ATP1A3 Mutations Research Articles

Abstract 4135211: Children with the D801N Variant of the ATP1A3- Encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate Paradoxical QT Response to Bradycardia and Increased Ventricular Arrhythmia Risk

Introduction: Alternating hemiplegia of childhood (AHC) is a rare condition most frequently caused by mutations in ATP1A3, encoding for the alpha-3 subunit of Na + /K + -ATPase, and D801N is the most common variant. Individuals with ATP1A3-D801N have shorter corrected QT (QTc) than those with other variants and can experience ventricular arrhythmias following bradycardia; however, the mechanism of why this occurs is unknown. Goals: To analyze how QT and QTc change with heart rate in ATP1A3-D801N compared to healthy individuals. Hypothesis: Individuals with ATP1A3-D801N have increased shortening of QT and QTc at lower heart rate. Methods: In this retrospective observational study, patients seen for evaluation of AHC at Duke University Medical Center were categorized by genotype: ATP1A3-D801N, ATP1A3 non-D801N single nucleotide variant, ATP1A3 loss-of-function variant, and genotype negative. A cohort of matched healthy children was also compiled. We collected average heart rate, QT, and QTc measurements over 5-minute intervals from Holter recordings using HScribe TM software and conducted manual blinded validation to ensure accuracy. We then used linear regression to investigate the relationship between heart rate, QT, and QTc. Results: The cohort consisted of 44 patients with ATP1A3 -related phenotypes with 81 total Holter recordings (52.27% female; mean age at first Holter 8.04 years), compared to 36 healthy individuals with 57 total Holter recordings (52.78% female; mean age at first Holter 9.84 years). Patients with ATP1A3-D801N showed diminished prolongation of QT with decreasing heart rate, manifested as a reduced mean slope for heart rate vs QT compared to healthy (-0.85 ± 0.46 vs -1.52 ± 0.42, p<0.0001). This blunted QT response resulted in paradoxical shortening of QTc at lower heart rate, demonstrated by an increased mean slope for heart rate vs QTc compared to healthy (0.80 ± 0.51 vs 0.22 ± 0.43, p<0.0001). Further, patients with ATP1A3- related phenotypes and very short baseline QTc showed increased shortening of QT and QTc at lower heart rate compared to those with normal QTc (p=0.0025 and p=0.0013, respectively). Conclusions: Children with AHC and ATP1A3-D801N demonstrate a paradoxical shortening of QT and QTc with slowing of heart rate. The impaired prolongation of QT and resultant further shortening of QTc increase the risk of arrhythmia. We put this forward as a novel mechanism of sudden cardiac arrest in patients with ATP1A3 mutations.

Developmental and Epileptic Encephalopathy Produced by the ATP1A2 Mutation

Developmental and Epileptic Encephalopathy Produced by the ATP1A2 Mutation

A novel ATP2A2 mutation in Darier and genotype phenotype: correlation analysis.

Darier's disease (DD) is a skin disorder caused by mutations in the ATP2A2 gene. Researchers have been investigating the correlation between genotype and phenotype in DD. Understanding the genotype-phenotype relationship in DD can enhance our comprehension of the genetic background and phenotypic characteristics of the condition, as well as the relationship between its systemic and localized manifestations. This study aimed to investigate the molecular pathogenesis of DD in a Chinese family, and to elucidate the genotype-phenotype correlation in DD by summarizing relevant literature. Gene mutations associated with DD were screened by whole-exome sequencing and verified using Sanger sequencing. Genetic analysis assessed the potential impact of these mutations. Genotype-phenotype correlation was obtained by chi-square analysis using literature search test. (1) A novel ATP2A2 Missense mutation, c.2560T>C (p.W854R), was identified and confirmed by Sanger sequencing. Annotation analysis with the ANNOVAR tool indicated that this mutation disrupts normal protein function and is linked to DD clinical manifestations. (2) Genotype-phenotype analysis showed a significant correlation between the prevalence of DD-related mental disorders and geographic regions (P = 0.00), but no association between mutation type and mental disorder prevalence (P = 0.324). The age of onset varied between sporadic and familial cases (P = 0.032), averaging 33years in sporadic cases and 16years in familial cases. By analyzing the genotype-phenotype correlation, we aim to enhance our understanding of the genetic basis of DD. This research could improve early diagnosis, intervention, and the development of personalized long-term health management plans.

Rare Manifestation of ATP1A3 Mutation with Clinical Response to Cannabidiol.

Rare Manifestation of ATP1A3 Mutation with Clinical Response to Cannabidiol.

Phenotype Distinctions in Mice Deficient in the Neuron-Specific α3 Subunit of Na,K-ATPase: Atp1a3tm1Ling/+ and Atp1a3 +/D801Y.

ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression (Atp1a3tm1Ling/+) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 +/D801Y). Both mouse lines had normal lifespans, but Atp1a3 +/D801Y had mild perinatal mortality contrasting with D801N mice (Atp1a3 +/D801N), which had high mortality. The phenotypes of Atp1a3tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a3tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 +/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well quantified by conventional tests. Paradoxically, Atp1a3 +/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3 +/D801Y mice were overactive in forced swimming and afterward had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3 +/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple Atp1a3 mutations in animal models to understand the roles of this gene in human disease.

Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities

Although most cases of Parkinson’s disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

Successful treatment of Darier's disease with apremilast and review of reported cases.

Darier's disease (DD) is a rare autosomal dominant genetic disorder caused by a mutation in ATP2A2, which encodes calcium (Ca2+) ATPase pumps in the endoplasmic reticulum. In this report, we present the first documented case in Japan successfully treated with apremilast. An 18-year-old female presented with red or brown hyperkeratotic papules and plaques on her head, neck, and chest. Histopathological examination revealed a hyperkeratotic, acanthotic epidermis, along with suprabasal acantholysis characterized by corps ronds and grains. Exome sequencing of DNA from peripheral blood mononuclear cells identified a missense mutation in ATP2A2. Based on the above results, we diagnosed her with DD despite the absence of a family history. Given the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, in treating Hailey-Hailey disease (HHD), a genetically related disorder involving ATPases in epidermal calcium channels, we opted for apremilast therapy. Eight weeks post-initiation, significant improvement was observed in the patient's skin lesions on the head, neck, and chest. In this paper, we discuss the successful treatment of DD and HHD cases with apremilast, providing insights into its therapeutic potential, and offer a comprehensive review.

Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease.

Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.

Na,K-ATPase Expression Can Be Limited Post-Transcriptionally: A Test of the Role of the Beta Subunit, and a Review of Evidence.

The Na,K-ATPase is an α-β heterodimer. It is well known that the Na,K-ATPase β subunit is required for the biosynthesis and trafficking of the α subunit to the plasma membrane. During investigation of properties of human ATP1A3 mutations in 293 cells, we observed a reciprocal loss of endogenous ATP1A1 when expressing ATP1A3. Scattered reports going back as far as 1991 have shown that experimental expression of one subunit can result in reduction in another, suggesting that the total amount is strictly limited. It seems logical that either α or β subunit should be rate-limiting for assembly and functional expression. Here, we present evidence that neither α nor β may be limiting and that there is another level of control that limits the amount of Na,K-ATPase to physiological levels. We propose that α subunits compete for something specific, like a private chaperone, required to finalize their biosynthesis or to prevent their degradation in the endoplasmic reticulum.

Establishment of a transgene-free iPS cell line (SDCHi007-A) from a young patient bearing a ATP1A2 mutation and suffering from Epilepsy

Epilepsy is a chronic neurological disease. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient diagnosed as epilepsy caused by ATP1A2 gene mutation. Induced pluripotent stem cells (iPSCs) were developed using non-integrating episomal vectors containing OCT4, SOX2, KLF4, BCL-XL and C-MYC. The established iPSC line (SDCHi007-A) displayed pluripotent cell morphology, high expression levels of pluripotency markers, differentiation potential in vitro, normal karyotype, and remaining the original ATP1A2 gene mutation.

CAPOS Syndrome with Fluctuating Symptoms

AbstractWe report a patient with CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) with classic features who also exhibited fluctuating vestibulocochlear symptoms that met the criteria for Meniere's disease. A male patient was initially symptomatic at 13 months of age with ataxia and loss of deep tendon reflexes in the setting of fever. This was followed by the development of baseline ataxia with superimposed spells of vertigo and ataxia, progressive hearing loss with episodic fluctuations, optic atrophy, pes cavus, and areflexia. Spells lasted minutes to hours and were frequently triggered by ambient heat and fever. He was diagnosed with a de novo pathogenic variant p.Glu818Lys mutation in ATP1A3. We provide detailed clinical features of this case, a summary of CAPOS cases reported to date, and an overview of allelically related syndromes.

Role of copper in central nervous system physiology and pathology.

Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

ATP1A3-alternating hemiplegia

Alternating hemiplegia (AH) is a rare and little researched disease. AH is characterized with early episodes of hemiplegia (from a few minutes to a few days), abnormal movements and cognition, and probable development of neurological defi ciency. Studies of genetic basis have led to discovery of mutations in gen ATP1A3, which codes alfa-3 subunit of Na+/K+-ATPase. For research, genetic data are considered most important prognostic information. Its diagnostics is diffi cult due to similarity of some symptoms to epilepsy and absence of deviations at neuro-visualisation. This article is an attempt to generalize world scientifi c experience and to determine most important research derections.

