 showed resolution of hemiplegia [6, 7]. In the third case, the patient had resolution of headache but persistent hemiparesis [8].…”

Calcium binding protein-mediated regulation of voltage-gated calcium channels linked to human diseases

“…Specifically, single channel recording showed that the mutations enhanced the open probability of the Ca V 2.1 channels and shifted the activation gating of the channel to more negative voltages, allowing increased Ca 2+ influx at more negative membrane potentials in cerebellar neurons [33,34] . Common treatments with Ca 2+ channel blockers, such as verapamil, is effective in some FHM1 patients, carrying the CACNA1A mutations due to decreased open probability of P/Q-type Ca V 2.1 channels and reduced Ca 2+ influx [35] . Consistent with reports of increased open-channel probability [32,33] , a recent study showed that FHM-1 missense mutants of the C-terminus in Ca V 2.1 subunit, R192Q and S218L, permitted a larger Ca 2+ influx during action potentials than the wildtype channels in the cerebellar neurons [36] .…”

Mutation Spectrum in the CACNA1A Gene in 49 Patients with Episodic Ataxia

“…Since the first CACNA1A disease-causing variants were described in EA2 7 , over 80 EA2 alterations have been reported in the gene 3 . Several other neurological disorders are caused by pathogenic variants in CACNA1A , including familial hemiplegic migraine (FHM1, MIM #301011) and spinocerebellar ataxia type 6 (SCA6, MIM #183086), and the gene has also been related to other hemiplegic migraine (HM)-associated phenotypes like alternating hemiplegia of childhood 8 , acute striatal necrosis 9 , hemiplegia-hemiconvulsion-epilepsy 10 or recurrent ischemic stroke 11 .…”