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The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short communication
The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura LiPing Zhang a, Yu Jia b,c, YuPing Wang b,c,⇑ a
Department of Pediatrics, Xuanwu Hospital, Capital Medical University, Beijing, China Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China c Beijing Key Laboratory of Neuromodulation, Beijing, China b
a r t i c l e
i n f o
Article history: Received 14 July 2019 Accepted 31 January 2020 Available online xxxx Keywords: Familial lateral temporal lobe epilepsy Auditory aura LGI1 gene Autosomal dominant epilepsy Gene detection
a b s t r a c t Auditory aura was the very important clinical character in familial temporal Lobe epilepsy. LGI1 was the main pathogenic gene. The inheritance mode of this disease was autosomal dominant. We describes the clinical characters and gene detection in 7 patients in a temporal lobe epilepsy family with auditory aura. All patients in this family were diagnosed as temporal lobe epilepsy and had the same mutation: the splice site mutation in No. 2 base of the intron after the first exon in gene LGI1, c.215+2T>A, which induced the abnormal expression of peptide protein after the No. 71 amino acid encoded by LGI1. Some of the antiepileptic drugs, such as carbamazepine, oxcarbazepine, could be effective. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Familial temporal lobe epilepsy (FTLE) comprises two genetic epilepsy syndromes: autosomal dominant lateral temporal epilepsy (ADLTE) and familial mesial temporal lobe epilepsy (FMTLE). ADLTE is characterized by focal seizures with auditory or aphasic auras, no brain structural abnormalities, and usually good outcome. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene are found in about 50% of the ADLTE families [1]. FMTLE is characterized by auras with prominent psychic and autonomic features, suggesting a mesial temporal origin [2]. Here we introduce an autosomal dominant familial temporal lobe epilepsy with auditory aura.
2. Clinical data The 10-year-old boy was admitted on 20th June 2018 because of paroxysmal convulsions for 9 months. He had afebrile convulsion expressed that the eyes were hanged, the mouth foamed, limbs quivered, accompanied by the incontinence of urine, which lasted for 1 min. Since the onset, there were a total of 4–5 similar convulsions and the internal periods were generally good. Before each episode, ears rang, a sound clip appeared repeatedly, three
to five minutes later, a convulsion came. Convulsions could occur during wakefulness and sleep. The patient had the auditory aura described during awake but not in sleep. The perinatal history was normal. His brother was healthy. Family history: His father, aunt, aunt’s son, grandmather’s brother, great uncle’s daughter and great uncle’s granddaughter, seven family members in three generations had similar symptoms (Fig. 1). All the patients suffered from the onset before and after puberty, and three of them who took antiepileptic drugs were all clinically seizure free. There were no positive signs of nervous system. No abnormalities were observed in serum biochemistry, parathyroid examination and brain MRI. Electroencephalogram background was normal, and bilateral frontal lobe and anterior superior temporal lobe dispersed sharp waves were observed in middle amplitude. The oxcarbazepine was gradually increased to 25 mg/kg, and he had seizure free after that. 3. Gene detection The project was approved by Ethics Committee of Beijing Xuanwu Hospital and the family members of the proband were consent with it. 3.1. Next-generation sequencing (NGS) and Sanger sequencing
⇑ Corresponding author at: Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. E-mail address: [email protected] (Y. Wang).
Genomic DNA sample was sheared and then hybridized with NimbleGen 2.0 probe sequence capture array of Roche (Joy Orient,
https://doi.org/10.1016/j.jocn.2020.01.091 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091
2
L. Zhang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Fig. 1. ADLTE family tree. Gene LGI1 mutation caused autosomal dominant lateral temporal epilepsy. h Normal male, s normal female, j male patient, d female patient, proband.