Alternating hemiplegia of childhood misdiagnosed as hysteria: a case report

BackgroundAlternating hemiplegia of childhood (AHC) is a rare pediatric syndrome characterized by recurring episodes of hemiplegia or quadriplegia, and frequently accompanied by dystonic posturing, choreoathetosis movements, anomalous ocular motions, and a gradual deterioration in cognitive function. The principal etiology of this disorder is traced back to mutations in the ATP1A3 gene.Case presentationHere, we report a 16-year-old girl with recurrent hemiplegia since her infancy. This patient has experienced paroxysmal limb weakness and aphasia for over 15 years, and has kept seeking medical attention but without receiving effective treatment. A misdiagnosis of hysteria persisted for over 4 years until the patient’s admission to our hospital. Whole-exome sequencing identified a known pathogenic heterozygous c.2270T>C (p.Leu757Pro) mutation in her ATP1A3 gene. Notably, her clinical manifestations, including pathological emotional responses and autonomic dysfunction, differed from the established profile associated with the same ATP1A3 mutation, which typically present with intellectual disability, a rostrocaudal symptom gradient, choreoathetosis, and dysarthria. The patient was finally diagnosed with AHC and treated with flunarizine thus significantly ameliorated hemiplegic episodes.ConclusionsThis case enhances our understanding of the intricate clinical manifestations of AHC, which require careful differentiation from various diseases such as epilepsy, hysteria, and paroxysmal dyskinesias. In the diagnosis of patients presenting with suspected symptoms, adhering to a systematic approach for localizing and diagnosing neurological disorders is crucial to prevent misdiagnosis and inappropriate treatments. Additionally, when AHC is suspected in a patient, genetic testing should be considered as part of the diagnostic approach.

Childhood-related neural genotype-phenotype in ATP1A3 mutations: comprehensive analysis.

ATP1A3 is a gene that encodes the ATPase Na + /K + transporting subunit alpha-3 isoenzyme that is widely expressed in GABAergic neurons. It maintains metabolic balance and neurotransmitter movement. These pathways are essential for the proper functioning of the nervous system. A mutation in the ATP1A3 gene demonstrates remarkable genotype-phenotype heterogeneity. To provide insight into patients with ATP1A3 mutation. These cases were identified using next generation sequencing. The patients' clinical and genetic data were retrieved. Detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data of all pediatric patients were extracted. The study included 14 females and 12 males in addition to two novel females cases. Their mean current age is 6.3 ± 4.24years. There were 11.54% preterm pregnancies with 5 cases reporting pregnancy complications. Mean age of seizure onset was 1.07 ± 1.06years. Seizure semiology included generalized tonic-clonic, staring spells, tonic-clonic, and others. Levetiracetam was the most frequently used Anti-seizure medication. The three most frequently reported classical symptoms included alternating hemiplegia of childhood (50%), cerebellar ataxia (50%), and optic atrophy (23.08%). Non-classical symptoms included dystonia (73.08%), paroxysmal dyskinesias (34.62%), and encephalopathy (26.92%). Developmental delay was reported among 84.62% in cognitive, 92.31% in sensorimotor, 80.77% in speech, and 76.92% in socioemotional. EEG and MRI were non-specific. Our study demonstrated high heterogeneity among patients with pathogenic variants in the ATP1A3 gene. Such variation is multifactorial and can be a predisposition of wide genetic and clinical variables. Many patients shared few similarities in their genetic map including repeatedly reported de novo, heterozygous, mutations in the gene. Clinically, higher females prevalence of atypical presentation was noted. These findings are validated with prior evidence and the comprehensive analysis in this study.

ATP13A2 (PARK9) and basal ganglia function.

ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.

Developmental and epileptic encephalopathy produced by the ATP1A2 mutation

A case of DEE98, a rare developmental and epileptic encephalopathy related to previously reported the de novo missense mutation p.Arg908Gln in the ATP1A2 gene, is described. A girl examined first time in 11 months had microcephaly, severe mental and motor delay, strabismus, spastic paraparesis and pachypolymicrogyria on brain MRI that is atypical for DEE98. Epilepsy with polymorphic seizures started at the age of 15 months. There was a remission lasting 9 months, after which seizures renewed. DEE98 was diagnosed at the age of 2 years 9 months by exome sequencing verified by trio Sanger sequencing. Another finding from high-throughput exome sequencing were two previously undescribed heterozygous variants of uncertain pathogenicity in the SPART gene, which causes autosomal recessive spastic paraplegia type 20 (SPG20); Sanger sequencing confirmed the trans position of the variants. The common clinical sign with typical SPG20 was early spastic paraparesis with contractures; other symptoms did not coincide. Considering the phenotypic diversity of SPG20 and the possibility of a combination of two independent diseases, we performed an additional study of the pathogenicity of SPART variants at the mRNA level: pathogenicity was not confirmed, and there were no grounds to diagnose SPG20.

Chapter 9 - Familial hemiplegic migraine

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

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.