RARE DISEASE
Alternating hemiplegia of childhood
Alternating hemiplegia of childhood
Alternating hemiplegia of childhood
Synonyms: AHC
Synonyms: AHC
Synonyms: AHC
Drug discovery
3
drugs
With orphan designations
Overview
Alternating Hemiplegia of Childhood (AHC) is a rare neurodevelopmental disorder caused by ATP1A3 gene mutations in 75-80% of cases [1][4][16]. It manifests before 18 months with recurrent hemiplegic episodes (lasting minutes to days) that alternate sides, resolve with sleep, and are often triggered by environmental factors [2][4][6]. Paroxysmal features include dystonia, nystagmus, and autonomic dysfunction, while chronic comorbidities involve intellectual disability, epilepsy (50%), and motor deficits [1][4][19].
Burden
Neurodevelopmental: 100% exhibit cognitive/adaptive delays; 30% require wheelchair [4][6][19]
Multisystem morbidity: Epilepsy, dysphagia, cardiac abnormalities, and psychiatric disorders [4][16][19]
Lifelong disability: Frequent hospitalizations, caregiver dependency, and reduced quality of life [9][13][19]
Therapies
Flunarizine: First-line prophylactic agent to reduce attack frequency/severity (50-80% efficacy in open-label use) [3][13][17]
Acute management: Benzodiazepines, sleep induction [3][13]; ATP supplementation trialed in select cases [8]
Supportive care: Trigger avoidance, antiepileptics for seizures, multidisciplinary rehabilitation [3][16][19]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
90 drug discovery papers about Alternating hemiplegia of childhood, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
90 drug discovery papers about Alternating hemiplegia of childhood, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-02 | Alternating Hemiplegia of Childhood in a Clinical Context Case Presentation
Introduction: Alternating hemiplegia of childhood (AHC) is a rare disease characterized by recurrent episodes of alternating hemiplegia or quadriplegia that improve during sleep and vary in duration. Onset occurs before 18 months of age and is preceded by abnormal eye movements, accompanied by tonic and dystonic attacks with subsequent developmental regression. The main etiology is related to the ATP1A3 genetic mutation. Clinical case: A 16-month-old male preschooler with no significant personal or family history. He had previously experienced psychomotor developmental delay in motor skills and language, accompanied by abnormal eye movements. At 12 months of age, he had two episodes: the first, in the context of an arboviral infection, resulted in diplegia; the second, following a prolonged bus trip, involved left hemiplegia lasting 7 days, with spontaneous recovery and no alteration of consciousness, followed by dystonic episodes. Complementary studies of cerebrospinal fluid cytochemistry and culture, multislice cranial CT scan, and normal metabolic studies in urine and serum were performed. Electroencephalography showed slow delta global activity without paroxysms. Treatment was initiated with flunarizine 5 mg daily at night. Follow-up was in the Neuropediatrics outpatient clinic. Genetic testing was limited. Conclusion: Alternating hemiplegia of childhood (AHC) is an entity whose diagnosis is essentially clinical, and our patient met the clinical criteria. Treatment with flunarizine is important to improve prognosis and quality of life.
2026-05-19 | ATP1A3-related syndromes: our case-series unveiling a dynamic, fever-triggered and overlapping array of neurological phenotypes.
ATP1A3-related neurological disorders show a broad spectrum of manifestations, usually with autosomal dominant transmission. Classical phenotypes include alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and syndrome characterized by cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS). Additional rarer forms include childhood-onset-schizophrenia (COS), encephalopathy with MRI abnormalities without hemiplegia (D-DEMØ), fever-induced paroxysmal weakness and encephalopathy (FIPWE), and relapsing encephalopathy with cerebellar ataxia (RECA). These conditions often overlap, sharing core symptoms due to dysfunction of the Na⁺/K⁺-ATPase α3 subunit. Some mutations result in a thermolabile enzyme, which impairs its function under stress, leading to weakness' episodes, encephalopathy and ataxia. We report a patients' cohort with ATP1A3 mutations followed at Santobono-Pausilipon Children's Hospital in Naples. The first family includes three siblings with RECA (p.Arg756Cys). The second cluster comprises a mother and son with FIPWE (p.Arg756His). We also describe one case of AHC (p.Asp801Asn) and one of CAPOS (p.Arg756Cys). All patients showed marked susceptibility to infection and fever. Our case series confirms the complex clinical scenarios in ATP1A3-related disorders, with symptoms overlapping and possible interfamilial variability, contributing to the diagnostic challenge posed by a rare genetic disorder, already observed in individuals with ATP1A3 gene mutations. The ongoing effort to characterize the clinical phenotype and identify "core" symptoms is necessary to expand our knowledge of the genotype-phenotype correlation, which is currently unclear. More importantly, our series highlights the molecular fragility of mutant ATP1A3, particularly its sensitivity to fever. Proactive prevention of fever and time management may be crucial to reducing the risk of neurological deterioration in affected individuals.
