Alternating Hemiplegia Of Childhood Research Articles

Real life retrospective study of cannabidiol therapy in alternating hemiplegia of childhood

BackgroundMany alternating hemiplegia of childhood (AHC) patients have received Cannabidiol (CBD) but, to our knowledge, there are no published data available. GoalsTest the hypothesis that CBD has favorable effects on AHC spells. MethodsRetrospective review of available data of AHC patients who received CBD. Primary analysis: Clinical Global Impression Scale of Improvement (CGI-I) score for response of AHC spells to CBD with calculation of 95% confidence interval (CI) for rejection of the null hypothesis. Secondary analyses, performed to achieve an understanding of the effect of CBD as compared to flunarizine, were CGI-I scores of 1) epileptic seizures to CBD, 2) AHC spells to flunarizine, 3) epileptic seizures to flunarizine. Also, Mann-Whitney test was done for comparison of CGI-I scores of CBD and flunarizine to both AHC spells and seizures. ResultsWe studied 16 AHC patients seen at Duke University and University of Lyon. CI of CGI-I scores for AHC spells in response to CBD and to flunarizine, each separately, indicated a positive response to each of these two medications: neither overlapped with the null hypothesis score, 4, indicating significant positive responses with p < 0.05 for both. These two scores also did not differ (p = 0.84) suggesting similar efficacy of both: CBD score was 2 ± 1.1 with a 95% CI of 1.5–2.6 and flunarizine score was 2.3 ± 1.3 with a 95% CI of 1.7–3.1. In patients who had seizures, CI calculations indicated a positive effect of CBD on seizure CGI scores but not of flunarizine on seizure scores. CBD was well tolerated with no patients discontinuing it due to side effects and with some reporting positive behavioral changes. ConclusionOur study indicates a real-life positive effect of CBD on AHC type spells.

Characteristics of non-sleep related apneas in children with alternating hemiplegia of childhood

BackgroundNon-sleep related apnea (NSA) has been observed in alternating hemiplegia of childhood (AHC) but has yet to be characterized. GoalsInvestigate the following hypotheses: 1) AHC patients manifest NSA that is often severe. 2) NSA is usually triggered by precipitating events. 3) NSA is more likely in patients with ATP1A3 mutations. MethodsRetrospective review of 51 consecutive AHC patients (ages 2–45 years) enrolled in our AHC registry. NSAs were classified as mild (not needing intervention), moderate (needing intervention but not perceived as life threatening), or severe (needing intervention and perceived as life threatening). Results19/51 patients (37 %) had 52 NSA events (6 mild, 11 moderate, 35 severe). Mean age of onset of NSA (± Standard Error of the Mean (SEM)): 3.8 ± 1.5 (range 0–24) years, frequency during follow up was higher at younger ages as compared to adulthood (year 1: 2.2/year, adulthood: 0.060/year). NSAs were associated with triggering factors, bradycardia and with younger age (p < 0.008 in all) but not with mutation status (p = 0.360). Triggers, observed in 17 patients, most commonly included epileptic seizures in 9 (47 %), anesthesia, AHC spells and intercurrent, stressful, conditions. Management included use of pulse oximeter at home in nine patients, home oxygen in seven, intubation/ventilatory support in seven, and basic CPR in six. An additional patient required tracheostomy. There were no deaths or permanent sequalae. ConclusionsAHC patients experience NSAs that are often severe. These events are usually triggered by seizures or other stressful events and can be successfully managed with interventions tailored to the severity of the NSA.

Abstract 12942: The D801N Variant in ATP1A3 -Encoded Na/K-atpase Alpha 3 Shortens the Cardiac Myocyte Action Potential and Increases Risk for Calcium Mediated Arrhythmias

