Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Alternating Hemiplegia of Childhood. Core disease mechanisms, molecular an...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 17
• Snippets retrieved: 20

Relevant Papers

[1] Advances for pediatricians in 2022: allergy, anesthesiology, cardiology, dermatology, endocrinology, gastroenterology, genetics, global health, infectious diseases, metabolism, neonatology, neurology, oncology, pulmonology

• Authors: C. Caffarelli, Francesca Santamaria, E. Piro, S. Basilicata, Lorenzo D'Antonio et al.
• Year: 2023
• Venue: Italian Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/11322879fbcc4194d6764fd92a408e1c2b1d9840
• DOI: 10.1186/s13052-023-01522-8
• PMID: 37679850
• PMCID: 10485969
• Citations: 1
• Summary: Novel valuable developments in epidemiology, pathophysiology, prevention, diagnosis and treatment that can rapidly change the approach to diseases in childhood have been included and discussed.
• Evidence snippets:
• Snippet 1 (score: 0.505) > Alternating hemiplegia of childhood is an uncommon complex disorder, which was first described in late 1960s by Verret and Steele [160]. Alternating hemiplegia of childhood is characterized by paroxysmal episodes of repeated, transient paresis involving either or both sides of the body and usually presents before age 18 months. The diagnosis of alternating hemiplegia of childhood is mainly clinical but may be supported by molecular analysis. Although the pathophysiologic mechanism of the disorder is partially unclear, it is well known that a relevant role is played by mutations in ATP1A2 and ATP1A3 genes, which encode two different alpha subunits of the Na+/K + ATPase transmembrane ion pump, respectively [161]. Pavone et al. [162] reported on the clinical and genetic findings of a couple of twins and a couple of siblings with alternating hemiplegia of childhood from two different Italian families affected. In the twins a pathogenic variant in ATP1A3 gene (c.2318 A > G) was detected. In the siblings, the younger brother showed a novel GRIN2A variant (c.3175 T > A), while the older one carried the same GRIN2A variant, associated with two likely pathogenetic variants in SCNIB (c.632 > A) and KCNQ2 (1870 G > A) genes, which have been implicated in childhood epilepsies. This report provides additional information about alternating hemiplegia of childhood, showing that the variability of clinical features is mirrored by an unexpected genetic heterogeneity. Clinical signs of alternating hemiplegia of childhood usually follow a sequential pattern, in which the paroxysmal episodes are triggered by precipitating factors such as environmental stress, bathing or other events. Non-paroxysmal features include developmental delay/ intellectual disability, epilepsy, autonomic dysfunctions, abnormal eye involvement, movement disorders, ataxia, dystonia, and choreoathetosis [163].

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

• Authors: P. Pavone, X. Pappalardo, M. Ruggieri, R. Falsaperla, E. Parano
• Year: 2022
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/66be2e43c32ba1ed3e66fd144bf09ce7e8632a40
• DOI: 10.1097/MD.0000000000029413
• PMID: 35945798
• PMCID: 9351909
• Citations: 11
• Summary: Historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.498) > Alternating hemiplegia of childhood (AHC) is an uncommon neurological disorder mainly characterized by paroxysmal transient events of paresis involving either or both sides of the body, usually before the age of 18 months. [1,2] Events are often preceded by precipitating factors such as environmental stress, bathing, and psychological factors. Paroxysmal episodes may occur independently or in association with other clinical manifestations, such as autonomic Medicine dysfunction, altered awareness, and abnormal movements, such as dystonia, ataxia, and choreoathetosis. Affected individuals may show developmental delay/intellectual disability (DD/ID) and epileptic seizures. [1][2][3][4] Some symptoms tend to occur in sequential distinctive phases and disappear with sleep. [1][2][3][4] The prevalence of AHC is 1/1,000,000 in children under the age of 16 years, but this number could be underestimated due to the variability in clinical presentation and the lack of genetic analysis in the preceding epidemiologic data. [5,6] The underlying pathophysiological mechanisms of AHC and/or the various complex co-morbidities are not completely known. Advanced molecular research has allowed a better understanding of causal genes involved and provides, at the same time, early confirmation of the diagnosis. Mutations in ATP1A2 (AHC1; OMIM#104290) and ATP1A3 (AHC2; OMIM#614820), which encode two different alpha subunits of the neuronal NA+-K+ ATPase transmembrane ion pump, are the most frequent involved genes. [7][8][9][10] AHC individuals with ATP1A3 mutations are numerically more common than those with ATP1A2 mutations. [11] The wider use of genetic technology has enabled it to differentiate AHC diagnosis from other similar disorders and to extend its clinical spectrum. The aim of this study was not only to review the most recent clinical features and genetic data of the AHC disorder with its distinctive clinical and comorbidity variability but especially to report on other conditions linked to ATP1A3 mutations: ATP1A3-related disorders and ATP