China) to generate DNA libraries. The libraries were qualified by quantitative-PCR and the Agilent Bioanalyzer 2100. Qualified samples were then sequenced on the Illumina hiseq2500 platform (Illumina, USA). Raw image files were processed by the BclToFastq (Illumina, USA) for base calling and generating the raw data. The low-quality variations were filtered out using the quality score 20 (Q20). The sequencing reads were aligned to the NCBI human reference genome (hg19) using BWA. Samtools and Pindel were used to analyzed SNP (Single Nucleotide Polymorphism) and indel (insertion and deletion). Synonymous changes and SNPs whose MAFs (Minor Allele Frequency) are higher than 5% were removed (http://www.ncbi.nlm.nih.gov/projects/SNP). Nonsynonymous changes were filtered using SIFT. Filtered variants were annotated. Variants associated with symptoms of the patient were selected. Sanger sequencing was used to confirm candidate mutations in proband.
4. Results Gene LGI1: c.215+2T>A mutation was found in all seven patients, which was also found in the grandmother of proband, the No. 4 girl (generation III) of grandmother, but with normal phenotype. LGI1: c.215+2T>A was a newly discovered mutation. There was no clinical literature or functional literature to report the pathogenicity of it. The variation occurred in second base of introns after the first exon of LGI1 gene, was the classic splice site mutation, might result in all introns between the first exon and the second one into exon parts, could cause the encoded peptide protein abnormal expression after the 71th amino acid. This variation was not included in the normal population database (ESP database, 1000 database, gnomAD database), and was a rare mutation (Fig. 2).
Fig. 2. Sequence diagram. The splice site mutation in No. 2 base of the intron after the first exon in gene LGI1, c.215+2T>A.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091
L. Zhang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
5. Discussion
Funding
Temporal lobe epilepsy was one of the most common types of epilepsy, including the lateral temporal lobe and the mesial temporal lobe. ADLTE was first reported by Ottman equals [3], the international union of epilepsy (ILAE) named it as a new kind of epilepsy syndrome in 2001, 50% family was caused by LGl1 mutations [1]. LGI1 was a gene encoding the secretary protein associated with human epilepsy in central nervous system. LGI1 mutation was associated with autosomal dominant temporal lobe epilepsy, which was characterized by convulsions and auditory hallucinations [4]. ADLTE, characterized by focal epilepsy with auditory aura, was usually followed by general tonic-clonic seizure. Among them, auditory aura was an important feature, and there was also sensory aphasia, mental symptoms and so on. The onset age was usually between 20 and 30 years. The disease was benign, and some of the antiepileptic drugs, such as carbamazepine, oxcarbazepine, could be effective. The gene analysis was performed in 19 members including 7 patients. The two family members who had the same mutation without any symptoms may due to the incomplete penetrance (60–70%) of LGI1 [5]. The incidence of male and female was similar, the onset age was between 12 and 23 years, and was consistent with autosomal dominant inheritance. There was an auditory aura, and the type of attack was a focal disorder or focal attack followed by the general tonic-clonic seizure. No status epileptics; 3–5 seizures per year; One male patient seizure was induced by alcohol, fatigue and staying up late. Oxcarbazepine were effective and met ILAE’s criteria for ADLTE.
This work was supported by Beijing Municipal Education Commission, Grant No. TJSH20161002502 and National Natural Science Foundation of China, Grant No. 81771398.
Ethics statement All procedures were approved by the ethics committee of Xuanwu Hospital. The parents of our patient provided written informed consent.
