Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy

Dilena, Robertino; Striano, Pasquale; Gennaro, Elena Di; Bassi, Laura; Olivotto, Sara; Tadini, L.; Mosca, Fabio; Barbieri, S.; Zara, Federico; Fumagalli, Monica

doi:10.1016/j.braindev.2016.10.015

Cited by 64 publications

(46 citation statements)

References 6 publications

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“…However, its alterations and their functional impact have not been estimated so far. In 2016, Dilena et al presented a case of newborn male with a manifestation of epileptic encephalopathy, characterized by abnormal EEG pattern and tonic-clonic migrating partial seizures [33]. The neurological examination showed hypotonia, poor movement and feeding difficulties as were noticed in our patient 2.…”

Section: Discussionsupporting

confidence: 53%

“…After NGS data analysis and variant filtering we detected a heterozygous NC_000002.11:g.166243337A>G transition affecting the SCN2A gene resulting in a p.Met1545Val substitution (Figure 3). To our knowledge, less than ten cases of this likely pathogenic variant have been reported so far [32,33]. Consequently, we performed targeted Sanger sequencing in patient 2 and her parents.…”

Section: Whole-genomic Analyses and Their Verificationmentioning

confidence: 99%

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Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

Wayhelova¹,

Oppelt²,

Smetana³

et al. 2017

J Neurol Disord

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Section: Discussionsupporting

confidence: 53%

Section: Whole-genomic Analyses and Their Verificationmentioning

confidence: 99%

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

Wayhelova¹,

Oppelt²,

Smetana³

et al. 2017

J Neurol Disord

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“…Although our advancements in diagnosis have improved our ability to convey prognosis, the model of precision medicine as it pertains to disease‐specific treatments in early onset epileptic encephalopathies remains challenging. In KCNQ2 and SCN2A encephalopathy, the use of sodium channel blockers can result in seizure freedom without substantial concomitant alterations in long‐term neurodevelopmental prognosis, even when therapies are initiated within the first months of life . In KCNT1 ‐associated EIMFS, quinidine's action can effectively block the pathologic constitutive activation of the KCNT1 channel at the molecular level in some variants .…”

Section: Discussionmentioning

confidence: 99%

“…In KCNQ2 and SCN2A encephalopathy, the use of sodium channel blockers can result in seizure freedom without substantial concomitant alterations in long-term neurodevelopmental prognosis, even when therapies are initiated within the first months of life. [27][28][29] In KCNT1-associated EIMFS, quinidine's action can effectively block the pathologic constitutive activation of the KCNT1 channel at the molecular level in some variants. 11 Clinical efficacy has been inconsistent.…”

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confidence: 99%

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

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Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.

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“…In addition, SCN2A mutations were recently described in 7 (26%) of 27 patients with EIMFS . To date, 13 children with SCN2A ‐related EIMFS have been published, rendering SCN2A the second most commonly mutated gene for EIMFS. Of note, EEG may show a burst‐suppression pattern at initial presentation of EIMFS, which persists during follow‐up in some children.…”

Section: The Spectrum Of Scn2a‐related Disordersmentioning

confidence: 99%

Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond

Wolff¹,

Brunklaus

Zuberi

2019

Epilepsia

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Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration.Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

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Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy

Cited by 64 publications

References 6 publications

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond

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