[3] Navigating the Complexity of Alternating Hemiplegia in Childhood: A Comprehensive Review

• Authors: J. Rissardo, Nilorfar Murtaza Vora, Yogendra Singh, S. Kishore, A. Caprara
• Year: 2024
• Venue: Rambam Maimonides Medical Journal
• URL: https://www.semanticscholar.org/paper/08e057b637af02f8cf013b32e89d9dc607e9b03c
• DOI: 10.5041/RMMJ.10529
• PMID: 39088707
• PMCID: 11294682
• Citations: 2
• Summary: New diagnostic criteria for AHC is proposed, dividing it into clinical, laboratory, supporting, and atypical features, and the location of the mutations in the ATP1A3 protein of individuals with AHC, rapid-onset dystonia-parkinsonism (RDP) variants, and early infantile epileptic encephalopathy (variants with hemiplegic attack).
• Evidence snippets:
• Snippet 1 (score: 0.490) > Alternating hemiplegia of childhood (AHC) is a complex neurodevelopmental disorder mainly characterized by paroxysmal transient events of unilateral or bilateral paresis, usually before 18 months. 1 It is a rare and severe neurological disorder with a prevalence of 1:100,000 to 1:1,000,000. 2 Little is known about the several genetic, environmental, and biological factors that could potentially contribute to the pathophysiology of AHC. In this way, diagnosis and management are empirical in many cases, with few evidence-based studies to support specific tests or therapeutic strategies. > The AHC disorder has been associated with mutations in the ATP1A3 gene, which encodes the alpha-3 subunit of the neuronal Na + /K + -ATPase transmembrane ion pump in approximately 75% of patients. 3 The ATP1A3 gene is highly expressed in brain regions that influence the autonomic nervous system. 4 In approximately a quarter of the patients, ATP1A2 mutations were encountered, while in a minority of the subjects, the etiology is still unknown. > The presentation of AHC is often associated with precipitating factors such as environmental and psychological stressors. Paroxysmal episodes may occur independently or in association with other clinical manifestations, such as autonomic dysfunction, altered mental status, and abnormal movements, such as dystonia, ataxia, and choreoathetosis. 5 typical clinical pattern can be observed in most individuals with AHC. In this way, it is possible to divide the clinical progression of the disease into three phases. The first phase occurs during the first 3 months of age, and the main clinical feature is abnormal ocular movements, which can be associated with dystonia. 1 The second phase generally starts at 4 months and usually extends until 6 years; it is characterized by hemiplegic spells. In this phase, the patient can also present delayed developmental milestones and seizures. 5 In the last phase, unremitting neurological deficits could be observed. Other significant findings in the last phase include persistent developmental delays and, less frequently, hemiplegic and dystonic spells.
• Snippet 2 (score: 0.410) > Alternating hemiplegia of childhood is a complex and diverse disorder characterized primarily by hemiplegic episodes, varying widely in frequency and intensity. These episodes commonly coincide with epilepsy, developmental delay, movement disorders, and autonomic nervous system dysfunction. Most AHC cases are associated with ATP1A3-related disorders, encompassing RDP, CAPOS syndrome, EIEE, childhood rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia.

[4] Alternating hemiplegia of childhood: new diagnostic options.