Background: Alternating hemiplegia of childhood (AHC) is a rare de novo syndrome that manifests with episodic hemiplegia, seizures, dystonia, and, notably, sudden unexplained death. Gene positive patients carry a pathogenic variant in the ATP1A3 -encoded Na/K ATPase alpha 3 isoform (ATP1A3), and the variant D801N is the most common pathogenic variant. Our group recently found that AHC patients with ATP1A3-D801N missense have short QTc and are at risk of ventricular fibrillation. Hypothesis: We hypothesized that the D801N variant results in reduced ATPase function leading to Ca 2+ overload resulting in shortened repolarization time and increased arrhythmogenic risk. Methods: We differentiated iPSCs into cardiomyocytes from an AHC patient hosting the ATP1A3-D801N variant (iPSC-CM D801N ), and an ostensibly healthy individual (iPSC-CM WT ). Patch clamp was conducted to determine APD90, and the ratio of cells with delayed after depolarization events (DADs). iPSC-CM WT were perfused with 10 -7 M ouabain, an ATP1A3 inhibitor, and APD90 and DADs were measured. SR store ([Ca 2+ ] SR ) was measured with Cal-520 dye under 10 mM caffeine. Resting [Ca 2+ ] i was measured with Fura-2 dye, and Na/Ca exchanger (NCX) peak current was measured as Ni 2+ sensitive current in a stepwise voltage-clamp protocol. Results: iPSC-CM D801N APD90 was shorter 40% than iPSC-CM WT . IPSC-CM WT treated with ouabain had 17% shorter APD90 than vehicle. iPSC-CM D801N had DADs (3/11 cells) when iPSC-CM WT (0/24) did not, and 6/12 ouabain treated iPSC-CM WT had DADs vs vehicle treated (0/18). Post caffeine, iPSC-CM D801N had higher [Ca 2+ ] SR than iPSC-CM WT . Finally, iPSC-CM D801N had higher resting [Ca 2+ ] i than iPSC-CM WT and iPSC-CM D801N had higher peak NCX current density at +80mV but no difference at RMP. Conclusions: Our results show that both iPSC-CM D801N and ouabain-treated iPSC-CM WT , have a shorter APD compared to WT controls and exhibit DADs. This is associated with higher NCX-mediated influx of Ca 2+ and increased intracellular Ca 2+ . Our findings highlight the emerging role of ATP1A3-D801N in creating a myocardium vulnerable to arrhythmias.

Development and testing of methods to record and follow up spells in patients with alternating hemiplegia of childhood.

Developing methods to record Alternating Hemiplegia of Childhood (AHC) spells is essential for clinical trials and patient care. Test the following hypotheses: 1) Video-library training improves participants' ability to correctly identify AHC spells. 2) A custom-designed event-calendar with weekly reviews results in consistent documentation of such events over time. 3) Use of an electronic diary (e-Diary) to register events is a useful tool. 1) A video-library of AHC type spells was developed along with specific training; the effect of the training was tested in 36 caregivers. 2) An event-calendar was similarly developed and provided to 5 caregivers with weekly videoconference meetings for 8 weeks. 3) An e-Diary was developed and offered to 33 patients; time of usage and caregivers' feedback (telephone interview) were analyzed. 1) Video-library training: Wilcoxon test showed improvement in caregiver identification of spells (p=0.047), Cohen's Kappa demonstrated high degree of agreement between caregivers'-experts' classifications (>0.9). 2) Event-calendar: 96.42% of entries had complete information; this did not change during follow up (p=0.804). 3) e-Diary: whereas 52% of respondents used the e-Diary when offered (duration: 10.5±8.1 months), 96.3% indicated they would use it in future studies. Those who used it for 13 months, were very likely to use it during the rest of that year. Video-library training improved spell identification. Calendar with weekly reviews resulted in a sustained and consistent record keeping. Caregivers' e-Diary feedback was encouraging with long-term usage in many. These approaches could be helpful for AHC and, potentially, in similar disorders.

