Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3

Abstract

SUMMARYThere are only two reports on epileptic patients associated with microduplication of 2q. We found a de novo duplication of chromosome 2q24.2q24.3 in another infant with neonatal epilepsy. The patient had refractory focal seizures since the third day of life. Her seizures were refractory against phenobarbital and levetiracetam, but were controlled by valproate. Array comparative genomic hybridization revealed a 5.3-Mb duplication of 2q24. 2q24.3, where at least 22 genes including a cluster of voltage-gated sodium channel genes (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A) and one noncoding RNA are located. KEY WORDS: Neonatal epilepsy, Voltage-gated sodium channels, 2q duplication, Array comparative genomic hybridization.Chromosomal deletions of 2q21-q31 have been known to be closely related to seizures and epilepsies, and the band 2q24 is the smallest commonly deleted segment in these patients (Davidsson et al., 2008). Several authors including us have reported that deletions of the voltage-gated sodium channel (SCN) cluster at 2q24 are associated with several epilepsy syndromes (Takatsuki et al., 2010). The deletions of the locus, including SCN1A, were found in patients with Dravet syndrome (Marini et al., 2009;Suls et al., 2010). The chromosomal deletions of 2q including SCN1A and SCN2A were reported in some patients with severe epilepsy of infantile onset, developmental delay, and dysmorphic features (Pereira et al., 2004;Langer et al., 2006;Pereira et al., 2006). A small deletion between the locus of SCN2A and SCN3A was seen in a patient with infantile seizures, mental retardation, and behavioral and psychiatric abnormalities (Bartnik et al., 2010). Compared to that, the duplications of this region have been identified in only two families (Heron et al., 2010;Raymond et al., 2011). Recently, we identified a chromosomal duplication of 2q24.2q24.3, in which SCN gene cluster is located, in an infant with refractory neonatal epilepsy and severe developmental delay. We report on this patient and discuss the genotype-phenotype correlation. Patient ReportA female infant was born spontaneously at 40 weeks of gestation following an uncomplicated pregnancy. She was the first product of unrelated healthy parents. Her birth weight was 2,796 g and head circumference was 33 cm. No dysmorphic features were recognized.Her mother had noticed mild convulsive movement and staring lasting for 10-20 s since the third day of life. The frequency of paroxysmal events gradually increased and she was admitted to the neonatal intensive care unit of Iwaki Kyoritsu Hospital at 9 days of age. Physical examinations were unremarkable other than for mild hypotonia. Head magnetic resonance imaging (MRI) and blood examination including metabolic screening of amino acids and organic acid analyses revealed no abnormalities. Interictal electroencephalography (EEG) showed markedly abnormal background activities with spiky transients. She was diagnosed as having neonatal seizures and treated with phenobarbital and midazolam. Although her seizures...

Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy

“…Figure 1 depicts the genetic aberrations detected in patients with 2q24 duplication. The duplication was found to be de novo in three patients (Okumura et al., 2011), including the two novel mutations presented herein, and in the mother of the index patient in the family described by Heron et al. (2010).…”

“…In the first two patients (Heron et al., 2010; Raymond et al., 2011), SCN2A and SCN3A are duplicated as well. In the following three cases (patients 1, 2, and Okumura et al., 2011), the respective duplication covers the complete SCN cluster on 2q24.…”

“…The 14 full‐text articles were screened for the inclusion criteria. Four articles describing seven patients from four families were included in this study (Heron et al., 2010; Okumura et al., 2011; Raymond et al., 2011; Vecchi et al., 2011). All publications were case reports.…”

Whole gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development

“…In most previously published cases, patients showed different degrees of DD and in a majority also ID . However, in the maternally inherited duplication reported by Boutry‐Kryza et al, there was a family history of neonatal epilepsy affecting 10 family members .…”

“…Duplications at 2q24.3 have been described in 10 individuals presenting with early onset epilepsy during the first days of life. In two of these, the duplications were familial with several affected family members .…”