• Authors: A. Gergont, M. Kaciński
• Year: 2014
• Venue: Neurologia i neurochirurgia polska
• URL: https://www.semanticscholar.org/paper/713528dee2a22d6a5e55652cd7ff24fea78e1f36
• DOI: 10.1016/j.pjnns.2013.05.003
• PMID: 24821639
• Citations: 14
• Summary: The variability of individual clinical presentations and evolution of symptoms have made diagnosis difficult, and the problems of misdiagnosis could account for the low prevalence of this syndrome.
• Evidence snippets:
• Snippet 1 (score: 0.457) > in 1976 as 'alternating hemiplegia in a child' [8]. The next case of a girl with AHC hospitalized at the Department of Neurology of Polish Mother's Memorial Research Institute Hospital (Centrum Zdrowia Matki Polki) in Łodź was described in 1995 as 'alternating hemiplegia' [9]. The term 'alternating hemiplegia of childhood' was applied in the paper related to the significance of neuronal channelopathies in the pathogenesis of migraine [10].
• Snippet 2 (score: 0.423) > Alternating hemiplegia of childhood (AHC, MIM 104290) was presented by Verret and Steel in 1971 [1]. Alternating hemiplegia of childhood is a rare syndrome with an early manifestation, and its diagnosis is based on the clinical symptoms fulfilling the criteria. The incidence has been estimated at 1 in 1000,000 births but the underestimation of the burden of AHC could be suspected due to the lack of sufficient knowledge about this syndrome or lack of diagnostic laboratory or radiological test confirming diagnosis with certainty [2]. Until recently, no hypothesis explaining AHC pathomechanism has been confirmed. Although in single cases pathological changes were detected suggesting vasculitis or mitochondrial enzymatic chain disorders, specific marker of the disease was not defined. The phenotypic features common with migraine (hemiplegia as a symptom of motor migraine aura) suggested that AHC constitutes migraine precursor or variant of hemiplegic migraine (FHM, familial hemiplegic migraine). Majority of presented cases were predominantly sporadic, however familial cases with transmission suggesting autosomal dominant trait were presented [3,4]. > Multicenter research on AHC pathomechanism succeeded with the identification of ATP1A3 mutation. The research was conducted in collaboration with European Network for Research on Alternating Hemiplegia (ENRAH), an organization including patients and their families as well as clinicians to help coordinate epidemiological data and to promote research efforts [5,6]. > The translation of the name of the syndrome into Polish was not unified. In the publication of the Polish version of the International Classification of Headache Disorders 'alternating plegia of childhood' (naprzemienne porażenie dziecięce) was presented in a section of childhood periodic syndromes that are commonly precursors of migraine [7]. A case of a patient hospitalized at the Department of Developmental Neurology AM in Gdańsk was presented in 1976 as 'alternating hemiplegia in a child' [8]. The next case of a girl with AHC hospitalized at the Department of Neurology of Polish Mother's Memorial Research Institute Hospital (Centrum Zdrowia Matki Polki) in Łodź was described in 1995 as 'alternating

[5] Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism are both ATP1A3-related disorders

• Authors: H. Rosewich, H. Thiele, A. Ohlenbusch, U. Maschke, P. Frommolt et al.
• Year: 2014
• Venue: Molecular and Cellular Pediatrics
• URL: https://www.semanticscholar.org/paper/1df28fb6e33b5935288ec8ee50937f875ab71285
• DOI: 10.1186/2194-7791-1-S1-A15
• PMCID: 4715209
• Summary: This study showed that AHC and RDP are not two distinct diseases but rather constitute a clinical continuum of one disorder with AHC at the severe end of the spectrum and R DP as a milder variant.
• Evidence snippets:
• Snippet 1 (score: 0.450) > Alternating hemiplegia of childhood (AHC) was first described as a distinctive disease in 1971 [1]. The disease is characterised by early-onset episodes of hemiplegia, dystonia, numerous paroxysmal symptoms, and developmental impairment [2]. Almost all cases of AHC are sporadic. > To identify de-novo mutations associated with this disease 40 clinically well-characterized patients were recruited from September 2004 till April 2013. Whole-exome sequencing was performed in three proband-parent trios. Informative genes were evaluated in the 37 remaining patients and ATP1A3 emerged as the gene associated with AHC [3]. Interestingly, this gene was already known to be associated with another movement disorder with later onset namely rapid-onset dystonia-parkinsonism (RDP) [4]. We then thoroughly analysed clinical and molecular findings of AHC and RDP to evaluate the phenotypic and genotypic spectrum. In addition, we started to analyse the functional consequences of the encoded Na+,K+ alpha 3 subunit for different ATP1A3 mutations associated with either AHC or RDP applying cell survival assays and two-electrode voltage clamp techniques. > 39 of 40 patients with a characteristic AHC/RDP phenotype displayed a de-novo mutation in ATP1A3. Our study first showed that AHC and RDP are not two distinct diseases but rather constitute a clinical continuum of one disorder with AHC at the severe end of the spectrum and RDP as a milder variant. Clinically overlapping features are abrupt onset of triggered dystonic episodes, a rostrocaudal gradient of involvement as well as brainstem dysfunction; clearly differentiating characteristics are fixed dystonia in RDP and episodic hemiplegia in AHC. Further, mutations affecting functional and transmembrane protein domains tend to be associated with an AHC phenotype and the majority of ATP1A3 mutations are located in only four exons [5]. To further elucidate the pathomechanisms of ATP1A3 related disorders in vitro studies on selected mutations are ongoing.

