A novel mutation in the ATP1A2 gene associated with a sporadic hemiplegic migraine and multiple supraventricular arrhythmias: A case report

Abstract

Introduction

ATP1A2 mutations are identified as a genetic cause of type 2 hemiplegic migraine, but to date, no ATP1A2 gene variant has been linked to heart rhythm disorders

Case presentation

A 37-year-old woman presented with sporadic hemiplegic migraine and multiple supraventricular arrhythmias refractory to medical treatment and electrophysiological interventions. Genetic workup revealed a mutation in the ATP1A2 gene (c.1827 + 10delT) which was not previously described. The co-segregation study supported the causal participation of the variant since it was found in the migrainous sister but not in the non-migrainous father.

Conclusions

We suggest that the c.1827 + 10delT mutation in the ATP1A2 gene is a novel pathogenic mutation linked to both hemiplegic migraine and supraventricular arrhythmias.

Introduction

Hemiplegic migraine (HM) is a rare subtype of migraine characterized by auras with transient motor weakness or hemiparesis that can last several days. Other symptoms can also occur, including visual impairment, paresthesia, hypesthesia, speech disturbance, or basilar-type symptoms. ¹ There are two forms of HM with an autosomal mode of inheritance: familial HM (FHM) when at least one first-degree or second-degree relative is affected or sporadic HM (SHM) when no relative fulfills the diagnostic criteria for HM according to the International Classification of Headache Disorders-3. ²

To date, three genes linked to FHM have been identified: CACNA1A, ATP1A2, and SCN1A, each one responsible for a subtype of FHM: FHM1 (MIM#301011), FHM2 (MIM#182340), and FHM3 (MIM#182389), respectively. Mutations in the PRRT2 gene associated with HM have also been reported. ³

The ATP1A2 gene is localized on chromosome 1q23.2 and encodes for the alpha2-subunit, harboring the catalytic site. It is composed of more than 1000 amino acids, of the Na/K ATPase (NKA), ¹ expressed in the brain (astrocytes), heart, skeletal, and smooth muscle tissue. ⁴ Patients affected by a pathological mutation in the ATP1A2 gene can present a wide clinical spectrum, including common migraine, ⁵ HM, ⁶ alternating hemiplegia of childhood, ⁷ epilepsy and polymicrogyria, ⁸ permanent mental retardation, ⁹ neuromuscular periodic paralysis disorders, ¹⁰ recurrent coma, and fever. ¹¹

Here we describe a patient suffering from multiple severe and refractory heart rhythm disorders—atrial fibrillation (AF), atrial flutter, and supraventricular tachycardia—and SHM and who carries a heretofore unknown deletion in the ATP1A2 gene. The causal involvement of the variant was supported by a segregation study in the patient's family.

Case presentation

This right-handed 37-year-old woman was admitted to the emergency room for an episode of vertigo, numbness, and right hemi-paresthesia but no headache. The magnetic resonance imaging (MRI) (Figure 1) did not show any acute ischemic lesion but revealed a right thalamic chronic ischemic sequela. Laboratory tests were normal, including the absence of antinuclear, anti-DNA, anti-neuromyelitis optica, anti-neuronal, and anti-phospholipid antibodies, and a negative genetic test for Fabry's disease. Trans-thoracic and trans-esophageal echocardiography, 24-h heart rate recording, electroencephalogram (EEG), and cervico-dorsal MRI were normal. By contrast, a 7-day heart rate recording revealed episodes of AF and atrial flutter. A treatment with rivaroxaban was started.

Figure 1.

Magnetic resonance imaging (MRI) showing right thalamic chronic ischemic sequela.

One year later, the patient was again admitted to the emergency room for right hemiparesis. The head MRI showed no abnormality except the previously described lesion. A year later, she presented with multiple episodes of tachycardia, palpitations, and precordial pain irradiating to the jaw and left arm. Some of these episodes eventually led to syncopes. The EEG, heart ultrasonography, cardiac MRI, and coronary computed tomography angiography were normal. The episodes of rapid AF were not controlled by sotalol, verapamil, and flecainide. The pulmonary veins were successfully ablated; a ridge hindered the ablation of the cavotricuspidian isthmus. The episodes of AF and rapid atrial tachycardia (AT) remained unabated. The eventual ablation of the cavotricuspidian isthmus did not halt AF and rapid AT episodes.

A few months later, during a perimenstrual period, she presented again with sudden right hemiparesis associated with pulsatile headaches, photophobia, and nausea. A head MRI did not show any new significant abnormalities. The cerebrospinal fluid examination was normal, especially the white blood cell count and protein levels. The patient totally recovered after several days without any specific medication.

Two more electrophysiological interventions were conducted to control the AF. After the last one, the patient had no further episodes of AF despite persisting AT periods.

She also presented many episodes of progressive dysarthria, left hemiparesis, and left hemihypesthesia often associated with headaches, which spontaneously resolved after several hours or a few days without any concurrent acute lesion on the MRI. The diagnosis of HM was finally made. Beta-blockers, Lamotrigine, Valproic acid, Clomipramine, and Topiramate did not prove useful in controlling migraines and were poorly tolerated. Pulsed high doses of intravenous methylprednisolone and subcutaneous sumatriptan partially controlled migraines.