2026-04-08 | D801N in ATP1A3-encoded Na/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger-mediated calcium overload.
Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.
2026-02-04 | Parallels between bipolar disorder and ATP1A3-related diseases: a window into the investigation of lithium for alternating hemiplegia of childhood.
BACKGROUND: Alternating hemiplegia of childhood (AHC) shares many aspects with the psychiatric condition, bipolar disorder. BODY: AHC is a heterogeneous genetic disorder that can manifest in various fashions but will usually involve paroxysmal neuropsychiatric symptoms that are precipitated by environmental events or stressors, superimposed over developmental abnormalities of various severities. It occurs as a consequence of a variety of mutations of the alpha3 subunit of the sodium pump (ATP1A3). Treatment is generally symptomatic with flunarizine a nonselective calcium channel blocker, but other approaches have been attempted. Nonetheless, given the inadequate response of most patients, there continues to be a significant unmet need for adequate treatment approaches. Bipolar disorder, a severe psychiatric illness, also manifests with paroxysmal neuropsychiatric symptoms that are precipitated by environmental events or stressors. It is also characterized by significant dysfunction of the sodium pump. Lithium is an effective intervention for bipolar disorder and has never been utilized in AHC. CONCLUSION: Both bipolar disorder and AHC are associated with sodium pump dysfunction and increased intracellular sodium concentration. Both conditions respond to calcium channel blockers and the ketogenic diet. Lithium trials in AHC are warranted.
2025-12-01 | Unraveling Alternating Hemiplegia of Childhood: A Case Report with Genetic and Clinical Insights.
Alternating hemiplegia of childhood (AHC) is a complex neurological disorder comprising paroxysmal episodes of repeated, transient paresis involving either or both sides of the body, with onset usually before the age of 18 months. The etiology is varied and includes channelopathy, mutations of the ATP1A3 gene that encode alpha subunit of the NA+-K+ ATPase pump. A 7-month-old girl presented with tonic neck deviation of the neck and eyes, episodic hemiparesis affecting both sides alternatively. Each episode resolved after sleep and was precipitated by hunger, fever, and sleep deprivation. Neurological examination and laboratory workup, including MRI and EEG, were normal. Whole-exome sequencing revealed a heterozygous de novo pathogenic mutation in the ATP1A3 gene (p.Asp801Asn), confirming AHC. She was started on flunarizine, a calcium channel blocker. Significant clinical improvement and catch-up in developmental milestones were observed on follow-up. AHC is frequently misdiagnosed due to its rarity and varied presentation. Diagnosis is clinical and supported by genetic testing. Mutations in ATP1A3 are common and often cluster at specific hotspots. Management includes symptomatic treatment and supportive care, with flunarizine offering some benefit. This case highlights the need for early recognition and genetic confirmation of AHC to initiate therapy and improve quality of life.