[6] Alternating Hemiplegia

• Authors: Unknown authors
• Year: 2019
• Venue: Definitions
• URL: https://www.semanticscholar.org/paper/7b2552d203bf4701f5aef7b5c6b23c617bf1280a
• DOI: 10.32388/379185
• Citations: 2
• Summary: Alternating hemiplegia is a rare neurological disorder that develops in childhood, most often before the child is 18 months old. T he disorder is characterized by recurrent episodes of paralysis that involve one or both sides of the body, multiple limbs, or a single limb. T he paralysis may affect different parts of the body at different times and may be brief or last for several days. Oftentimes these episodes will resolve after sleep. Affected children may also have abnormal movements invol...
• Evidence snippets:
• Snippet 1 (score: 0.448) > Alternating hemiplegia is a rare neurological disorder that develops in childhood, most often before the child is 18 months old. T he disorder is characterized by recurrent episodes of paralysis that involve one or both sides of the body, multiple limbs, or a single limb. T he paralysis may affect different parts of the body at different times and may be brief or last for several days. Oftentimes these episodes will resolve after sleep. Affected children may also have abnormal movements involving stiffening or "dance-like" movements of a limb, as well as walking and balance problems. Some children have seizures. Children may have normal or delayed development. T here are both benign and more serious forms of the disorder. Alternating hemiplegia is primarily caused by mutations in the AT P1A3 gene. Occasionally, a mutation in the AT P1A2 gene is involved in the condition. T hese genes provide instructions for making very similar proteins. Mutations in these genes reduce the activity of an enzyme called Na+/K+ AT Pase, which affects the signals that control muscle movement. However, it not yet clear how the reduced enzyme activity leads to the symptoms of the disorder. Qeios · Definition, November 11, 2019

[7] Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood

• Authors: A. Gropman, M. Uittenbogaard, C. Brantner, Yue Wang, L. Wong et al.
• Year: 2020
• Venue: Molecular Genetics and Metabolism Reports
• URL: https://www.semanticscholar.org/paper/7b19702f1dff967d80ee93e4781d45d75f256bfa
• DOI: 10.1016/j.ymgmr.2020.100609
• PMID: 32489883
• PMCID: 7262444
• Citations: 9
• Summary: Comprehensive genetic and metabolic analyses suggest an oligogenic inheritance among the nuclear and mitochondrial variants for the mitochondrial etiology of proband's atypical form of AHC, thereby providing critical insight in terms of genetic clues and bioenergetic deficit.
• Evidence snippets:
• Snippet 1 (score: 0.448) > The rare neurodevelopmental disorder, alternating hemiplegia of childhood (AHC) (OMIM 614820), originally described by Verret and Steele in 1971 [1], is characterized by an extensive phenotypic variability. Thus, its clinical diagnosis is challenging, but facilitated by the Aicardi criteria [2]: 1) onset before the age of 18 months; 2) recurrent transient attacks of hemiplegia involving either side; 3) paroxysmal involuntary movements, such as nystagmus, tonic attacks, dystonic posturing, choreoathetosis, and autonomic abnormalities; 4) progressive neurological deficits, such as speech disorder, behavioral deficits, cognitive impairment, and developmental delay. Our understanding of the pathophysiological mechanisms of AHC remains limited, thereby hindering the development of effective therapeutic options. > The advent of next-generation sequencing led to the discovery of the first pathogenic clue of AHC, revealing that AHC is a predominantly sporadic disorder [3]. About 75% of AHC patients harbor a de novo heterozygous mutation in the ATP1A3 gene encoding the alpha 3 subunit of the neuronal Na + /K + ATPase protein involved in the regulation of neuronal excitability [4][5][6]. Mutations in the ATP1A2 gene encoding for the alpha 2 subunit of the Na + /K + ATPase protein also cause a very small number of AHC cases (OMIM 104290) [7][8][9]. Thus, additional causative genes remain to be identified, resulting in patients clinically diagnosed with AHC of unknown etiology and molecular genetic diagnosis. Several studies have evoked a mitochondrial etiology in a few https://doi.org/10.1016/j.ymgmr.2020.100609 Received 21 May 2020; Accepted 21 May 2020 patients with AHC. Mitochondrial abnormalities have been observed by 31 P magnetic resonance spectroscopy in skeletal muscle [10], while abnormal enzyme activities of the mitochondrial oxidative phosphorylation (OXPHOS) pathway were detected in skin biopsies from a handful of AHC patients [11,12].