Brain structural changes in alternating hemiplegia of childhood using single-case voxel-based morphometry analysis.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by ATP1A3 mutations. Using voxel-based morphometry (VBM) analysis, we compared an AHC patient cohort with controls. Additionally, with single-case VBM analysis, we assessed the associations between clinical severity and brain volume in patients with AHC. To investigate structural brain changes in gray matter (GM) and white matter (WM) volumes between 9 patients with AHC and 20 age-matched controls, VBM analysis was performed using three-dimensional T1-weighted magnetic resonance imaging. Single-case VBM analysis was also performed on nine patients with AHC to investigate the associations between the respective volumes of GM/WM differences and the motor level, cognitive level, and status epilepticus severity in patients with AHC. Compared with controls, patients with AHC showed significant GM volume reductions in both hippocampi and diffuse cerebellum, and there were WM reductions in both cerebral hemispheres. In patients with AHC, cases with more motor dysfunction, the less GM/WM volume of cerebellum was shown. Three of the six cases with cognitive dysfunction showed a clear GM volume reduction in the insulae. Five of the six cases with status epilepticus showed the GM volume reduction in hippocampi. One case had severe status epilepticus without motor dysfunction and showed no cerebellar atrophy. With single-case VBM analysis, we could show the association between region-specific changes in brain volume and the severity of various clinical symptoms even in a small sample of subjects.

The clinical spectrum associated with ATP1A2 variants in Chinese pediatric patients

PurposeTo evaluate the clinical spectrum associated with ATP1A2 variants in Chinese children with hemiplegia, migraines, encephalopathy or seizures. MethodsSixteen children (12 males and 4 females), including ten patients with ATP1A2 variants whose cases had been published previously, were identified using next-generation sequencing. ResultsFifteen 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. ConclusionsThe 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.

Alternating Hemiplegia of Childhood with ATP1A3 Gene Mutation- A Case Report

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder manifested by transient repeated episodes of alternating hemiplegia associated with other neurological events. Though the exact etiology was largely unknown, recently the pathogenic mutation in the ATP1A3 gene encoding for the alpha3 catalytic subunit of Na+/ K+ATPase was found to be the primary cause of AHC. We present the case of 8.5 year old girl with AHC who had a heterozygous de-novo p.Leu839Pro (c.2516T&gt;C) pathogenic mutation of ATP1A3 gene on chromosome 19q13.&#x0D; BANGLADESH J CHILD HEALTH 2021; VOL 45 (3) : 175-177

Abstract 15039: International Multicenter Registry Study of Patients With Variants in ATP1A3 -Encoded Sodium-Potassium ATPase 3 Finds an Association With Short QT and Life-Threatening Ventricular Arrhythmias

Introduction: Variants in the ATP1A3 -encoded sodium-potassium ATPase-3 can result in Alternating Hemiplegia of Childhood (AHC), which was previously believed to primarily be a neurologic disease. Patients with ATP1A3 variants can experience sudden unexplained death (SUD) which has been linked with cardiac arrhythmias. Given that pathogenic variants in ATP1A3 are rare, the goal was to conduct a multicenter study to determine the impact of ATP1A3 variants on cardiac repolarization and lethal arrhythmia predisposition. Methods: This study was conducted by members of the International AHC Research Consortium (IAHCRC) according to the collaboration rules defined in the IAHCRC Charter. We analyzed 12-lead electrocardiograms from 134 patients from 12 centers across 7 countries. Of these patients, 120 had variants in ATP1A3 . Patients were grouped as follows: ATP1A3 variant status (positive vs. negative) and variant frequency (D801N vs. E815K vs. G947R vs. other). Blinded, manual measurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. The Gollob criteria was used to establish an abnormally short QTc measurement of &lt;370 ms. Results: QTcs were significantly shorter when comparing ATP1A3 variant positive patients to negative ( P =0.004). Patients with the ATP1A3 -D801N variant had significantly shorter QTcs compared to E815K, G947R, and all other less common variants ( P =0.0105, P =0.0234, P =0.0076, respectively). ATP1A3 -D801N variant average QTc was 363.9 ms and remained &lt;380 ms throughout adulthood for 68% of this population. Of the 34 patients with the ATP1A3 -D801N variant, 23 had short QTcs and 3 of those patients had ventricular tachycardia/ventricular fibrillation arrest, cardiac death, or an ICD implanted for exercise-induced syncope. Conclusions: In the largest study to date of the impact of ATP1A3 variants on the heart, we find that patients with ATP1A3 -D801N variants have shorter QTcs and are more likely to experience arrhythmias, which can cause syncope and even sudden death. The shortened QTc, which is a predisposing factor for the generation of ventricular arrhythmias, may underlie the SUD etiology in patients with AHC. Patients with variants in ATP1A3 should receive regular cardiac evaluation.

