Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia

Schwarz, Niklas; Hahn, Andreas; Bast, Thomas; Müller, Stephan; Löffler, Heidi; Maljevic, Snezana; Gaily, Eija; Prehl, Isabelle; Biskup, Saskia; Joensuu, Tarja; Lehesjoki, Anna Elina; Neubauer, Bernd A.; Lerche, Holger; Hedrich, Ulrike B. S.

doi:10.1007/s00415-015-7984-0

Cited by 77 publications

(82 citation statements)

References 35 publications

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“…For SCN2A , in addition to ID in three of these patients, two of the four families that could be recontacted also reported seizures; SCN2A has been previously implicated in epilepsy32. We also identified three patients with DN CHD8 LGD mutations.…”

Section: Discussionmentioning

confidence: 71%

De novo genic mutations among a Chinese autism spectrum disorder cohort

et al. 2016

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Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation. In aggregate, ∼4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations is SCN2A (1.1% of patients) followed by CHD8, DSCAM, MECP2, POGZ, WDFY3 and ASH1L. We identify novel DN LGD recurrences (GIGYF2, MYT1L, CUL3, DOCK8 and ZNF292) and DN mutations in previous ASD candidates (ARHGAP32, NCOR1, PHIP, STXBP1, CDKL5 and SHANK1). Phenotypic follow-up confirms potential subtypes and highlights how large global cohorts might be leveraged to prove the pathogenic significance of individually rare mutations.

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Section: Discussionmentioning

confidence: 71%

De novo genic mutations among a Chinese autism spectrum disorder cohort

et al. 2016

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“…In the mammalian brain, the most highly expressed VGSC α subunits are SCN1A , SCN2A , SCN3A , and SCN8A, which encode Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 respectively. Mutations in these VGSCs are responsible for an increasing number of epilepsy syndromes (Escayg et al, 2000; Estacion et al, 2014; Fung et al, 2015; Howell et al, 2015; Schwarz et al, 2016; Sugawara et al, 2001; Surovy et al, 2016). Mutations in SCN1A have been established as the main cause of Dravet syndrome and have also been identified in some families with generalized epilepsy with febrile seizures plus (GEFS+) (Escayg and Goldin, 2010; Scheffer et al, 2009; Volkers et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

SCN3A deficiency associated with increased seizure susceptibility

Lamar

Vanoye

Calhoun

et al. 2017

Neurobiology of Disease

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Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

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“…For example, KCNA2 encephalopathy is associated with ataxia and dystonia, 1,2 SCN2A encephalopathy with dystonia, choreoathetosis, 37 and EA, 38 and SCN8A encephalopathy with choreoathetosis, dystonia, and ataxia. 39 The diversity of movement disorders for each genetic encephalopathy expands as further cases are identified.…”

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confidence: 99%

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

Corbett

Bellows

et al. 2016

Neurology

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Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G.A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. Neurology ® 2016;87:1975-1984 GLOSSARY EA 5 episodic ataxia; EE 5 epileptic encephalopathy; GATK 5 genome analysis toolkit; GGE 5 genetic generalized epilepsies; GTCS 5 generalized tonic-clonic seizures; ICCA 5 infantile convulsions choreoathetosis syndrome; RMS 5 root mean square.De novo mutations of KCNA2 have recently been reported in infantile-onset epileptic encephalopathies (EEs) in which infants present with uncontrolled seizures, developmental slowing or regression, and frequent epileptiform activity on EEG.1-6 Inherited mutations have not been described. KCNA2 has not been implicated in common pharmacoresponsive epilepsies such as the genetic generalized epilepsies (GGE), nor has an association with paroxysmal movement disorders been established.Paroxysmal neurologic disorders are often due to disorders of ion channel function. The episodic ataxias (EAs) are usually dominantly inherited and associated with a range of ion channel *These authors contributed equally to this work.

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Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia

Cited by 77 publications

References 35 publications

De novo genic mutations among a Chinese autism spectrum disorder cohort

De novo genic mutations among a Chinese autism spectrum disorder cohort

SCN3A deficiency associated with increased seizure susceptibility

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

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