[8] De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

• Authors: E. Heinzen, K. Swoboda, Y. Hitomi, F. Gurrieri, S. Nicole et al.
• Year: 2012
• Venue: Nature genetics
• URL: https://www.semanticscholar.org/paper/74faf2f2bb39510b57e36559dc960c624079096f
• DOI: 10.1038/ng.2358
• PMID: 22842232
• PMCID: 3442240
• Citations: 383
• Influential citations: 16
• Summary: De novo ATP1A3 mutations are identified as the primary cause ofAlternating hemiplegia of childhood and insight into disease pathophysiology is offered by expanding the spectrum of phenotypes associated with mutations in ATP 1A3.
• Evidence snippets:
• Snippet 1 (score: 0.444) > Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

[9] Alternating Hemiplegia of Childhood Caused by ATP1A3 Mutations: A Report of Two Cases.

• Authors: Guanzhao Yang, Z. Zhao, Yang Yang, Li Lin, Conglei Song et al.
• Year: 2021
• Venue: Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih
• URL: https://www.semanticscholar.org/paper/63b53d21f673ec159fddd8a29c3649247ebbd103
• DOI: 10.24920/003850
• PMID: 34231463
• Citations: 4
• Summary: Funarizine can significantly improve the paroxysmal motor symptoms of pediatric patients with alternating hemiplegia and carry heterozygous missense mutations in theATP1A3 gene.
• Evidence snippets:
• Snippet 1 (score: 0.440) > Alternating Hemiplegia of Childhood Caused by ATP1A3 Mutations: A Report of Two Cases.

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

• Authors: R. Islam, K. Fatema, M. Rahman
• Year: 2022
• Venue: Bangladesh Journal of Child Health
• URL: https://www.semanticscholar.org/paper/2d32d1969b834ff7ef78c1d2c23268c3655ae7d1
• DOI: 10.3329/bjch.v45i3.62896
• Summary: The case of 8.5 year old girl with AHC who had a heterozygous de-novo p.Leu839Pro (c.2516T>C) pathogenic mutation of ATP1A3 gene on chromosome 19q13 is presented.
• Evidence snippets:
• Snippet 1 (score: 0.435) > Alternating Hemiplegia of Childhood with ATP1A3 Gene Mutation- A Case Report

[11] Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry

• Authors: L. Viollet, Gwênlyn Glusman, Kelley J. Murphy, T. Newcomb, S. Reyna et al.
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/d8182c5129a2b47e26b6f9cbe86e51235c65a300
• DOI: 10.1371/journal.pone.0127045
• PMID: 25996915
• PMCID: 4440742
• Citations: 72
• Influential citations: 5
• Summary: A more deleterious effect of the E815K mutation on selected neurologic outcomes is confirmed and the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
• Evidence snippets:
• Snippet 1 (score: 0.435) > Alternating Hemiplegia of Childhood (AHC, MIM#614820) is a rare and complex neurodevelopmental disorder described initially by Verret and Steele in 1971, and named for the characteristic recurrent attacks of hemiplegia that affected first one side of the body, then another.However, episodes of paroxysmal neurologic dysfunction in this unusual disorder encompass a wide range of abnormal movements and episode types ranging from hemiplegia to quadriplegia to dystonia, and lasting from minutes to hours or even days.A variety of external or emotional stressors trigger the onset or worsening of paroxysmal symptoms, but they are consistently relieved by sleep, whether pharmacologically or naturally induced [1,2].Although rare familial cases with autosomal dominant inheritance have been reported [3][4][5][6], AHC is predominantly a sporadic disorder.Estimated incidence of the classic form of the disease is 1 in one million: males and females are affected in roughly equal numbers.The variability and the complexity of presenting symptoms have historically led to considerable delays in diagnosis, which was until recently based solely on carefully conceived clinical diagnostic criteria.These criteria specified an infantile onset (< 18 months) of recurrent paroxysmal episodes of hemiplegia, dystonia and ocular movement abnormalities, and were ultimately characterized by the appearance of additional fixed neurologic signs and symptoms including chorea, dysarthria, dyskinesia, ocular apraxia, ataxia and global developmental delay [2,7,8].The variable course of the disease and limited longitudinal follow-up and neuropathologic data have led to ongoing speculation as to whether or not AHC represents a static neurodevelopmental or a progressive disorder [9][10][11]. > The pathophysiology of AHC was totally unknown until the recent identification of mutations in ATP1A3, which encodes a neuron specific sodium/potassium ATPase involved in the regulation of neuronal excitability [12].We and others initially identified de novo recurrent mutations in ATP1A3 by performing whole exome studies in trios in a series of simplex AHC patients.

