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FARIMPD (Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies) syndrome is a severe condition caused by ATP1A2 gene variants. The syndrome's novelty and rarity have limited its clinical and molecular knowledge. This research tries to provide new insight by investigating the cause of the early deaths due to FARIMPD syndrome in a particular family and reviewing previous studies. DNA and RNA were extracted from the blood samples of newborns and their parents, followed by whole exome sequencing and segregation analysis. A pathogenic homozygous nonsense variant (c.1234C > T: p.Arg412*) in the ATP1A2 gene was found in newborns. This variant is reported as homozygous for the first time. The migraine symptoms were the result of the heterozygous state of this particular variant, which supported the dominant inheritance pattern of this disease. Real-time PCR was used to analyze ATP1A2 gene expression in the newborns compared to parents and control subjects. The expression analysis also showed significant mRNA degradation in the newborns compared to heterozygous and healthy individuals, due to Nonsense-mediated mRNA Decay phenomena. Our study describes an ATP1A2 nonsense variant (c.1234C > T) that appears compatible with infant survival in the heterozygous and compound heterozygous states but is lethal in the homozygous state. [ABSTRACT FROM AUTHOR]

Alternating hemiplegia of childhood (AHC) is a complex neurodevelopmental disorder characterized by paroxysmal and transient events of unilateral or bilateral paresis, usually occurring before 18 months of age. Mutations in the ATP1A3 gene, mainly p.Asp801Asn, p.Glu815Lys, and p.Gly947Arg at the protein level, are found in around 80% of the individuals with AHC. Interestingly, these mutations reflect the degree of severity of the neurological symptoms (p.Glu815Lys > p.Asp801Asn > p.Gly947Arg). Some channels involved in this disorder are N-type voltage-gated calcium channels, ATP-sensitive potassium channels, and the sodium/calcium exchanger. In this context, the management of AHC should be divided into the treatment of attacks, prophylactic treatment, and management of comorbidities commonly found in this group of individuals, including epilepsy, attention-deficit/hyperactivity disorder, aggressive behavior, cognitive impairment, movement disorders, and migraine. The importance of an integrated approach with a multidisciplinary team, such as neuropsychologists and dietitians, is worth mentioning, as well as the follow-up with a neurologist. In the present study, we propose new diagnostic criteria for AHC, dividing it into clinical, laboratory, supporting, and atypical features. Also, we review the location of the mutations in the ATP1A3 protein of individuals with AHC, rapid-onset dystonia-parkinsonism (RDP) variants, and early infantile epileptic encephalopathy (variants with hemiplegic attack). We also include a section about the animal models for ATP1A3 disorders. [ABSTRACT FROM AUTHOR]

Alternating hemiplegia of childhood (AHC) is a complex neurodevelopmental disorder characterized by paroxysmal and transient events of unilateral or bilateral paresis, usually occurring before 18 months of age. Mutations in the ATP1A3 gene, mainly p.Asp801Asn, p.Glu815Lys, and p.Gly947Arg at the protein level, are found in around 80% of the individuals with AHC. Interestingly, these mutations reflect the degree of severity of the neurological symptoms (p.Glu815Lys > p.Asp801Asn > p.Gly947Arg). Some channels involved in this disorder are N-type voltage-gated calcium channels, ATP-sensitive potassium channels, and the sodium/calcium exchanger. In this context, the management of AHC should be divided into the treatment of attacks, prophylactic treatment, and management of comorbidities commonly found in this group of individuals, including epilepsy, attention-deficit/hyperactivity disorder, aggressive behavior, cognitive impairment, movement disorders, and migraine. The importance of an integrated approach with a multidisciplinary team, such as neuropsychologists and dietitians, is worth mentioning, as well as the follow-up with a neurologist. In the present study, we propose new diagnostic criteria for AHC, dividing it into clinical, laboratory, supporting, and atypical features. Also, we review the location of the mutations in the ATP1A3 protein of individuals with AHC, rapid-onset dystonia-parkinsonism (RDP) variants, and early infantile epileptic encephalopathy (variants with hemiplegic attack). We also include a section about the animal models for ATP1A3 disorders.