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review.

Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.

Molecular and clinical characteristics of ATP1A3-related diseases.

ObjectiveWith detailed studies of ATP1A3-related diseases, the phenotypic spectrum of ATP1A3 has greatly expanded. This study aimed to potentially identify the mechanisms by which ATP1A3 caused neurological dysfunction by analyzing the clinical features and phenotypes of ATP1A3-related diseases, and exploring the distribution patterns of mutations in the subregions of the ATP1A3 protein, thus providing new and effective therapeutic approaches.MethodsDatabases of PubMed, Online Mendelian Inheritance in Man, and Human Gene Mutation Database, Wanfang Data, and Embase were searched for case reports of ATP1A3-related diseases. Following case screening, we collected clinical information and genetic testing results of patients, and analyzed the disease characteristics on the clinical phenotype spectrum associated with mutations, genetic characteristics of mutations, and effects of drug therapy.ResultsWe collected 902 clinical cases related to ATP1A3 gene. From the results of previous studies, we further clarified the clinical characteristics of ATP1A3-related diseases, such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism; cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome, and relapsing encephalopathy with cerebellar ataxia, frequency of mutations in different phenotypes and their distribution in gene and protein structures, and differences in mutations in different clinical phenotypes. Regarding the efficacy of drug treatment, 80 of the 124 patients with AHC were treated with flunarizine, with an effectiveness rate of ~64.5%.ConclusionsNervous system dysfunction due to mutations of ATP1A3 gene was characterized by a group of genotypic–phenotypic interrelated disease pedigrees with multiple clinical manifestations. The presented results might help guide the diagnosis and treatment of ATP1A3-related diseases and provided new ideas for further exploring the mechanisms of nervous system diseases due to ATP1A3 mutations.

Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). Fisher Exact test, Spearman correlations. These patients underwent 129 procedures (3.79±2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.

Alternating Hemiplegia of Childhood associated with a pathogenic variant of the ATP1A3 gene

Alternating hemiplegia of childhood (AHC), is a rare disease characterized by episodes of hemi/quadriplegia, dystonic postures, abnormal eye movements, and movement disorders. ATP1A3 gene mu tations are the most frequently associated with AHC. To present a clinical case of AHC, where genetic study and the observation of home videos were of great diagnostic utility. Female patient who at 3 months of age presented with several episodes of dystonic postures, clonic movements of extremities, cephalic version, and lateral gaze deviation lasting several minutes. Epilepsy was diagnosed and levetiracetam was administrated, without improvement. EEG and brain MRI were performed, with normal results. Therefore, epilepsy was ruled out and transient dystonia of infancy was suspected, however, the events became more frequent, longer in duration, and charac teristically subsided during sleep. Family members provided home videos that clarified the events. At 6 months of age, the patient presented with alternating hemiparesis. Dystonia genetic panel showed a pathogenic variant of the ATP1A3 gene, confirming the diagnosis. Flunarizine treatment was ini tiated with a good clinical response at 12 months of follow-up. The diagnosis of AHC is complex and is frequently confused with epilepsy, so it is important to correctly perform the diffe rential diagnosis, including anamnesis, tests such as EEG, and careful observation of clinical events that, with the current access to audiovisual technology, becomes more accurate. The genetic analysis is a great diagnostic tool that, when performed in time, avoids other unnecessary tests and therapies.

Frequent Fall: Seizure or Weakness? A Case Report of Alternating Hemiplegia of Childhood

Alternating Hemiplegia of Childhood (AHC) is a complex disease which causes recurrent hemiplegic attacks. Although ATP1A3 gene has been identified as the cause of this neurological entity, many variants are being reported nowadays, adding to the spectrum of ATP1A3 gene-related disorders due to the advancement in genetic testing. Hereby, authors presents a case report of a 3-year-old male child who presented with a complaint of frequent falls while walking with gait abnormality and has been on treatment for seizure disorder since, 5 months of age. On assessing the history and evaluating the child, AHC was suspected and the same was confirmed using genetic tests.