[12] A case of alternating hemiplegia in 2-month-old children with nystagmus as the first symptom: A case report

• Authors: Qicheng Qiao, Qiubo Li
• Year: 2024
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/02b1132b61c337ee1f8abf2a4660f480a9a58c2e
• DOI: 10.1097/MD.0000000000039774
• PMID: 39331927
• PMCID: 11441957
• Summary: A case of a 2-month-old child with nystagmus as the initial symptom, followed by limb movement disorder in the left upper limb and weakness in the right limbs diagnosed with alternating hemiplegia of childhood, underscores the importance of early recognition and prompt intervention in managing children with AHC.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Alternating hemiplegia of childhood (AHC) is a rare neurological condition that typically presents in infants under the age of 18 months with intermittent episodes of hemiplegia, affecting one or both sides of the body. These episodes are often triggered by stressors such as environmental changes, bathing, or emotional stress. They can manifest alone or alongside other symptoms including autonomic instability, altered consciousness, and movement disorders, such as dystonia, ataxia, and choreoathetosis. Patients may also develop developmental or intellectual disabilities and experience epileptic seizures. Notably, certain symptoms appear in distinct phases and typically resolve during sleep. The incidence of AHC is estimated at 1 in 1,000,000 among children under the age of 16 years, a figure that may underrepresent the true prevalence due to the Qiao and Li • Medicine (2024) Medicine condition's diverse clinical presentations and the limited genetic testing in past studies. [1,2] The precise pathophysiology of AHC, including its associated comorbidities, remains incompletely understood. However, recent advances in molecular genetics have led to a clearer understanding of the genes implicated in AHC, facilitating earlier and more definitive diagnoses. The most commonly associated genes are mutations in ATP1A2 and ATP1A3, which are responsible for producing different alpha subunits of the neuronal Na+-K + ATPase pump. Individuals with ATP1A3 mutations are more frequently affected than those with ATP1A2 mutations. The increased application of genetic testing has not only improved the differentiation of AHC from other similar disorders but also expanded the recognized clinical spectrum of the condition. This article reports a case of alternating hemiplegia in children with nystagmus as the first symptom.

[13] Alternating Hemiplegia of Childhood: neurological comorbidities and intrafamilial variability

• Authors: P. Pavone, X. Pappalardo, Naira M Mustafa, S. Cho, D. Jin et al.
• Year: 2022
• Venue: Italian Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/bd96c802f4dee91e3cddeb3b66267225cf30a3f2
• DOI: 10.1186/s13052-021-01194-2
• PMID: 35177115
• PMCID: 8851838
• Citations: 6
• Summary: Clinical features of AHC may be also the result of an unexpected genetic heterogeneity and neurological co-morbidities are various and frequently reported including developmental delay, epilepsy, tonic or dystonic spells, nystagmus,autonomic manifestations with intrafamilial variability.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Alternating Hemiplegia of Childhood (AHC) is an uncommon complex disorder, mainly characterized by paroxysmal episodes of repeated, transient paresis involving either or both sides of the body with onset usually before the age of 18 months. This disorder was first described in late 1960s by Verret and Steele on their study, which included eight children with migraine, among whom three showed the characteristic features of AHC [1]. Diagnostic criteria for AHC were expressed by Krageloh and Aicardi [2] and Bourgeois et al. [3] and consist of: a) onset before the age of 18-months; b) autonomic phenomena; c) cognitive impairment; d) repeated episodes of hemiplegia that sometimes involve both sides of the body; e) neurological abnormalities such as choreoathetosis; f) disappearance of the symptoms with the sleep and their resume after waking. The clinical signs of AHC are complex, heterogeneous, and follow a unique pattern: their clinical progression tends to occur in sequential distinctive phases, the paroxysmal episodes are often preceded by precipitating factors such as environmental stress, bathing and other events [4]. Nonparoxysmal features of subjects with AHC are various and include developmental delay/intellectual disability (DD/ID), epilepsy, autonomic dysfunctions, abnormal eye involvement, movement disorders, ataxia, dystonia, and choreoathetosis [4][5][6][7][8]. > Although the pathophysiologic mechanism causing the clinical expression of the disorder remain unknown, significant research advances over the years, particularly those seen in the clinical genetics field, allowed a better mechanistic understanding of the attributed genes and enabled early diagnosis and precocious treatment. Relevant etiopathogenetic role in AHC is linked to mutations in ATP1A2 (AHC-1; OMIM#104290) and in ATP1A3 genes (AHC-2; OMIM#614820), respectively which encode two different alpha subunits of the Na + /K + ATPase transmembrane ion pump [9,10]. ATP1A3 is by far more common than ATP1A2 mutation [11]. It is worth mentioning

