Review articleClinical spectrum of SCN2A mutations
Introduction
Voltage-gated sodium channels, comprised of α and β subunits, are the major mediators of normal neuronal firing. The α subunit includes four homologous domains (D1–D4) and exhibits significant homology with voltage-gated potassium and calcium channels. There are at least four α subunits (SCN1A, SCN2A, SCN3A, and SCN8A) are primarily responsible for encoding sodium currents in the brain, three of them (SCN1A, SCN2A, SCN3A) are associated with a variety of epilepsies [1], [2], [3]. Specifically, most SCN2A mutations have been identified in cases of BFNIS [2], [4], [5]. While NaV1.2 mutations were thought infrequently associated with severe epilepsy, recent studies have shown SCN2A mutations in both severe myoclonic epilepsy in infancy (SMEI) and some intractable childhood epilepsies [6], [7]. In addition, microduplication involving SCN2A, SCN3A, and the 3′ end of SCN1A has been reported in a family with dominantly inherited neonatal seizures and intellectual disability [8]. All SCN2A mutations identified in BFNIS are missense mutations inherited from a single parent; most SCN2A mutations-nonsense and missense-identified in severe cases are de novo.
Section snippets
BFNIS and BFIS
Benign familial neonatal–infantile seizures (BFNIS) are one of the first year of life’s three benign autosomal dominant seizure syndromes. It was first described as an intermediate phenotype between benign familial neonatal seizures (BFNS) and benign familial infantile seizures (BFIS) [9], characterized by sudden onset (from the neonatal period to 13 months of age) and later remission of seizures in infancy (by 13 months) [2].
BFNIS is the most common phenotype associated with SCN2A mutations
GEFS+
Generalized epilepsy with febrile seizures plus (GEFS+) was first described by Scheffer and Berkovic [12] as an autosomal dominant epilepsy syndrome, characterized by a variety of mainly generalized epilepsy phenotypes occurring within the same family. The most common phenotypes include febrile seizures (FS) and febrile seizures plus (FS+). Scheffer [13]recently proposed changing the name of GEFS+ to “genetic epilepsy with febrile seizures plus” from “generalized epilepsy with febrile seizures
Intractable childhood epilepsy
Intractable epilepsy, which includes a variety of epilepsies, is defined one in which seizures can’t be adequately controlled by antiepileptic drugs. SCN1A mutations have been reported in a broad spectrum of intractable childhood epilepsies including West syndrome, myoclonic-astatic epilepsy and Lennox-Gastaut syndrome [16].
Kamiya et al. [17] reported the first SCN2A mutation (R102X) resulting in a truncated channel protein at position 102, in a patient with sporadic intractable childhood
Dravet syndrome
Dravet syndrome (DS) is a rare and malignant epilepsy syndrome, which usually develops in the first year of life [18], [19] and is now used as a disease entity which includes severe myoclonic epilepsy in infancy (SMEI) and its borderline phenotype (SMEB) [20]. The majority of the genetic abnormalities underlying DS have been found in SCN1A, though a few mutations were found in GABRG2 encoding gamma-aminobutyric acid GABAA receptor, gamma 2.
Our previous study identified three novel SCN2A
Functional analysis of SCN2A mutations
Although almost all SCN2A mutations are missense, electrophysiological analyses show that different mutations cause diverse effects on NaV1.2 channel. Consider R1319Q, L1330F and L1563V, SCN2A missense mutations identified in BFNIS. Using whole-cell patch-clamp recording of heterologously expressed human NaV1.2, Misra et al. [21] characterized the functional properties of WT and mutant sodium channels. They found that: R1319Q displayed mixed effects on activation and fast inactivation gating,
Conclusions
SCN2A mutations are associated with a variety of human epilepsy syndromes. Functional consequences of mutant channels range from loss- to gain-of-function. Mutations identified in intractable epilepsies alter the channel properties of NaV1.2 to a greater extent than do BFNIS mutations, suggesting a mechanism for more severe epileptic phenotypes. Correlation between genotype and phenotype, however, remains elusive. Further studies using animal models with genetically engineered NaV1.2 mutations
Acknowledgments
We thank Ms. Takako Umemoto and Hideko Takeda for formatting and typing the manuscript and Ms. Minako Yonetani and Akiyo Hamachi for the technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (S) 16109006, (A) 18209035 and 21249062, Exploratory Research 1659272, and “High-Tech Research Center” Project for Private Universities-matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology, 2006–2010- “The Research Center for
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