• Nine patients harbor pathological (P) or likely pathological (LP) mutations (31%) and three patients have VUS variants (10%) out of 29 DEE patients. • De novo mutations were identified in SCN2A, KCNMA1 and MECP2 genes. • Four novel variations were detected in SCN2A, SCN1A, ATP1A2 and KCNQ2 genes. • Two patients have autosomal recessive inherited mutations in NPC2 and CLN6 genes. • MD simulations revealed the destructive effects of the mutations on protein structures. In Developmental and Epileptic Encephalopathies (DEEs), identifying the precise genetic factors guides the clinicians to apply the most appropriate treatment for the patient. Due to high locus heterogeneity, WES analysis is a promising approach for the genetic diagnosis of DEE. Therefore, the aim of the present study is to evaluate the utility of WES in the diagnosis and treatment of DEE patients. The exome data of 29 DEE patients were filtrated for destructive and missense mutations in 1896 epilepsy-related genes to detect the causative variants and examine the genotype-phenotype correlations. We performed Sanger sequencing with the available DNA samples to follow the co-segregation of the variants with the disease phenotype in the families. Also, the structural effects of p.Asn1053Ser, p.Pro120Ser and p.Glu1868Gly mutations on KCNMA1, NPC2, and SCN2A proteins, respectively, were evaluated by molecular dynamics (MD) and molecular docking simulations. Out of 29, nine patients (31%) harbor pathological (P) or likely pathological (LP) mutations in SCN2A, KCNQ2, ATP1A2, KCNMA1, and MECP2 genes, and three patients have VUS variants (10%) in SCN1A and SCN2A genes. Sanger sequencing results indicated that three of the patients have de novo mutations while eight of them carry paternally and/or maternally inherited causative variants. MD and molecular docking simulations supported the destructive effects of the mutations on KCNMA1, NPC2, and SCN2A protein structures. Herein we demonstrated the effectiveness of WES for DEE with high locus heterogeneity. Identification of the genetic etiology guided the clinicians to adjust the proper treatment for the patients. [ABSTRACT FROM AUTHOR]

ATP1A2 encodes a subunit of sodium/potassium‐transporting adenosine triphosphatase (Na+/K+‐ATPase). Heterozygous pathogenic variants of ATP1A2 cause familial hemiplegic migraine, alternating hemiplegia of childhood, and developmental and epileptic encephalopathy. Biallelic loss‐of‐function variants in ATP1A2 lead to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, resulting in fetal death. Here, we describe a patient with compound heterozygous ATP1A2 variants consisting of missense and nonsense variants. He survived after birth with brain malformations and the fetal akinesia/hypokinesia sequence. We report a novel type of compound heterozygous variant that might extend the disease spectrum of ATP1A2. [ABSTRACT FROM AUTHOR]

This study presents a case report of a male adolescent diagnosed with familial hemiplegic migraine type 2 (FHM2), an autosomal dominant inheritance disorder caused by ATP1A2 mutation. We report the patient who presented with headache, aphasia, and left-sided weakness. Cerebrovascular disease and various infectious agents were unremarkable during the patient's extended hospital stay. Our case revealed that brain hyperperfusion in familial hemiplegic migraine (FHM) persists over an extended duration, and despite the disease being in a state of recovery, enhanced brain magnetic resonance imaging (MRI) continues to exhibit hyperperfusion. A genetic testing was performed which revealed a mutation in the FHM2 gene (c.1133C > T). The patient has been followed for 3 years after hospital discharge. The boy suffered four episodes of hemiplegia and multiple episodes of headaches, and gradually developed seizures and cognitive impairment. It is advisable to consider FHM as a potential diagnosis for patients presenting with typical symptoms such as recurrent paroxysmal headaches and limb activity disorders. [ABSTRACT FROM AUTHOR]

Alternating hemiplegia of childhood (AHC) is characterized by recurrent hemiplegic episodes and paroxysmal disorders, dystonia, nystagmus, epileptic seizure, mental retardation, and intellectual impairment. Alternating hemiplegia of childhood is caused by pathogenic variants in the genes encoding α-1, -2, and -3 subunits of Na,K-ATPase. Among them, pathogenic variants in ATP1A3 are responsible for almost 80% of cases. The aim of our study was to present a patient with de novo ATP1A2 mutation as the primary cause of AHC and to study the spectrum of phenotypes associated with mutation in this gene. Our study presents a case of a 9-year-old boy who was correctly diagnosed with AHC at the age of 8 years. The example of our patient proves that pathogenic variants in ATP1A2 correlate with milder phenotype.