[14] Alternating Hemiplegia of Childhood and Neurological Comorbidities. Variable Intrafamilial Clinical Features.

• Authors: P. Pavone, X. Pappalardo, Naira M Mustafa, S. Cho, D. Jin et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/76a5e6e02442e2a646cb88082b78d11e25b270ac
• DOI: 10.21203/rs.3.rs-73126/v1
• Summary: The view of the disorder should be greatly changed to the term “AHC spectrum disorder" due to how the genetic framework is not recurrent, but may result from an unexpected greater genetic heterogeneity, such as seen in siblings carrying a new set of gene variants implicated in channelopathies likely to be eligible as further risk factors for AHC.
• Evidence snippets:
• Snippet 1 (score: 0.423) > Alternating Hemiplegia of Childhood (AHC) is an uncommon complex disorder, characterized mainly by paroxysmal episodes of repeated, transient paresis involving either or both sides of the body with onset usually before the age of 18 months. Subjects with AHC also present with non-paroxysmal features including Developmental Delay/Intellectual Disability (DD/ID), epileptic seizures, autonomic dysfunction, abnormal eye movements, motor impairment, ataxia, dystonia and movement disorders such as choreoathetosis [1][2][3] .This disorder was rst described in late 1960s by Verret and Steele on their study, which included eight children with migraine, among whom three showed the characteristic features of AHC [1]. > Although the pathophysiologic mechanisms causing the clinical expression of the disorder remain unknown, signi cant research advances over the years, particularly those seen in the clinical genetics eld, allowed for a better mechanistic understanding of the attributed genes and enabled early diagnosis and effective treatment. Two types of AHC have been described; AHC-1 (OMIM#104290) and AHC-2 (OMIM#614820), characterized by mutations in ATP1A2 and ATP1A3 genes respectively, which encode two different alpha subunits of the Na + /K + ATPase transmembrane ion pump [4,5]. ATP1A3 is by far more common than ATP1A2 mutation [6]. It is worth mentioning that clinical expression of ATP1A3 mutations are expanding and includes the complex disorders ATP1A3-related [7]. The rise and widespread implementation of the whole exome sequencing (WES) technology has notably enhanced the gene mutation panel analyzing additional genes clinically-overlapped with the AHC spectrum. It is essential to highlight that AHC as observed in the literature is a complex disorder in which the paroxysmal hemiplegia is only one feature, even if the most relevant, among several other clinical manifestations each of which is considered as a primary component of this disorder. Consequently, we agree that the extensive term "AHC spectrum disorder" may be correctly applied.

[15] Alternating Hemiplegia of Childhood: Genotype–Phenotype Correlations in a Cohort of 39 Italian Patients

