Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients

Pisciotta, Livia; Gherzi, Marcella; Stagnaro, Michela; Calevo, Maria Grazia; Giannotta, Melania; Vavassori, Maria Rosaria; Veneselli, Edvige; Grandis, Elisa De

doi:10.1016/j.braindev.2017.02.001

Cited by 38 publications

(28 citation statements)

References 10 publications

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“…Flunarizine is one of the most commonly used drugs in AHC to prevent triggered episodes, although patients do not consistently respond to treatment (Panagiotakaki et al, 2015;Pisciotta et al, 2017;Sasaki et al, 2001). Chronic in vitro treatment with flunarizine did not have an impact on this stress-triggered phenotype in our study.…”

Section: Discussioncontrasting

confidence: 46%

“…A non-specific sodium and calcium channel blocker, flunarizine, has been anecdotally used to treat many patients for the past several decades (Casaer, 1987). Flunarizine has been reported in several recent studies to reduce the severity, duration, or frequency of hemiplegic spells in some patients with AHC, although not all individuals respond to treatment (Delorme et al, 2017;Kansagra et al, 2013;Pisciotta et al, 2017). Conclusions from these studies are limited by small numbers of patients and lack of randomized control groups.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Snow

Westlake

Klofas

et al. 2020

Preprint

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ABSTRACTAlternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by heterozygous de novo missense mutations in the ATP1A3 gene that encodes the neuronal specific α3 subunit of the Na,K-ATPase (NKA) pump. Mechanisms underlying patient episodes including environmental triggers remain poorly understood, and there are no empirically proven treatments for AHC. In this study, we generated patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls for the E815K ATP1A3 mutation that causes the most phenotypically severe form of AHC. Using an in vitro iPSC-derived cortical neuron disease model, we found elevated levels of ATP1A3 mRNA in AHC lines compared to controls, without significant perturbations in protein expression. Microelectrode array analyses demonstrated that in cortical neuronal cultures, ATP1A3+/E815K iPSC-derived neurons displayed a non-significant trend toward less overall activity than neurons differentiated from isogenic mutation-corrected and unrelated control cell lines. However, induction of cellular stress by elevated temperature revealed a hyperactivity phenotype following heat stress in ATP1A3+/E815K lines compared to control lines. Treatment with flunarizine, a drug commonly used to prevent AHC episodes, did not impact this stress-triggered phenotype. These findings support the use of iPSC-derived neuronal cultures for studying complex neurodevelopmental conditions such as AHC and provide a potential route toward future therapeutic screening and mechanistic discovery in a human disease model.

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Section: Discussioncontrasting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Snow

Westlake

Klofas

et al. 2020

Preprint

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“…Alternating hemiplegia of childhood [64][65][66][67][68][69][70] x phenotype comparable to GTP cyclohydrolase deficiency and readily respond to L-DOPA. 9 Sepiapterin reductase deficiency (SRD) has a comparable neonatal presentation to THD but is also associated with spasticity.…”

Section: Episodicmentioning

confidence: 99%

Treatable Movement Disorders of Infancy and Early Childhood

Aravamuthan

Pearson

2020

Semin Neurol

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Movement disorders in childhood can be difficult to diagnose early. Disease processes present variably and can mimic each other. It is particularly important to remain vigilant for the subset of these movement disorders that are treatable. These disorders can be managed with (1) treatments specific to the disease that substantially reduce symptoms; (2) treatments that can prevent progression; (3) treatments that can hasten recovery; or (4) surveillance and management of the associated, sometimes life-threatening, comorbidities. Here, we present a practical and phenomenology-oriented framework for diagnosing and managing these treatable movement disorders of infancy and early childhood.

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“…A recent cohort study and reviews summarize the spectrum of these disorders, genetic associations, and phenotypic pleiotropy of the paroxysmal disorders, such as exercise‐induced dystonia observed in both GLUT1 deficiency as well as GTP cyclohydrolase deficiency . There is also therapeutic pleiotropy in these disorders, for example, acetazolamide may be useful for episodic ataxia type 2, but can also benefit alternating hemiplegia or GLUT1‐deficiency–related movement disorders …”

Section: Symptomatic Therapiesmentioning

confidence: 99%

Current therapies and therapeutic decision making for childhood‐onset movement disorders

2019

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Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society

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Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients

Cited by 38 publications

References 10 publications

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype

Treatable Movement Disorders of Infancy and Early Childhood

Current therapies and therapeutic decision making for childhood‐onset movement disorders

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