To evaluate the clinical spectrum associated with ATP1A2 variants in Chinese children with hemiplegia, migraines, encephalopathy or seizures. Sixteen children (12 males and 4 females), including ten patients with ATP1A2 variants whose cases had been published previously, were identified using next-generation sequencing. Fifteen patients had FHM2 (familial hemiplegic migraine type 2), including three who had AHC (alternating hemiplegia of childhood) and one who had drug-resistant focal epilepsy. Thirteen patients had DD (developmental delay). The onset of febrile seizures, which occurred between 5 months and 2 years 5 months (median 1 year 3 months) was earlier than the onset of HM (hemiplegic migraine), which occurred between 1 year 5 months and 13 years (median 3 years 11 months). Disturbance of consciousness subsided first, at 40 h to 9 days (median 4.5 days); hemiplegia and aphasia were resolved slowly, taking 30 min to 6 months (median 17.5 days) for the former and 24 h to over 1 year (median 14.5 days) for the latter. Cranial MRI showed edema in the cerebral hemispheres, mainly the left hemisphereacute attacks. All thirteen FHM2 patients recovered to baseline in 30 min to 6 months. Fifteen patients had between 1 and 7 (median 2) total attacks between the baseline and follow-up timepoints. We report twelve missense variants, including a novel variant ATP1A2 variant, p.G855E. The known genotypic and phenotypic spectra of Chinese patients with ATP1A2 -related disorders were further expanded. Recurrent febrile seizures and DD combined with paroxysmal hemiplegia and encephalopathy should raise the clinical suspicion of FHM2. The avoidance of triggers and thus the prevention of attacks may be the most effective therapy for FHM2. [ABSTRACT FROM AUTHOR]

Increasing the number of brite cells (browning) in white adipocytes has attracted considerable attention to combat obesity because brite cells also help elevate energy expenditure. Sodium-potassium adenosine triphosphatase α2 subunit (ATP1A2) has been studied extensively in migraine and cancers. On the other hand, the role of ATP1A2 in adipocytes biology with a focus on fat browning needs to be elucidated. In this study, suppression of ATP1A2 induced browning in white adipocytes. The siRNA-mediated knockdown was used to identify the functional roles of the ATP1A2 gene in white adipocytes browning and the lipid metabolism. A deficiency of ATP1A2 promoted the expression of brown adipocyte-specific proteins and genes, suppressed adipogenesis and lipogenesis, and enhanced lipolysis and fat oxidation, as well as mitochondrial biogenesis. Moreover, silencing of ATP1A2 enhanced the expression of marker proteins for UCPl-dependent (β3-AR, PKA, p38, ATF2, and ERK) and UCP1-independent (α1-AR, SERCA, and RyR) thermogenesis. A mechanistic study showed that a deficiency of ATP1A2 induces browning in white adipocytes by activating the β3-AR/ERK signaling pathways as well as α1-AR/SERCA-based thermogenesis through an ATP-consuming process. In conclusion, ATP1A2 is a previously unrecognized player in thermogenesis in white adipocytes, and downregulating ATP1A2 and activating both UCP1-dependent and UCP1-independent thermogenesis in adipocytes could be a novel pharmacotherapeutic approach to treat obesity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alternating hemiplegia of childhood (AHC) is characterized by recurrent hemiplegic episodes and paroxysmal disorders, dystonia, nystagmus, epileptic seizure, mental retardation, and intellectual impairment. Alternating hemiplegia of childhood is caused by pathogenic variants in the genes encoding a-1, -2, and -3 subunits of Na,K-ATPase. Among them, pathogenic variants in ATP1A3 are responsible for almost 80% of cases. The aim of our study was to present a patient with de novo ATP1A2 mutation as the primary cause of AHC and to study the spectrum of phenotypes associated with mutation in this gene. Our study presents a case of a 9-year-old boy who was correctly diagnosed with AHC at the age of 8 years. The example of our patient proves that pathogenic variants in ATP1A2 correlate with milder phenotype. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM‐2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS‐like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura. Methods: The patient was an 8‐year‐old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS‐like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole‐exome sequencing (WES). Results: WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic. Conclusion: At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS‐like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied. [ABSTRACT FROM AUTHOR]

Abstract Background Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM‐2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS‐like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura. Methods The patient was an 8‐year‐old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS‐like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole‐exome sequencing (WES). Results WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic. Conclusion At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS‐like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.