Author contributions L. Zhang, Y. Jia and Y. wang were the major contributors in writing the manuscript. L. Zhang and Y. Jia contributed to the analysis of genetic examination. Y. Wang contributed to checking the manuscript. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2020.01.091. References [1] Michelucci R, Pasini E, Malacrida S, et al. Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1mutations. Epilepsia 2013;54:1288–97. [2] Berkovic SF, McIntosh A, Howell RA, et al. Familial temporal lobe epilepsy: a common disorder identified in twins. Ann Neurol 1996;40:227–35. [3] Ottman R, Risch N, Hauser WA, et al. Localization of a geneforpartial epilepsy to chromosome lOq. Nat Genet 1995;10:56–60. [4] Kegel L, Aunin E, Meijer D, Bermingham JR. LGI proteins in the nervous system. ASN Neuro 2013;5:167–81. [5] Cowell JK. LGI1: from zebrafish to human epilepsy. Prog Brain Res 2014;213:159–79.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short communication
The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura LiPing Zhang a, Yu Jia b,c, YuPing Wang b,c,⇑ a
Department of Pediatrics, Xuanwu Hospital, Capital Medical University, Beijing, China Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China c Beijing Key Laboratory of Neuromodulation, Beijing, China b
a r t i c l e
i n f o
Article history: Received 14 July 2019 Accepted 31 January 2020 Available online xxxx Keywords: Familial lateral temporal lobe epilepsy Auditory aura LGI1 gene Autosomal dominant epilepsy Gene detection
a b s t r a c t Auditory aura was the very important clinical character in familial temporal Lobe epilepsy. LGI1 was the main pathogenic gene. The inheritance mode of this disease was autosomal dominant. We describes the clinical characters and gene detection in 7 patients in a temporal lobe epilepsy family with auditory aura. All patients in this family were diagnosed as temporal lobe epilepsy and had the same mutation: the splice site mutation in No. 2 base of the intron after the first exon in gene LGI1, c.215+2T>A, which induced the abnormal expression of peptide protein after the No. 71 amino acid encoded by LGI1. Some of the antiepileptic drugs, such as carbamazepine, oxcarbazepine, could be effective. Ó 2020 Elsevier Ltd. All rights reserved.
1. Introduction Familial temporal lobe epilepsy (FTLE) comprises two genetic epilepsy syndromes: autosomal dominant lateral temporal epilepsy (ADLTE) and familial mesial temporal lobe epilepsy (FMTLE). ADLTE is characterized by focal seizures with auditory or aphasic auras, no brain structural abnormalities, and usually good outcome. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene are found in about 50% of the ADLTE families [1]. FMTLE is characterized by auras with prominent psychic and autonomic features, suggesting a mesial temporal origin [2]. Here we introduce an autosomal dominant familial temporal lobe epilepsy with auditory aura.
2. Clinical data The 10-year-old boy was admitted on 20th June 2018 because of paroxysmal convulsions for 9 months. He had afebrile convulsion expressed that the eyes were hanged, the mouth foamed, limbs quivered, accompanied by the incontinence of urine, which lasted for 1 min. Since the onset, there were a total of 4–5 similar convulsions and the internal periods were generally good. Before each episode, ears rang, a sound clip appeared repeatedly, three
to five minutes later, a convulsion came. Convulsions could occur during wakefulness and sleep. The patient had the auditory aura described during awake but not in sleep. The perinatal history was normal. His brother was healthy. Family history: His father, aunt, aunt’s son, grandmather’s brother, great uncle’s daughter and great uncle’s granddaughter, seven family members in three generations had similar symptoms (Fig. 1). All the patients suffered from the onset before and after puberty, and three of them who took antiepileptic drugs were all clinically seizure free. There were no positive signs of nervous system. No abnormalities were observed in serum biochemistry, parathyroid examination and brain MRI. Electroencephalogram background was normal, and bilateral frontal lobe and anterior superior temporal lobe dispersed sharp waves were observed in middle amplitude. The oxcarbazepine was gradually increased to 25 mg/kg, and he had seizure free after that. 3. Gene detection The project was approved by Ethics Committee of Beijing Xuanwu Hospital and the family members of the proband were consent with it. 3.1. Next-generation sequencing (NGS) and Sanger sequencing
⇑ Corresponding author at: Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. E-mail address: [email protected] (Y. Wang).
Genomic DNA sample was sheared and then hybridized with NimbleGen 2.0 probe sequence capture array of Roche (Joy Orient,
https://doi.org/10.1016/j.jocn.2020.01.091 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091
2
L. Zhang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Fig. 1. ADLTE family tree. Gene LGI1 mutation caused autosomal dominant lateral temporal epilepsy. h Normal male, s normal female, j male patient, d female patient, proband.
China) to generate DNA libraries. The libraries were qualified by quantitative-PCR and the Agilent Bioanalyzer 2100. Qualified samples were then sequenced on the Illumina hiseq2500 platform (Illumina, USA). Raw image files were processed by the BclToFastq (Illumina, USA) for base calling and generating the raw data. The low-quality variations were filtered out using the quality score 20 (Q20). The sequencing reads were aligned to the NCBI human reference genome (hg19) using BWA. Samtools and Pindel were used to analyzed SNP (Single Nucleotide Polymorphism) and indel (insertion and deletion). Synonymous changes and SNPs whose MAFs (Minor Allele Frequency) are higher than 5% were removed (http://www.ncbi.nlm.nih.gov/projects/SNP). Nonsynonymous changes were filtered using SIFT. Filtered variants were annotated. Variants associated with symptoms of the patient were selected. Sanger sequencing was used to confirm candidate mutations in proband.
