Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 443-445, September 2010

Milder phenotype with SCN1A truncation mutation other than SMEI

Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China

Received 14 December 2009; received in revised form 9 June 2010; accepted 17 June 2010. published online 15 July 2010.

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Abstract 

Till now truncation mutations of voltage-gated sodium channel alpha subunit type I (SCN1A) gene were mostly found in severe myoclonic epilepsy of infancy (SMEI) patients. In this research we first identified two novel de novo truncation mutations (S662X and M145fx148) in two patients whose phenotypes were quite milder compared with SMEI patients. One patient was diagnosed as generalized epilepsy with febrile seizures plus (GEFS+); the other had focal seizures. Both patients had good response to anti-epileptic therapy (valproate or the combination of valproate and topiramate). Our findings extended the utility of the SCN1A gene testing and further confirmed the complex relationship between genotype and phenotype of SCN1A mutations. Further work is needed to optimize the protocol for specific genetic testing in children with epilepsy.

Keywords: GEFS+, SMEI, Epilepsy, SCN1A, Mutation

 

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1. Introduction 

SCN1A, the neuronal voltage-gated sodium channel α1-subunit gene, is thought as the most important pathogenic gene, whose mutation can cause different types of epilepsy.1 Mutations of SCN1A have been mainly identified in generalized epilepsy with febrile seizures plus (GEFS+) and in severe myoclonic epilepsy of infancy (SMEI) with occasional findings in other kinds of epilepsy, for example, infantile spasms and Lennox–Gastaut syndrome.2, 3, 4, 5, 6 To date, most reported GEFS+ cases display autosomal-dominant transmission with highly variable phenotypes. SMEI mostly arises do novo, which is considered to be extreme severe phenotype of the large SCN1A spectrum.7, 8

The type of SCN1A mutation was considered to be the reason for that mutations in the same SCN1A gene resulted in such different phenotypes. Truncaton mutations could cause complete loss of sodium channel function, which resulted in the severe phenotype.9 However, these phenotype–genotype correlations were not absolute. While in this research, we first identified truncation mutations in two patients whose phenotypes were quite milder compared with SMEI patients.

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2. Case reports 

Respective parents of the two patients were unrelated and of Southern China ancestry.

Patient 1: The 16-year-old boy was born full time and his early development was normal. At age 2 years, he had two episodes of febrile generalized tonic-clonic seizures (GTCS) lasting about 5min. At 13 years of age, he had first afebrile seizure. He complained of uncomfortable feeling, then followed by secondary generalization. Seizure frequency was four times a year. At 14 years the boy was successfully treated with valproate and became seizure free. EEG (performed at age 13 years) showed an almost normal background with a little excessive β rhythms during wakefulness. Brain magnetic resonance imaging (MRI) scans showed no abnormality. Now he was a high-school student and his academic performance was average. He was diagnosed as GEFS+. His father was healthy but his mother had several febrile seizures (FS) in her childhood. His younger brother had one FS at 1 year old (Pedigree shown in Fig. 1).

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  • Fig. 1. 

    Pedigree, DHPLC and sequencing analysis of patient 1. (A) Pedigree. (B) DHPLC chromatograms of all family members. Arrow showed the mutation peak. (C) Partial nucleotide sequences of exon 11 of SCN1A, showing the heterozygous A>C substitution that corresponds to the truncation mutation S662X.

Patient 2: The 2-year-old girl was born without any obvious problems. At age 4 months old, she had her first GTCS lasting for 3min without any provoked factors. Seizure frequency was one time 2 months. When she was 11 months old, she had complex partial seizures (panic attack, occurring about 4–5 times per month), which occasionally occurred during a febrile illness. Since 14 months old, she had secondarily GTCS, once every 2 weeks. At 16 months, she accepted the treatment with combination of valproate and topiramate and became seizure free. Video-EEG (performed at age 16 months) showed almost normal, with regular high aptitude θ waves and 1.5–2.0Hz slow activity in the frontal/middle left temporal area. MRI (done at age 8 months) was normal. So far her psychomotor development was normal. The family history of FS or epilepsy was negative.

Genomic DNA was obtained from blood samples of the both patients and their respective parents. The parents gave written informed consents and the study was approved by the institutional review board of the hospital. Methods for mutational analysis of SCN1A were described previously.10 The results of denaturing high performance liquid chromatography (DHPLC) and sequencing were shown in Fig. 1, Fig. 2. Two do novo truncation mutations in SCN1A were detected in the two patients respectively. For patient 1, genetic analysis detected a nucleotide change (c.1985C>A), which led to premature termination at 662 in protein (S662X). In patient 2, we detected a nucleotide change (c.[AT]433-434del), which resulted in a frame-shift mutation (M145fsX148).

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  • Fig. 2. 

    Pedigree, DHPLC and sequencing analysis of patient 2. (A) Pedigree. (B) DHPLC chromatograms of all family members. Arrow showed the mutation peak. (C) Partial nucleotide sequences of exon 3 of SCN1A, showing the heterozygous deletion c.[AT]433-434del that corresponds to the truncation mutation M145fsX148.

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3. Discussion 

Early previous studies have shown that truncation mutations of SCN1A were exclusively associated to SMEI.11, 12, 13 An exception was found later in a patient with cryptogenic focal epilepsy (CFE), which was considered as one subtype of infantile epileptic encephalopathies.14 Generally speaking, truncation mutation of SCN1A led to serious phenotypes. However, in rare familial SMEI cases, SCN1A truncation mutation was found to be transmitted by the asymptomatic or mildly symptomatic parent.15 These findings emphasized the difficulty of predicting the SMEI phenotype based on the finding of SCN1A mutation, also suggested significant roles of genetic backgrounds or environmental modifiers.

In the present study, two truncation mutations were found to associate with milder epilepsy other than SMEI. For patient 1, because his mother and younger brother had FS, we suspected the mother might transmit the pathogenic gene to her sons. To our surprise, the patient carried the truncation mutation while his relatives did not, which may be explained by the polygenetic factors of FS.16 He was diagnosed as GEFS+. For patient 2, she had partial seizures, and her initial seizures were not related to febrile circumstances, which was corresponding to CFE.14 However, till now she did not show intellectual disability and had good response to anti-epileptic drugs (AEDs), which was not consistent with CFE.14 Although the seizures occurred occasionally during febrile illness, close relationship between the seizures and febrile events was not defined, probably due to the well control of seizures. Otherwise a diagnosis of partial epilepsy with febrile seizures might be considered.10 The final diagnosis may be confirmed by the later follow-up. Our results indicate that mutations leading to a truncated protein are not necessarily specific for the diagnosis of SMEI. Then why some people carrying the SCN1A truncation mutation show only mild phenotype should cause our attention in future studies.

It has been a few years since the application of SCN1A gene test in GEFS+/SMEI patients. It is of great importance to determine what kind of patients needs such a gene test. The present two cases suggested the isolated milder cases might also be candidates for SCN1A gene test. Our findings are clinically significant in two aspects. Firstly, although seizure aggravations induced by AEDs (lamotrigine, carbamazepine, and probably phenytoin) are known for SMEI patients,17, 18, 19, 20 the danger of seizure aggravations in isolated milder cases is usually ignored. Recently we found that sodium channel blockers could cause seizure aggravation in patients with SCN1A mutations associated with loss of function.10 Therefore, these milder cases with the same genetic basis may also have the similar AEDs response. An early genetic diagnosis will help clinicians to choose AEDs correctly, which may be critical in preventing seizure aggravation and the generation of intractable epilepsy. Our two cases both had good response to the valproate (or combination with topiramate), which was also in accordance with the AEDs response of SMEI patients.21, 22 Secondly, comparing with SMEI patients who have few chances to have offspring because of devastating intractable epilepsy, milder cases may have more chances to have their own children. The genetic diagnosis, even prenatal diagnosis, is thus required for genetic counseling.

Overall, the present study demonstrated two novel, do novo SCN1A truncation mutations in milder cases other than SMEI, which extended the utility of the SCN1A gene testing and further confirmed the complex relationship between genotype and phenotype of SCN1A mutation. Further work is needed to optimize the protocol for specific genetic testing in children with epilepsy.

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Acknowledgments 

This work was supported by The National Natural Science Foundation of China (Grant nos. 30900451; 30700247; 30600198). We are grateful to He Shanheng Charity Foundation for contributing to the development of this institute.

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References 

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PII: S1059-1311(10)00139-1

doi:10.1016/j.seizure.2010.06.010

Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 443-445, September 2010

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