The impact of Transcranial Magnetic Stimulation (TMS) on seizure course in people with and without epilepsy

ObjectiveTo elucidate the effects of single and paired-pulse TMS on seizure activity at electrographic and clinical levels in people with and without epilepsy. MethodsA cohort of 35 people with epilepsy, two people with alternating hemiplegia of childhood (AHC) with no epilepsy, and 16 healthy individuals underwent single or paired-pulse TMS combined with EEG. Clinical records and subject interviews were used to examine seizure frequency four weeks before and after TMS. ResultsThere were no significant differences in seizure frequency in any subject after TMS exposure. There was no occurrence of seizures in healthy individuals, and no worsening of hemiplegic attacks in people with AHC. ConclusionsNo significant changes in seizure activity were found before or after TMS. SignificanceThis study adds evidence on the safety of TMS in people with and without epilepsy with follow-up of four weeks after TMS.

Non-Stationary Outcome of Alternating Hemiplegia of Childhood into Adulthood.

ABSTRACTBackgroundAlthough described as non‐progressive, alternating hemiplegia of childhood (AHC) can display a sudden deterioration, anecdotally reported mainly in childhood. Outcome in adulthood is uncertain.ObjectivesAim of this study is to describe the long‐term follow‐up of neurological function in adults with AHC.MethodsSeven adults with AHC were included in this retrospective single‐center study. Clinical history and previous investigation data were gathered from the review of medical records. Video‐documented neurological examination was performed at the last follow‐up visit in four out of the seven reported indivisuals.ResultsOver a median follow‐up of 16 years, neurological outcome and trajectories were heterogeneous. All individuals showed new neurological signs or symptoms. Three experienced a serious irreversible neurological deterioration after prolonged quadriplegic episodes and/or status epilepticus in their second or third decade. One patient died at age 29.ConclusionsThis video‐series suggests that AHC in adulthood is not stationary; larger cohorts are needed to identify genotype–phenotype correlations and clinically useful outcome predictors.

ATP1A3-related disorders in the differential diagnosis of acute brainstem and cerebellar dysfunction.

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia-Parkinsonism (RDP), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) are all caused by mutations in the same gene: ATP1A3. Although initially they were considered separate disorders, recent evidence suggests a continuous clinical spectrum of ATP1A3-related disorders. At onsetall these disorders can present with acute brainstem dysfunction triggered by a febrile illness. An infectious or autoimmune disorder is usually suspected. A genetic disorder is rarely considered in the first acute episode. We present three patients with ATP1A3 mutations: one patient with AHC, one patient with RDP, and one patient with CAPOS syndrome. We describe the acute onset and overlapping clinical features of these three patients with classical phenotypes. These cases highlight ATP1A3-related disorders as a possible cause of acute brainstem dysfunction with normal ancillary testing.

ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.

BackgroundPathogenic variation in the ATP1A3‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements.Methods and ResultsWe analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype‐negative status, and significantly shorter in patients with the ATP1A3‐D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3‐D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death.ConclusionsPatients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

A case report of atypical hemiplegic migraine with nonheadache onset in a Chinese child

BackgroundHemiplegic 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 presentationWe 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.ConclusionsHM 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.

Advances in genotype-phenotype associations for CACNA1A-related epilepsies

Voltage-gated calcium channels play an important part in neuronal excitability. Pathogenic CACNA1A variants have been reported in a variety of neurological disorders including those affecting movement and balance such as Episodic Ataxia type 2 (EA2) and Spinocerebellar Ataxia type 6 (SCA6) as well as those causing transient hemiplegic symptoms including Familial Hemiplegic Migraine type 1 (FHM1) and Alternating Hemiplegia of Childhood (AHC). More recently pathogenic CACNA1A variants were identified as an important cause of epileptic encephalopathies expanding the phenotypic spectrum of CACNA1A-related disorders [1] with an incidence of approximately 1 per 85,000 live births [2].

De novo ATP1A2 variants in two Chinese children with alternating hemiplegia of childhood upgraded the gene\u2013disease relationship and variant classification: a case report

BackgroundATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far.Case presentationWe 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.ConclusionsThe 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.