gene therapies
2025-11-30 | USE OF CRISPR BASE EDITING AND PRIME EDITING IN NEUROLOGICAL DISEASES
Next-generation gene editing technologies, particularly base editing and prime editing, have emerged as highly promising approaches for the treatment of neurological diseases driven by pathogenic mutations and genomic instability. Unlike conventional CRISPR-Cas9 methods that introduce double-strand breaks, these systems enable precise nucleotide conversions or guided sequence replacements, thereby reducing off-target events and increasing safety for central nervous system (CNS) applications. Recent studies demonstrate their applicability in cellular and animal models of conditions such as Alternating Hemiplegia of Childhood, Huntington’s disease, and repeat-associated ataxias, showing functional restoration, decreased somatic repeat expansion, and improvement of neurological phenotypes. However, the clinical translation of these tools still faces substantial challenges, including limitations in CNS delivery, target-dependent efficiency, and the need for comprehensive biosafety evaluation. Viral and nonviral platforms—such as optimized AAVs, lipid nanoparticles, and virus-like particles—are under active development to overcome these barriers. Additional gaps remain regarding editing durability, immunogenicity, and scalability. This article provides an integrated analysis of the principles, preclinical applications, technical limitations, and future perspectives of base editing and prime editing in neurological diseases, emphasizing their transformative potential and the necessity of rigorous, safety-driven research.
2025-10-06 | Alternating Hemiplegia of Childhood and ATP1A3-Related Diseases: Insights From a Decade of Discovery and Collaboration.
This report presents key insights from the 2022 annual conference held in Edinburgh, commemorating the 10th anniversary of the discovery of ATP1A3 variants in alternating hemiplegia of childhood (AHC). This milestone event marked a decade of rapid advancements in research and clinical understanding, bringing together international experts and those with lived experience to reflect on progress, identify ongoing challenges, and shape the future of ATP1A3-related disease research. Over the past 10 years, our knowledge of ATP1A3-related diseases has expanded significantly, revealing a broader clinical spectrum, complex genotype-phenotype correlations, and novel pathophysiologic mechanisms. This symposium provided new data on cardiac and respiratory involvement in AHC, the impact of Na+, K+-ATPase dysfunction on neurodevelopment, and the evolving understanding of progressive disease trajectories. The conference also showcased emerging therapeutic strategies, including gene therapy, antisense oligonucleotides, and small-molecule interventions. This article synthesizes these discussions, offering a comprehensive overview of a decade of progress while highlighting the urgent need for continued collaboration. By integrating research, clinical expertise, and lived experience advocacy, the ATP1A3 community is paving the way for improved diagnosis, enhanced care, and the development of targeted treatments for these ultra-rare conditions.
2025-07-23 | In vivo prime editing rescues alternating hemiplegia of childhood in mice.
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K+ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%-90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain cortex. In vivo PE rescued clinically relevant phenotypes, including restoration of ATPase activity; amelioration of paroxysmal spells, motor defects, and cognition deficits; and dramatic extension of animal lifespan. This work suggests a potential one-time PE treatment for AHC and establishes the ability of PE to rescue a neurological disease in animals.
2022-01-31 | Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.
Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.
proteins
2022-06-17 | Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.
Abstract Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl− ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood–brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.
cell therapies
2024-12-24 | Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (~40% of patients) and p.E815K (~25% of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815 variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
small molecules
2026-06-02 | Alternating Hemiplegia of Childhood in a Clinical Context Case Presentation
Introduction: Alternating hemiplegia of childhood (AHC) is a rare disease characterized by recurrent episodes of alternating hemiplegia or quadriplegia that improve during sleep and vary in duration. Onset occurs before 18 months of age and is preceded by abnormal eye movements, accompanied by tonic and dystonic attacks with subsequent developmental regression. The main etiology is related to the ATP1A3 genetic mutation. Clinical case: A 16-month-old male preschooler with no significant personal or family history. He had previously experienced psychomotor developmental delay in motor skills and language, accompanied by abnormal eye movements. At 12 months of age, he had two episodes: the first, in the context of an arboviral infection, resulted in diplegia; the second, following a prolonged bus trip, involved left hemiplegia lasting 7 days, with spontaneous recovery and no alteration of consciousness, followed by dystonic episodes. Complementary studies of cerebrospinal fluid cytochemistry and culture, multislice cranial CT scan, and normal metabolic studies in urine and serum were performed. Electroencephalography showed slow delta global activity without paroxysms. Treatment was initiated with flunarizine 5 mg daily at night. Follow-up was in the Neuropediatrics outpatient clinic. Genetic testing was limited. Conclusion: Alternating hemiplegia of childhood (AHC) is an entity whose diagnosis is essentially clinical, and our patient met the clinical criteria. Treatment with flunarizine is important to improve prognosis and quality of life.
2026-05-19 | ATP1A3-related syndromes: our case-series unveiling a dynamic, fever-triggered and overlapping array of neurological phenotypes.
