Familial hemiplegic migraine.

Hemiplegic migraine consists of attacks of migraine with aura that includes reversible motor weakness. It is classified as familial or sporadic depending on the involvement or not of a first or second degree relative. The most described subtypes of familial hemiplegic migraine include FHM1, FHM2, and FHM3. These have been demonstrated to have a mutation in either CACNA1A, ATP1A2 or SCN1A, which encode different subunits of channels, involving P/Q-type calcium channel, Na/K pump and Na channel, respectively, located in neurons and glial cells. Mutations localized in different genes are defined as "other loci." Patients with a known mutation can have different genetic penetrance, and may present a more complex and disabling phenotype that develops earlier in life. The clinical manifestations can be similar in the three mutations, including neurologic comorbidities other than muscular weakness, such as episodes of loss of consciousness, epilepsy, gait or limb ataxia or movement disorders, among others. Treatment includes antiepileptics such as lamotrigine, valproate or topiramate, calcium blockers such as flunarizine or verapamil and acetazolamide.

Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and Emerging Approaches.

Migraine is a severe, debilitating neurovascular disorder. Hemiplegic migraine (HM) is a rare and debilitating neurological condition with a strong genetic basis. Sequencing technologies have improved the diagnosis and our understanding of the molecular pathophysiology of HM. Linkage analysis and sequencing studies in HM families have identified pathogenic variants in ion channels and related genes, including CACNA1A, ATP1A2, and SCN1A, that cause HM. However, approximately 75% of HM patients are negative for these mutations, indicating there are other genes involved in disease causation. In this review, we explored our current understanding of the genetics of HM. The evidence presented herein summarises the current knowledge of the genetics of HM, which can be expanded further to explain the remaining heritability of this debilitating condition. Innovative bioinformatics and computational strategies to cover the entire genetic spectrum of HM are also discussed in this review.

Astrocytic Na+, K+ ATPases in physiology and pathophysiology.

The Na+, K+ ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+, K+ ATPases, the review focuses on the role of the astrocytic Na+, K+ pumps in extracellular K+ and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+, K+ ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na+, K+ ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na+, K+ ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na+, K+ ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.

Familial hemiplegic migraine in pediatric patients: A genetic, clinical, and follow-up study.

OBJECTIVE: The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. BACKGROUND: Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts. METHODS: We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years. RESULTS: We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2). CONCLUSION: The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.

Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD.

Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na+ homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded α2-isoform of Na+/K+-ATPase (α2NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via α2NaKA. Thus, α2NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. α2NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. α2NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.

Astrocytic Glutamate Transporters and Migraine.

Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.

Recurrent de novo single point variant on the gene encoding Na+/K+ pump results in epilepsy.

The etiology of epilepsy remains undefined in two-thirds of patients. Here, we identified a de novo variant of ATP1A2 (c.2426 T > G, p.Leu809Arg), which encodes the α2 subunit of Na+/K+-ATPase, from a family with idiopathic epilepsy. This variant caused epilepsy with hemiplegic migraine in the study patients. We generated the point variant mouse model Atp1a2L809R, which recapitulated the epilepsy observed in the study patients. In Atp1a2L809R/WT mice, convulsions were observed and cognitive and memory function was impaired. This variant affected the potassium binding function of the protein, disabling its ion transport ability, thereby increasing the frequency of nerve impulses. Valproate (VPA) and Carbamazepine (CBZ) have limited therapeutic efficacy in ameliorating the epileptic syndromes of Atp1a2L809R/WT mice. Our work revealed that ATP1A2L809R variants cause a predisposition to epilepsy. Moreover, we provide a point variant mouse model for epilepsy research and drug screening.

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases.

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.

De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms.

BACKGROUND: Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. METHODS: Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. RESULTS: Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. CONCLUSIONS: ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

Hemiplegic migraine type 2 caused by a novel variant within the P-type ATPase motif in ATP1A2 concomitant with a CACNA1A variant.