Following the clinical presentation, a genetic analysis was requested. The patient was found to be heterozygous for the variant c.1827 + 10delT in the ATP1A2 gene. This variant was identified through targeted gene panel sequencing for FHM using the NovaSeq 6000 platform (Illumina). The sequencing specifically targeted the CACNA1A, ATP1A2, and SCN1A genes, with variant annotation and interpretation performed using Alissa Interpret. The variant was subsequently confirmed by Sanger sequencing and was noted to be novel, with no previous descriptions in mutation or population databases Her father, who never presented migraines, was negative for this mutation, and her sister, who previously had a diagnosis of migraine with visual aura, was also heterozygous for the same mutation (Figure 2).

Figure 2.

Family tree indicating ATP1A2 mutation status.

Discussion

We describe a patient who suffers from both a SHM type 2 and refractory supraventricular heart arrhythmias (AF, atrial flutter, and ST) and carries a heretofore unreported variant of the ATP1A2 gene. The causal involvement of this variant is strongly supported by the segregation study, which shows that migrainous family members carry the mutation in contrast to family members free from migraine (although most of the family members could not be tested). The ATP1A2 gene encodes the α2 isoform of the catalytic subunit of the NKA ion pump. ⁴ This pump is mainly expressed in brain cells (astrocytes), heart, skeletal, and smooth muscle tissue and regulates the electrochemical gradients across the cell membranes. ⁴

The HM-linked mutations lead to neuronal hyperexcitability by increasing cerebral levels of K+ and glutamate in the synaptic cleft, thus facilitating cortical spreading depression (CSD), which is likely responsible for aura symptoms. ¹

The functional consequences of this mutation are hard to predict since, to our knowledge, this mutation was heretofore not reported. The “c.1827 + 10delT” variant is a deletion of a thymine (T) nucleotide in the intron (non-coding region) of the ATP1A2 gene, near a splice site. It does not cause a frameshift but may affect splicing. It is tantalizing to suggest that alternative splicing of the ATP1A2 pre-mRNA would produce an altered or truncated α2 subunit of the NKA and consequently enhanced excitability facilitating the CSD.

To the best of our knowledge, ATP1A2 variants were never associated with supraventricular arrhythmia, in contrast to mutations in the SCN1A gene that can lead to atrioventricular nodal reentry tachycardia. ¹² We are intrigued by the co-occurrence of FHM and arrhythmias resistant to several antiarrhythmic drugs and multiple electrophysiological interventions, which suggest a channelopathy. ¹³ The α2 subunit of the NKA accounts for about 15% of the total NKA content in the cardiomyocytes (the α1 subunit accounts for the last 85%), and a causal relationship between the mutation and the heart arrhythmias is plausible. Indeed, the NKA ion pump regulates cardiomyocyte contractility by controlling the intracellular Na+ concentration and consequently the Ca²⁺ intracellular concentration through the Na⁺/Ca²⁺ exchanger. ¹⁴ Altered Ca²⁺ and Na⁺ concentrations can lead to both atrial and ventricular arrhythmias.

Furthermore, we hypothesize that the refractory response to ablation procedures in this patient may suggest that the arrhythmogenic substrate is not confined to localized areas but rather involves a broader section of atrial tissue. This could be analogous to the CSD observed in migraine with aura, where a wave of neuronal and glial depolarization spreads across large regions of the cortex, leading to temporary disruptions in brain function.

This hypothesis is further supported by the fact that ATP1A2 mutations have been implicated in other conditions characterized by widespread excitability disturbances, such as CSD in migraine with aura. Therefore, it is plausible that a similar mechanism might be at play in cardiac tissue, leading to the observed refractory arrhythmias. We suggest that a common pathophysiological mechanism affecting both nerve and cardiac muscle may exist, warranting further investigation into the systemic effects of ATP1A2 mutations. ⁴

Interestingly, the phenotype differed between the two positive family members since our patient presents HM and her sister, also positive for the same mutation, suffered from common migraine with aura. Furthermore, the sister does not present any heart rhythm disorder. These observations suggest a variable phenotype and a variable penetrance of this mutation.

In addition, in light of the presence of characteristic symptoms in multiple family members, the designation of this syndrome as “sporadic” may warrant reassessment. This classification could be subject to revision should further genetic analyses on additional members of the pedigree provide supporting evidence for a potential familial inheritance pattern.

In conclusion, we report a new ATP1A2 mutation potentially associated with HM and multiple supraventricular arrhythmias. This association should be considered in the prevention of neurovascular events (including ischemic strokes) since migraine with aura (including FHM) carries a higher risk of cardiovascular disorders than the general population. ¹⁵ Further studies should assess the functional consequences of this variant on protein structure and function.

Clinical implications

• Identification of a novel ATP1A2 gene mutation (c.1827 + 10delT) in a patient with sporadic hemiplegic migraine.

• First reported case of ATP1A2 gene mutation associated with multiple refractory supraventricular arrhythmias.

• Segregation study supporting the causal link between ATP1A2 mutation and clinical phenotype in migrainous family members.

• Potential implications for understanding the genetic underpinnings of hemiplegic migraine and associated arrhythmias.