Both 2 cases developed hemiplegic migraine at an early age. The clinical manifestations were almost the same, featuring visual disturbance (such as visual flash) and hemiplegia or hemiparesis. A unilateral pulsating headache with nausea and vomiting developed soon after these auras which lasted about half an hour. The headache was relieved after rest. No abnormality was found in the neurological examination, cranial CT, MRI, electroencephalogram and metabolic disease examination. According to The International Classification of Headache Disorders, 3rd edition (ICHD-3), both 2 cases were presented as typical pure hemiplegic migraine without other neurological disorders. Genetic sequencing showed ATP1A2 gene mutation in the 2 patients. Heterozygous mutation c.G2284A/p.G762S was present in case 1 and it has previously been shown to be a pathogenic mutation. Case 2 was identified with c.C3022T/p.R1008W, and no related reports were found in the previous literature and databases. According to the standard of American College of Medical Genetics and Genomics (ACMG), c. G2284A/p. G762S in case 1 was as "likely pathogenic" and c.C3022T/p.R1008W in case 2 was as "uncertain significance". [ABSTRACT FROM AUTHOR]

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. • We analyzed clinical symptoms and their genes in 43 Japanese patients with hemiplegic migraine. • Genetic analysis of these hemiplegic migraine (HM) patients revealed four genetic mutations, including the novel ATP1A2 mutations. • We report the detailed clinical course of the four patients and present the possible efficacy of combination therapy (lomerizine and topiramate). [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract Background Hemiplegic migraine (HM) is an uncommon subtype of migraine with aura including motor weakness. The core symptoms of HM are headache and motor weakness. However, we report a rare case of atypical HM with nonheadache onset in a Chinese child who was misdiagnosed several times. Case presentation We report a Chinese boy whose onset was sudden when he was 3 years old. He presented with a variety of phenotypes, including fever, vomiting, alternating hemiplegia, and drowsiness, but no headache in the initial stages. Magnetic resonance imaging (MRI) demonstrated unilateral cerebral oedema during the initial episode of hemiplegia. These symptoms recurred many times. As the disease progressed, the patient developed episodic headache. The patient was misdiagnosed several times with encephalitis, alternating hemiplegia of childhood (AHC) and mitochondrial encephalopathy. Whole-exome next-generation sequencing revealed a de novo heterozygous missense mutation in the ATP1A2 gene(p.Gly715Arg) classified as pathogenic and eventually led to a diagnosis of HM when he was 11 years old. Flunarizine was subsequently administered, and no recurrence was found during follow-up. Conclusions HM in children may be atypical in the initial stage of the disease, which could manifest as fever, alternating hemiplegia and drowsiness but no headache at the onset. This could easily lead to misdiagnosis. With age, it may eventually manifest as typical HM. Therefore, attention should be given to differentiation in clinical practice.When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment.

Abstract Background ATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far. Case presentation We reported two Chinese patients with de novo ATP1A2 variants (c.970G>A and c.889G>A). Both patients presented with episodes of alternating hemiplegia, seizures and mild developmental delay. Brain magnetic resonance imaging revealed abnormal signals in both patients. Conclusions The new genetic evidence we reported here strengthened the gene–disease relationship, and the gene curation level between ATP1A2 and AHC became “Moderate” following the ClinGen Standard Operation Procedure. Consequently, the two variants can be reclassified as likely pathogenic.

Abstract 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.

Abdominal aortic aneurysm (AAA) is characterized by abdominal aorta dilatation and progressive structural impairment and is usually an asymptomatic and potentially lethal disease with a risk of rupture. To investigate the underlying mechanisms of AAA initiation and progression, seven AAA datasets related to human and mice were downloaded from the GEO database and reanalysed in the present study. After comprehensive bioinformatics analysis, we identified the enriched pathways associated with inflammation responses, vascular smooth muscle cell (VSMC) phenotype switching and cytokine secretion in AAA. Most importantly, we identified ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) as a key gene that was significantly decreased in AAA samples of both human and mice; meanwhile, its reduction mainly occurred in VSMCs of the aorta; this finding was validated by immunostaining and Western blot in human and mouse AAA samples. Furthermore, we explored the potential upstream transcription factors (TFs) that regulate ATP1A2 expression. We found that the TF AT-rich interaction domain 3A (ARID3A) bound the promoter of ATP1A2 to suppress its expression. Our present study identified the ARID3A-ATP1A2 axis as a novel pathway in the pathological processes of AAA, further elucidating the molecular mechanism of AAA and providing potential therapeutic targets for AAA. [ABSTRACT FROM AUTHOR]

The ATP1A2 coding α2 subunit of Na,K‐ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G‐CaMP7 in cortical neurons and astrocytes (Atp1a2+/−), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− were higher than those in wild‐type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− may contribute to FHM2 pathophysiology.

Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed. [ABSTRACT FROM AUTHOR]

Migraine and major depression are debilitating disorders with high lifetime prevalence rates. Interestingly these disorders are highly comorbid and show significant heritability, suggesting shared pathophysiological mechanisms. Non-homeostatic function of ion channels and neuroinflammation may be common mechanisms underlying both disorders: The excitation-inhibition balance of microcircuits and their modulation by monoaminergic systems, which depend on the expression and function of membrane located K+, Na+, and Ca+2 channels, have been reported to be disturbed in both depression and migraine. Ion channels and energy supply to synapses not only change excitability of neurons but can also mediate the induction and maintenance of inflammatory signaling implicated in the pathophysiology of both disorders. In this respect, Pannexin-1 and P2X7 large-pore ion channel receptors can induce inflammasome formation that triggers release of pro-inflammatory mediators from the cell. Here, the role of ion channels involved in the regulation of excitation-inhibition balance, synaptic energy homeostasis as well as inflammatory signaling in migraine and depression will be reviewed.

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. [ABSTRACT FROM AUTHOR]

Background: Hemiplegic migraine (HM) is an uncommon subtype of migraine with aura including motor weakness. The core symptoms of HM are headache and motor weakness. However, we report a rare case of atypical HM with nonheadache onset in a Chinese child who was misdiagnosed several times.Case Presentation: We report a Chinese boy whose onset was sudden when he was 3 years old. He presented with a variety of phenotypes, including fever, vomiting, alternating hemiplegia, and drowsiness, but no headache in the initial stages. Magnetic resonance imaging (MRI) demonstrated unilateral cerebral oedema during the initial episode of hemiplegia. These symptoms recurred many times. As the disease progressed, the patient developed episodic headache. The patient was misdiagnosed several times with encephalitis, alternating hemiplegia of childhood (AHC) and mitochondrial encephalopathy. Whole-exome next-generation sequencing revealed a de novo heterozygous missense mutation in the ATP1A2 gene(p.Gly715Arg) classified as pathogenic and eventually led to a diagnosis of HM when he was 11 years old. Flunarizine was subsequently administered, and no recurrence was found during follow-up.Conclusions: HM in children may be atypical in the initial stage of the disease, which could manifest as fever, alternating hemiplegia and drowsiness but no headache at the onset. This could easily lead to misdiagnosis. With age, it may eventually manifest as typical HM. Therefore, attention should be given to differentiation in clinical practice.When similar clinical cases appear, gene detection is particularly important, which is conducive to early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: ATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far. Case presentation: We reported two Chinese patients with de novo ATP1A2 variants (c.970G>A and c.889G>A). Both patients presented with episodes of alternating hemiplegia, seizures and mild developmental delay. Brain magnetic resonance imaging revealed abnormal signals in both patients. Conclusions: The new genetic evidence we reported here strengthened the gene–disease relationship, and the gene curation level between ATP1A2 and AHC became "Moderate" following the ClinGen Standard Operation Procedure. Consequently, the two variants can be reclassified as likely pathogenic. [ABSTRACT FROM AUTHOR]

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. • ATP1A2 c.2438T > A (p.Met813Lys) is associated with infantile onset hemiplegic attacks, epilepsy, and movement disorders. • Rare severe attacks with sustained, stepwise regression were seen in two patients with ATP1A2 c.2438T>A (p.Met813Lys). • Clinicians should consider sequencing ATP1A2 in patients with infantile onset hemiplegic attacks, refractory epilepsy, and movement disorders that do not fulfill criteria for AHC. [ABSTRACT FROM AUTHOR]