ATP1A3-related neurological disorders show a broad spectrum of manifestations, usually with autosomal dominant transmission. Classical phenotypes include alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and syndrome characterized by cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS). Additional rarer forms include childhood-onset-schizophrenia (COS), encephalopathy with MRI abnormalities without hemiplegia (D-DEMØ), fever-induced paroxysmal weakness and encephalopathy (FIPWE), and relapsing encephalopathy with cerebellar ataxia (RECA). These conditions often overlap, sharing core symptoms due to dysfunction of the Na⁺/K⁺-ATPase α3 subunit. Some mutations result in a thermolabile enzyme, which impairs its function under stress, leading to weakness' episodes, encephalopathy and ataxia. We report a patients' cohort with ATP1A3 mutations followed at Santobono-Pausilipon Children's Hospital in Naples. The first family includes three siblings with RECA (p.Arg756Cys). The second cluster comprises a mother and son with FIPWE (p.Arg756His). We also describe one case of AHC (p.Asp801Asn) and one of CAPOS (p.Arg756Cys). All patients showed marked susceptibility to infection and fever. Our case series confirms the complex clinical scenarios in ATP1A3-related disorders, with symptoms overlapping and possible interfamilial variability, contributing to the diagnostic challenge posed by a rare genetic disorder, already observed in individuals with ATP1A3 gene mutations. The ongoing effort to characterize the clinical phenotype and identify "core" symptoms is necessary to expand our knowledge of the genotype-phenotype correlation, which is currently unclear. More importantly, our series highlights the molecular fragility of mutant ATP1A3, particularly its sensitivity to fever. Proactive prevention of fever and time management may be crucial to reducing the risk of neurological deterioration in affected individuals.
2026-04-08 | D801N in ATP1A3-encoded Na/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger-mediated calcium overload.
Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.
2026-02-04 | Parallels between bipolar disorder and ATP1A3-related diseases: a window into the investigation of lithium for alternating hemiplegia of childhood.
BACKGROUND: Alternating hemiplegia of childhood (AHC) shares many aspects with the psychiatric condition, bipolar disorder. BODY: AHC is a heterogeneous genetic disorder that can manifest in various fashions but will usually involve paroxysmal neuropsychiatric symptoms that are precipitated by environmental events or stressors, superimposed over developmental abnormalities of various severities. It occurs as a consequence of a variety of mutations of the alpha3 subunit of the sodium pump (ATP1A3). Treatment is generally symptomatic with flunarizine a nonselective calcium channel blocker, but other approaches have been attempted. Nonetheless, given the inadequate response of most patients, there continues to be a significant unmet need for adequate treatment approaches. Bipolar disorder, a severe psychiatric illness, also manifests with paroxysmal neuropsychiatric symptoms that are precipitated by environmental events or stressors. It is also characterized by significant dysfunction of the sodium pump. Lithium is an effective intervention for bipolar disorder and has never been utilized in AHC. CONCLUSION: Both bipolar disorder and AHC are associated with sodium pump dysfunction and increased intracellular sodium concentration. Both conditions respond to calcium channel blockers and the ketogenic diet. Lithium trials in AHC are warranted.
2025-12-01 | Unraveling Alternating Hemiplegia of Childhood: A Case Report with Genetic and Clinical Insights.
Alternating hemiplegia of childhood (AHC) is a complex neurological disorder comprising paroxysmal episodes of repeated, transient paresis involving either or both sides of the body, with onset usually before the age of 18 months. The etiology is varied and includes channelopathy, mutations of the ATP1A3 gene that encode alpha subunit of the NA+-K+ ATPase pump. A 7-month-old girl presented with tonic neck deviation of the neck and eyes, episodic hemiparesis affecting both sides alternatively. Each episode resolved after sleep and was precipitated by hunger, fever, and sleep deprivation. Neurological examination and laboratory workup, including MRI and EEG, were normal. Whole-exome sequencing revealed a heterozygous de novo pathogenic mutation in the ATP1A3 gene (p.Asp801Asn), confirming AHC. She was started on flunarizine, a calcium channel blocker. Significant clinical improvement and catch-up in developmental milestones were observed on follow-up. AHC is frequently misdiagnosed due to its rarity and varied presentation. Diagnosis is clinical and supported by genetic testing. Mutations in ATP1A3 are common and often cluster at specific hotspots. Management includes symptomatic treatment and supportive care, with flunarizine offering some benefit. This case highlights the need for early recognition and genetic confirmation of AHC to initiate therapy and improve quality of life.