• Authors: R. Cordani, M. Stagnaro, L. Pisciotta, F. Tiziano, M. Calevo et al.
• Year: 2021
• Venue: Frontiers in Neurology
• URL: https://www.semanticscholar.org/paper/9faa9248277ffe749885faf4b1619ad2189b909c
• DOI: 10.3389/fneur.2021.658451
• PMID: 33897609
• PMCID: 8060701
• Citations: 22
• Influential citations: 1
• Summary: The research suggests a genotype–phenotype correlation and provides information on this disorder's features, clinical course, and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.423) > Alternating Hemiplegia of Childhood (AHC) (OMIM #614820) is a rare and peculiar neurologic disorder, first described in 1971 (1). The annual incidence is < 1/100,000 newborns (2). In AHC, a complex phenotype combines paroxysmal non-epileptic episodes, often triggered by contact with water, changes in temperature, physical or psychological stress, and epileptic seizures, both focal and generalized, with a high rate of refractory/super refractory status epilepticus (3). Developmental issues, cognitive deficits, neuropsychological impairments, and persistent neurologic disorders (2,(4)(5)(6) are expected hallmarks. In 1993, specific diagnostic criteria for AHC were first introduced (7) and then periodically updated. Aicardi's criteria for AHC (8) are (1) onset of paroxysmal events before 18 months of age; (2) repeated bouts of hemiplegia involving the right and left sides of the body during some attacks; (3) episodes of bilateral hemiplegia or quadriplegia starting either as a generalization of a hemiplegic episode or as bilateral from the start; (4) other paroxysmal disturbances including tonic/dystonic attacks, nystagmus, strabismus, dyspnea, and other autonomic phenomena occurring during hemiplegic bouts or in isolation; (5) immediate disappearance of all symptoms upon sleep, with probable recurrence of long-lasting bouts, 10-20 min after awakening; (6) evidence of developmental delay, intellectual disability, neurological abnormalities, choreoathetosis, and dystonia or ataxia; and (7) not attributable to other disorders. A great effort was made to understand the disease's genetic basis. In 2012, In 2012, two independent research groups -a group of German researchers (9) and an international consortium (10)-identified de novo heterozygous mutations in the ATP1A3 gene performing next-generation sequencing to examine the genome of AHC patients (11). Next, this finding was replicated by an independent Japanese study that found ATP1A

[16] Unraveling Alternating Hemiplegia of Childhood: A Case Report with Genetic and Clinical Insights

• Authors: Samanwita Mahapatra, Abhishek Singh, Aditi Das, Rohit Bhowmick, N. S. Bhunia et al.
• Year: 2025
• Venue: Case Reports in Neurology
• URL: https://www.semanticscholar.org/paper/f2d89856112f0b3e186567721a338e5858ff2bf7
• DOI: 10.1159/000548497
• PMID: 41322064
• PMCID: 12659400
• Summary: The need for early recognition and genetic confirmation of AHC to initiate therapy and improve quality of life is highlighted, with flunarizine offering some benefit.
• Evidence snippets:
• Snippet 1 (score: 0.419) > 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 18 months [1,2]. The exact pathophysiology remains unknown, but a few postulates point towards energy depletion due to a mutation in the Na + -K + ATPase alpha subunit [3]. Common mutations involve ATP1A3 and ATP1A2; ATP1A3 being the most common [1,2]. The disease most often manifests as a nystagmus, usually involving the ipsilateral eye. Gradually, the infant develops a tonic neck deviation toward the affected side. The disease usually comes to notice when the infant develops flaccid hemiparesis. The weakness usually lasts from a few minutes to hours, and often improves after sleep. The usual precipitating factors are dehydration, stress, and fever. Diagnosis is mainly clinical, with confirmation by genetic analysis. Till now, there is no specific treatment available, but drugs like flunarizine, topiramate, aripiprazole, etc., are shown to reduce the frequency and severity of paroxysms, although the effect on long-term prognosis is still questionable.
• Snippet 2 (score: 0.419) > Unraveling Alternating Hemiplegia of Childhood: A Case Report with Genetic and Clinical Insights

[17] [Alternating Hemiplegia of Childhood associated with a pathogenic variant of the ATP1A3 gene].

• Authors: Francisca Sandoval, F. Lopez
• Year: 2022
• Venue: Andes pediatrica : revista Chilena de pediatria
• URL: https://www.semanticscholar.org/paper/c9b47e302ac7ae2580f9fdeb3aa567cfe44cfa98
• DOI: 10.32641/andespediatr.v93i1.3972
• PMID: 35856955
• Summary: The diagnosis of AHC is complex and is frequently confused with epilepsy, so it is important to correctly perform the diagnosis, including anamnesis, tests such as EEG, and careful observation of clinical events that, with the current access to audiovisual technology, becomes more accurate.
• Evidence snippets:
• Snippet 1 (score: 0.406) > INTRODUCTION > 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. > OBJECTIVE > To present a clinical case of AHC, where genetic study and the observation of home videos were of great diagnostic utility. > CLINICAL CASE > 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. > CONCLUSIONS > 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.

Notes

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