Objective: Variants in the ATP1A2 gene exhibit a wide clinical spectrum, ranging from familial hemiplegic migraine to childhood epilepsies and early infantile developmental epileptic encephalopathy (EIDEE) with movement disorders. This study aims to describe the epileptology of three unpublished cases and summarize epilepsy features of the other 17 published cases with ATP1A2 variants and EIDEE., Methods: Medical records of three novel patients with pathogenic ATP1A2 variants were retrospectively reviewed. Additionally, the PUBMED, EMBASE, and Cochrane databases were searched until December 2023 for articles on EIDEE with ATP1A2 variants, without language or publication year restrictions., Results: Three female patients, aged 6 months-10 years, were investigated. Epilepsy onset occurred between 5 days and 2 years, accompanied by severe developmental delay, intellectual disability, drug-resistant epilepsy, severe movement disorder, and recurrent status epilepticus. All individuals had pathogenic variants of the ATP1A2 gene (ATP1A2 c.720_721del (p.Ile240MetfsTer9), ATP1A2c.3022C > T (p.Arg1008Trp), ATP1A2 c.1096G > T (p.Gly366Cys), according to ACMG criteria. Memantine was p) rescribed to three patients, one with a reduction in ictal frequency, one with improvement in gait pattern, coordination, and attention span, and another one in alertness without significant side effects., Significance: This study reinforces the association between ATP1A2 variants and a severe phenotype. All patients had de novo variants, focal motor seizures with impaired awareness as the primary type of seizure; of the 11 EEGs recorded, 10 presented a slow background rhythm, 7 multifocal interictal epileptiform discharges (IED), predominantly temporal IEDs, followed by frontal IED, as well as ten ictal recordings, which showed ictal onset from the same regions mentioned above. Treatment with antiseizure medication was generally ineffective, but memantine showed moderate improvement. Prospective studies are needed to enlarge the phenotype and assess the efficacy of NMDA receptor antagonist therapies in reducing seizure frequency and improving quality of life., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The ATP1A2 coding α2 subunit of Na,K‐ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G‐CaMP7 in cortical neurons and astrocytes (Atp1a2+/−), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− were higher than those in wild‐type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− may contribute to FHM2 pathophysiology. [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant inheritance disorder caused by ATP1A2 mutation, and the clinical spectrum is heterogeneous even with acute severe encephalopathy. However, up to now, early treatments against acute and severe attacks in FHM2 are still insufficient. Here, we report a 15-year-old female with intellectual disability due to FHM2 caused by a pathogenic ATP1A2 gene mutation, presenting mild-to-moderate headache at the onset, followed by confusion, complete right hemiparalysis, epileptic partial seizures, and conscious disturbance with rapid progression in acute attack. Brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have revealed left extensive cerebral cortex edema, slightly decreased N-acetylaspartate for neuronal damage, and mildly increased lactate acid for mitochondrial dysfunction throughout the hemispheric swollen cortex. The patient is diagnosed as severe encephalopathy caused by FHM2. Based on literature review about pathophysiologic mechanism described in FHM2 recently, we use early treatments including prevention of glutamatergic excitotoxicity and protection of mitochondria function, as well as traditional antimigraine drug. The symptoms are all greatly improved and recovered within a short time, and follow-up MRI also shows complete disappearance of edema throughout the left hemispheric cortex. Altogether, the approach in our case may reduce the severity and duration of encephalopathy effectively, expend therapeutic options, and provide helpful references for acute severe encephalopathy in FHM2. [ABSTRACT FROM AUTHOR]

Abstract Background Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine. Case presentation We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine. Conclusions Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission.

Yiqing Huang,1 Hai Xiao,1 Xingyue Qin,1 Yuan Nong,1 Donghua Zou,2 Yuan Wu3 1Department of Neurology, Guigang City People’s Hospital and the Eighth Affiliated Hospital of Guangxi Medical University, Guigang, People’s Republic of China; 2Department of Neurology, The Fifth Affiliated Hospital of Guangxi Medical University and the First People’s Hospital of Nanning, Nanning, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China Abstract: Epilepsy and migraine are common diseases of the nervous system and share genetic and pathophysiological mechanisms. Familial hemiplegic migraine is an autosomal dominant disease. It is often used as a model of migraine. Four genes often contain one or more mutations in both epilepsy and hemiplegic migraine patients (ie, CACNA1A, ATP1A2, SCN1A, and PRRT2). A better understanding of the shared genetics of epilepsy and hemiplegic migraine may reveal new strategic directions for research and treatment of both the disorders. Keywords: epilepsy, migraine, CACNA1A, ATP1A2, SCN1A

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., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene. [ABSTRACT FROM AUTHOR]

Background: ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation.Methods: Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay.Results: All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability.Conclusion: G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit. [ABSTRACT FROM AUTHOR]

Breast cancer is the first in incidence and the second in death among all solid tumors occurring in women. The identification of molecular genetic abnormalities in breast cancer is important to improve the results of treatment. In the present study, we analyzed microarray data of breast cancer expression profiling (NCBI GEO database, accession GSE65194), focusing on Na +/K +-ATPase coding genes. We found overexpression of the ATP1A1 and down-regulation of the ATP1A2. We expect that our research could help to improve the understanding of predictive and prognostic features of breast cancer.