BACKGROUND: Familial hemiplegic migraine (FHM) is an inherited autosomal dominant disorder characterized by migraine with reversible hemiplegia. FHM1 is caused by variants in CACNA1A, encoding a P/Q type neuronal voltage-gated calcium channel α subunit, which is also associated with episodic ataxia type 2 (EA2). FHM2 is associated with ATP1A2, which codes for an Na+/K+-ATPase isoform 2 subunit. CASE PRESENTATION: We identified an FHM2 family, the mother and her daughter, with a novel variant in ATP1A2, p.Gly377Asp, located in a well-conserved P-type ATPase motif. Additionally, the mother harbored deletion in the CACNA1A, associated with EA2, but her daughter did not. The mother presented migraine with typical aura without motor deficit, whereas her daughter had migraine accompanied by recurrent motor deficit and altered consciousness. The additional CACNA1A deletion in the mother might serve as a modifier. CONCLUSION: Our report emphasizes the importance of genetic analysis to diagnose neurological ion channel/transporter diseases.

Epilepsy in patients with familial hemiplegic migraine.

OBJECTIVE: The coexistence of epilepsy in familial hemiplegic migraine (FHM) has not been reviewed systematically. We investigated the associations of epilepsy in patients with FHM with CACNA1A, ATP1A2, SCN1A or PRRT2 mutations along with clinical and genetic data. MATERIALS AND METHODS: We performed a search in the PubMed bibliographic database and the Cochrane Library was screened for eligible studies, from April 1997 to December 2020. Additionally, Online Mendelian Inheritance in Man (OMIM) was searched for mutations in the CACNA1A, ATP1A2, SCN1A and PRRT2 genes. Brief reports, letters, and original articles about FHM and epilepsy were included in the review if their mutations and clinical course of diseases were identified. RESULTS: Of the included patients with FHM whose information could be accessed, there were 28 families and 195 individuals, 78 of whom had epilepsy; 30 patients had focal epilepsy and 30 patients had generalized epilepsy. All mutations except ATP1A2, which could not be evaluated due to insufficient data, revealed first epilepsy then HM. In 60 patients for whom the epilepsy prognosis was evaluated, only 3.5% of patients were drug-resistant, and the remainder had a self-limited course or responded to anti-epileptic drug treatment. CONCLUSION: Mutations in all three and possibly four FHM genes can cause epilepsy. Contrary to our expectations, the well-known epilepsy gene SCN1A mutations are not the leading cause; the highest number of cases associated with epilepsy belongs to the ATP1A2 mutation. Drug-resistant forms of epilepsy are rare in all FHM mutations, and this information is important for counseling patients.

Serial magnetic resonance imaging findings during severe attacks of familial hemiplegic migraine type 2: a case report.

BACKGROUND: Hemiplegic migraines represent a heterogeneous disorder with various presentations. Hemiplegic migraines are classified as sporadic or familial based on the presence of family history, but both subtypes have an underlying genetic etiology. Mutations in the ATP1A2 gene are responsible for Familial Hemiplegic type 2 (FHM2) or the sporadic hemiplegic migraine (SHM) counterpart if there is no family history of the disorder. Manifestations include migraine with aura and hemiparesis along with a variety of other symptoms likely dependent upon the specific mutation(s) present. CASE PRESENTATION: We report the case of an adult man who presented with headache, aphasia, and right-sided weakness. Workup for stroke and various infectious agents was unremarkable during the patient's extended hospital stay. We emphasize the changes in the Magnetic Resonance Imaging (MRI) over time and the delay from onset of symptoms to MRI changes in Isotropic Diffusion Map (commonly referred to as Diffusion Weighted Imaging (DWI)) as well as Apparent Diffusion Coefficient (ADC). CONCLUSIONS: We provide a brief review of imaging findings correlated with signs/symptoms and specific mutations in the ATP1A2 gene reported in the literature. Description of the various mutations and consequential presentations may assist neurologists in identifying cases of Hemiplegic Migraine, which may include transient changes in ADC and DWI imaging throughout the course of an attack.

Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2.

BACKGROUND: The mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted. CASE PRESENTATION: We describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members. CONCLUSIONS: Co-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.

A novel ATP1A2 variant associated with severe stepwise regression, hemiplegia, epilepsy and movement disorders in two unrelated patients.

Pathogenic variants in ATP1A2, a gene encoding the α subunit of the Na,K-ATPase, cause familial hemiplegic migraine type 2 (FHM2). In contrast, pathogenic variants in ATP1A3, an ATP1A2 paralog, cause alternating hemiplegia of childhood (AHC), a severe neurodevelopmental disorder with infantile onset hemiplegic attacks, seizures, dystonia, chorea and developmental delay. Despite high sequence homology with ATP1A3, ATP1A2 variants rarely associate with severe phenotypes resembling those linked to ATP1A3. Here we describe two unrelated patients with infantile onset hemiplegic attacks, refractory epilepsy, movement disorders, abnormal eye movements and truncal ataxia with a shared de novo variant in ATP1A2, c.2438T > A (p.Met813Lys). The variant is not found in population databases, is predicted to be damaging by in silico analysis, and affects a highly conserved residue. Both patients experienced severe attacks with unilateral cerebral edema followed by sustained, stepwise regression. This report highlights the need to sequence ATP1A2 in the workup of patients with features of AHC that do not fulfill AHC diagnostic criteria.

Differential Expression of Cytokine-Coding Genes among Migraine Patients with and without Aura and Normal Subjects.

Migraine is a prevalent disorder in humans and represents one of the top 10 causes of years lived with disability. Several genetic and environmental factors are involved in the pathobiology of migraine. A number of studies have underscored the role of dysregulated immune reactions. We compared the expression levels IL-2, IL-4, CXCL8, IL-17, IFN-γ, TGF-ß and TNF-α cytokines in blood specimens of patients with migraine and those of healthy persons to identify any possible dysregulation in their expression and to propose mechanisms for this disorder. Expression of INF-γ was suggestively higher in migraine cases than in healthy individuals (posterior beta = 0.35, adjusted P value = 0.017). In addition, expression of this cytokine was lower in female subjects than in male subjects (posterior beta = -0.712, adjusted P value = 0.012). Expression of IL-4, TGF-ß and TNF-α was also higher in cases compared with controls (posterior beta = 1.34, adjusted P value = 0.04; posterior beta = 0.849, adjusted P value = 0.036; posterior beta = 0.451, adjusted P value = 0.042, respectively). On the other hand, CXCL8 expression was lower in migraine cases than in controls (posterior beta = -0.78, adjusted P value = 0.039). Expression levels of IL-1B, IL-17 and IL-2 were not meaningfully different between cases and controls. The current study highlights the dysregulation of cytokine-coding genes in the blood of patients with migraine.

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.

The α2 Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation.

Na+/K+-ATPase is a transmembrane ion pump that is essential for the maintenance of ion gradients and regulation of multiple cellular functions. Na+/K+-ATPase has been associated with nuclear factor kappa B (NFκB) signalling, a signal associated with lipopolysaccharides (LPSs)-induced immune response in connection with activated Toll-like receptor 4 (TLR4) signalling. However, the contribution of Na+/K+-ATPase to regulating inflammatory responses remains elusive. We report that mice haploinsufficient for the astrocyte-enriched α2Na+/K+-ATPase isoform (α2+/G301R mice) have a reduced proinflammatory response to LPS, accompanied by a reduced hypothermic reaction compared to wild type litter mates. Following intraperitoneal injection of LPS, gene expressions of Tnf-α, Il-1ß, and Il-6 was reduced in the hypothalamus and hippocampus from α2+/G301R mice compared to α2+/+ littermates. The α2+/G301R mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that α2Na+/K+-ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation.