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:
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.
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.
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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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