gene therapies
2025-11-30 | USE OF CRISPR BASE EDITING AND PRIME EDITING IN NEUROLOGICAL DISEASES
Next-generation gene editing technologies, particularly base editing and prime editing, have emerged as highly promising approaches for the treatment of neurological diseases driven by pathogenic mutations and genomic instability. Unlike conventional CRISPR-Cas9 methods that introduce double-strand breaks, these systems enable precise nucleotide conversions or guided sequence replacements, thereby reducing off-target events and increasing safety for central nervous system (CNS) applications. Recent studies demonstrate their applicability in cellular and animal models of conditions such as Alternating Hemiplegia of Childhood, Huntington’s disease, and repeat-associated ataxias, showing functional restoration, decreased somatic repeat expansion, and improvement of neurological phenotypes. However, the clinical translation of these tools still faces substantial challenges, including limitations in CNS delivery, target-dependent efficiency, and the need for comprehensive biosafety evaluation. Viral and nonviral platforms—such as optimized AAVs, lipid nanoparticles, and virus-like particles—are under active development to overcome these barriers. Additional gaps remain regarding editing durability, immunogenicity, and scalability. This article provides an integrated analysis of the principles, preclinical applications, technical limitations, and future perspectives of base editing and prime editing in neurological diseases, emphasizing their transformative potential and the necessity of rigorous, safety-driven research.
2025-10-06 | Alternating Hemiplegia of Childhood and ATP1A3-Related Diseases: Insights From a Decade of Discovery and Collaboration.
This report presents key insights from the 2022 annual conference held in Edinburgh, commemorating the 10th anniversary of the discovery of ATP1A3 variants in alternating hemiplegia of childhood (AHC). This milestone event marked a decade of rapid advancements in research and clinical understanding, bringing together international experts and those with lived experience to reflect on progress, identify ongoing challenges, and shape the future of ATP1A3-related disease research. Over the past 10 years, our knowledge of ATP1A3-related diseases has expanded significantly, revealing a broader clinical spectrum, complex genotype-phenotype correlations, and novel pathophysiologic mechanisms. This symposium provided new data on cardiac and respiratory involvement in AHC, the impact of Na+, K+-ATPase dysfunction on neurodevelopment, and the evolving understanding of progressive disease trajectories. The conference also showcased emerging therapeutic strategies, including gene therapy, antisense oligonucleotides, and small-molecule interventions. This article synthesizes these discussions, offering a comprehensive overview of a decade of progress while highlighting the urgent need for continued collaboration. By integrating research, clinical expertise, and lived experience advocacy, the ATP1A3 community is paving the way for improved diagnosis, enhanced care, and the development of targeted treatments for these ultra-rare conditions.
2025-07-23 | In vivo prime editing rescues alternating hemiplegia of childhood in mice.
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K+ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%-90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain cortex. In vivo PE rescued clinically relevant phenotypes, including restoration of ATPase activity; amelioration of paroxysmal spells, motor defects, and cognition deficits; and dramatic extension of animal lifespan. This work suggests a potential one-time PE treatment for AHC and establishes the ability of PE to rescue a neurological disease in animals.
2022-01-31 | Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.
Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.
proteins
2022-06-17 | Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.
Abstract Claudin-5 is the most enriched tight junction protein at the blood–brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl− ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood–brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.
cell therapies
2024-12-24 | Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (~40% of patients) and p.E815K (~25% of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then, performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815 variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
3 orphan drug designations for Alternating hemiplegia of childhood.
3 orphan drug designations for Alternating hemiplegia of childhood.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
flunarizine | small molecules | FDA | 2018-11-20 | — | Xenon Pharmaceuticals, Inc. |
flunarizine | small molecules | FDA | 2013-06-24 | — | Marathon Pharmaceuticals, LLC |
flunarizine | small molecules | FDA | 1986-01-06 | — | Janssen Research Foundation |
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