4. Results Gene LGI1: c.215+2T>A mutation was found in all seven patients, which was also found in the grandmother of proband, the No. 4 girl (generation III) of grandmother, but with normal phenotype. LGI1: c.215+2T>A was a newly discovered mutation. There was no clinical literature or functional literature to report the pathogenicity of it. The variation occurred in second base of introns after the first exon of LGI1 gene, was the classic splice site mutation, might result in all introns between the first exon and the second one into exon parts, could cause the encoded peptide protein abnormal expression after the 71th amino acid. This variation was not included in the normal population database (ESP database, 1000 database, gnomAD database), and was a rare mutation (Fig. 2).
Fig. 2. Sequence diagram. The splice site mutation in No. 2 base of the intron after the first exon in gene LGI1, c.215+2T>A.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091
L. Zhang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
5. Discussion
Funding
Temporal lobe epilepsy was one of the most common types of epilepsy, including the lateral temporal lobe and the mesial temporal lobe. ADLTE was first reported by Ottman equals [3], the international union of epilepsy (ILAE) named it as a new kind of epilepsy syndrome in 2001, 50% family was caused by LGl1 mutations [1]. LGI1 was a gene encoding the secretary protein associated with human epilepsy in central nervous system. LGI1 mutation was associated with autosomal dominant temporal lobe epilepsy, which was characterized by convulsions and auditory hallucinations [4]. ADLTE, characterized by focal epilepsy with auditory aura, was usually followed by general tonic-clonic seizure. Among them, auditory aura was an important feature, and there was also sensory aphasia, mental symptoms and so on. The onset age was usually between 20 and 30 years. The disease was benign, and some of the antiepileptic drugs, such as carbamazepine, oxcarbazepine, could be effective. The gene analysis was performed in 19 members including 7 patients. The two family members who had the same mutation without any symptoms may due to the incomplete penetrance (60–70%) of LGI1 [5]. The incidence of male and female was similar, the onset age was between 12 and 23 years, and was consistent with autosomal dominant inheritance. There was an auditory aura, and the type of attack was a focal disorder or focal attack followed by the general tonic-clonic seizure. No status epileptics; 3–5 seizures per year; One male patient seizure was induced by alcohol, fatigue and staying up late. Oxcarbazepine were effective and met ILAE’s criteria for ADLTE.
This work was supported by Beijing Municipal Education Commission, Grant No. TJSH20161002502 and National Natural Science Foundation of China, Grant No. 81771398.
Ethics statement All procedures were approved by the ethics committee of Xuanwu Hospital. The parents of our patient provided written informed consent.
Author contributions L. Zhang, Y. Jia and Y. wang were the major contributors in writing the manuscript. L. Zhang and Y. Jia contributed to the analysis of genetic examination. Y. Wang contributed to checking the manuscript. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2020.01.091. References [1] Michelucci R, Pasini E, Malacrida S, et al. Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1mutations. Epilepsia 2013;54:1288–97. [2] Berkovic SF, McIntosh A, Howell RA, et al. Familial temporal lobe epilepsy: a common disorder identified in twins. Ann Neurol 1996;40:227–35. [3] Ottman R, Risch N, Hauser WA, et al. Localization of a geneforpartial epilepsy to chromosome lOq. Nat Genet 1995;10:56–60. [4] Kegel L, Aunin E, Meijer D, Bermingham JR. LGI proteins in the nervous system. ASN Neuro 2013;5:167–81. [5] Cowell JK. LGI1: from zebrafish to human epilepsy. Prog Brain Res 2014;213:159–79.
Please cite this article as: L. Zhang, Y. Jia and Y. Wang, The clinical characters and gene detection in a familial temporal lobe epilepsy with auditory aura, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.091