Background Familial hemiplegic migraine (FHM) is a rare monogenic form of migraine with aura with three distinct genetic subtypes (FHM1-3). Imaging studies during acute FHM attacks are scarce in the literature. This is particularly true for the FHM2 subtype. Patients and methods In this monocentric study, we retrospectively evaluated imaging data of four different patients with genetically confirmed FHM2. Analysis comprised a total of eight cMRI and two CT perfusion studies, which were obtained during a total of six different attacks. Results cMRI investigations at all available time-points were without evidence of cytotoxic edema. The most prominent finding (four attacks in three patients) was swelling and/or cortical hyperintensity of the affected cerebral hemisphere on T2/FLAIR-weighted MRI. Further changes, encountered only in a few patients, included increased perfusion of the affected hemisphere (as assessed by perfusion CT) as well as dilatation of the middle cerebral artery. Conclusion Our data from a sizeable cohort of FHM2 patients highlight that swelling / cortical hyperintensity of the clinically affected cerebral hemisphere - which has been previously reported mainly in FHM1 - can be observed also in FHM2. Further, they suggest that these changes, which tend to be present not in the very beginning, but rather later on during attacks, may be a possible correlate of the prolonged attack duration in our patients. [ABSTRACT FROM AUTHOR]

Background Patients with familial hemiplegic migraine type 2 (FHM2) have a mutated ATP1A2 gene (encoding Na+,K+-ATPase α2 subunit) and show prolonged migraine aura. Cortical spreading depression (CSD), which involves mass depolarization of neurons and astrocytes that propagates slowly through the gray matter, is profoundly related to aura. Methods In two types of Atp1a2-defective heterozygous mice, Atp1a2tm1Kwk (C-KO) and Atp1a2tm2Kwk (N-KO), the sensitivity and responsiveness to CSD were examined under urethane anesthesia. Results In both cases, heterozygotes exhibited a low threshold for induction of CSD, faster propagation rate, slower recovery from DC deflection, and profound suppression of the electroencephalogram, compared to wild-type mice. A high dose of KCl elicited repeated CSDs for a longer period, with a tendency for a greater frequency of CSD occurrence in heterozygotes. The difference of every endpoint was slightly greater in N-KO than C-KO. Change of regional cerebral blood flow in response to CSD showed no significant difference. Conclusion Heterozygotes of Atp1a2-defective mice simulating FHM2 demonstrated high susceptibility to CSD rather than cortical vasoreactivity, and these effects may differ depending upon the knockout strategy for the gene disruption. These results suggest that patients with FHM2 may exhibit high susceptibility to CSD, resulting in migraine. [ABSTRACT FROM AUTHOR]

Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach. [ABSTRACT FROM AUTHOR]

The article describes the individual peculiarities of a rare disease — hemiplegic migraine — in 3 patients (two girls aged 2 and 14 years old and a boy of 16 years). In common clinical aspect there was a correlation between the migraine-attack and the slight head trauma in all patients. Attack symptoms were almost identical: hemiparesis, aphasia, ataxia. The family history for migraine was burdened in both girls. A genetic testing in the boy and in the smallest girl demonstrated CACNA1A gene mutation, in the teen girl — ATP1A2 gene mutation. The electroencephalograms in all patients during the acute phase presented signs of hemipcortical brain dysfunction. The magnetic resonance imaging revealed prominent but reversible hemicortical oedema. The repeated MRI studies diagnosed nonrelevant for this disease hemicortical atrophy (girl 2 years) and atrophy of the cerebellum (the boy). Due to the rarity of the disease so far there are no clear guidelines for its treatment and prevention. In view of the pathogenesis for the prevention patients were prescribed medications changing the activity of cytoplasmic calcium and sodium canals.

Background: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described.Patient Description: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis.Results: Whole-exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred.Conclusions: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management. [ABSTRACT FROM AUTHOR]