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중개의학석사 학위논문
Electroclinical Spectrum of SCN1A Mutation Positive Dravet
syndrome Patients
SCN1A 돌연변이 양성 Dravet 증후군 환자의 임상 양상에 대한 연구
2017년 2월
서울대학교 의과대학원
의학과 중개의학 전공
유일한
중개의학석사 학위논문
Electroclinical Spectrum of SCN1A Mutation Positive Dravet
syndrome Patients
SCN1A 돌연변이 양성 Dravet 증후군 환자의 임상 양상에 대한 연구
2017년 2월
서울대학교 의과대학원
의학과 중개의학 전공
유 일 한
iii
A thesis of the Master's degree
SCN1A 돌연변이 양성 Dravet 증후군 환자의 임상 양상에 대한
연구
Electroclinical Spectrum of SCN1A Mutation Positive Dravet Syndrome
Patients
February 2017
The Department of Medicine
Seoul National University Graduate School
Il Han Yoo
SCN1A 돌연변이 양성 Dravet 증후군 환자의 임상 양상에 대한
연구
지도교수 김 기 중
이 논문을 의학석사학위논문으로 제출함
2017 년 2 월
서울대학교 의과대학원 의학과 중개의학 전공
유 일 한
유일한의 석사학위 논문을 인준함 2017 년 2 월
위 원 장 (인) 부 위 원 장 (인) 위 원 (인)
v
Electroclinical Spectrum of SCN1A Mutation Positive Dravet
syndrome Patients
by Il Han Yoo
A thesis submitted to the Department of Medicine in partial fulfillment of the requirements for the
Degree of Master of Science in Medicine at Seoul National University Graduate School
February 2017
Approved by Thesis Committee:
Professor Chairman
Professor Vice chairman
Professor
Abstract
Electroclinical Spectrum of SCN1A Mutation Positive Dravet patients
Il Han Yoo Translational, Medicine The Graduate School Seoul National University
Purpose:
With the widespread use of
SCN1Agenetic tests, electroclinical spectrum observed in patients with
SCN1Amutation is expanding beyond classic Dravet syndrome. This study reviews the electroclinical features of
SCN1Amutation positive patients to discuss the point of consideration for diagnosing Dravet syndrome.
Methods:
We reviewed the electroclinical features of 55 patients with confirmed
SCN1Amutations focusing on core features of Dravet syndrome.
SCN1A
mutational analysis was performed with direct Sanger sequencing and multiple ligation dependent probe amplification.
Results:
Twenty-nine of 55 patients were male. The mean age of seizure
vii
onset was 5.8 months (range 1 day – 12.0 months). Fifty-three percent patients presented fever or illness and 29% patients had prolonged seizure at seizure onset. Eight-five percent patient showed generalized tonic-clonic seizure or hemi-clonic seizure as first seizure. All patients showed normal development before seizure onset. Twenty-five (83%) patients showed normal findings in initial interictal electroencephalography (EEG). At steady state, patients show various seizures such as focal seizures (78%), hemi- clonic seizures (59%), myoclonic seizures (40%) and atypical absence seizures (28%). Generalized epileptiform discharges was detected in 39%
patients and focal epileptiform discharges were confirmed in 65% patients.
All patients had the resistant to antiepileptic drugs and showed developmental delay or regression after 2 years old.
Conclusion
Dravet syndrome patients with SCN1A mutation have consistent characteristics at seizure onset including age, interictal EEG finding, the type of seizure. However, at steady state, seizure semiology and EEG patterns show significant variations between patients. Careful investigation about the mode of early stage is crucial for diagnosing Dravet syndrome
Keywords:
Dravet syndrome,
SCN1Amutations, Diagnosis
Student Number: 2015-20024
Contents
Abstract ...i
Contents ...iii
List of Tables and Figures ...iv
Introduction ...1
Materials and Methods ...3
Results ...6
Discussion ...14
References ...17
Abstract in Korean ...21
ix
List of Tables and Figures
Table 1. Summary of SCN1Amutations ...12 Table 2. Characteristics of first seizure...15
Figure 1. The distribution of SCN1A mutations ...11
1. Introduction
SCN1Agene is clinically one of the most relevant genes that cause epilepsy syndrome, and was first detected in generalized epilepsy with febrile seizures plus (GEFS+) in 20001. SCN1A encodes neuronal sodium channel alpha 1 subunit, which has a significant function in maintaining the activation of inhibitory interneurons2,3. Mutations in this gene causes various epilepsy syndromes that range from a milder form such as GEFS+ to a severe form of disease such as migrating partial seizure of infancy and Dravet syndrome1,4-6. Among the various phenotypes, typical Dravet syndrome is known as the most common phenotype of SCN1A mutation related epilepsy, and upon including borderline Dravet syndrome, it accounts for about 90% of the patients with SCN1Amutations7-9.
Dravet syndrome makes up the largest proportion of SCN1Amutation related epilepsy and was first described by Dravet. C in 1978 as severe myoclonic epilepsy in infancy10. Afterwards, borderline Dravet syndrome which lacked some of the key clinical features observed in typical form such as myoclonic seizures or generalized epileptiform discharges were reported11,12. Because these patients showed similar clinical outcomes with typical Dravet syndrome13, International League Against Epilepsy (ILAE) proposed to change the disease terminology from SMEI to Dravet syndrome which included typical and borderline forms in 198914. According to this report, Dravet syndrome was defined by the following: (1) febrile and afebrile generalized and unilateral, clonic or tonic clonic, seizures occurring in the first year of life in normal infants at seizure onset; (2) later associated with
2
myoclonic, atypical absence, partial seizure; (3) all seizure type are resistance to antiepileptic drugs; (4) apparent developmental delay within the second year of life. After this modification, with the widespread use of SCN1A genetic tests, patients with SCN1A mutation positive Dravet syndrome have been increasingly reported. Some do not show one or more of the core features of Dravet syndrome. Patients without generalized seizure and epileptiform discharges showing slow developmental delay at onset were reported15. One study reported that some patients with a deletion of the chromosome 2q24.3 showed only multifocal or hemi-clonic seizure16. Accordingly, the electroclinical spectrum ofSCN1A mutation positive Dravet patients seems to be expanding. Therefore, the clinical boundary and strict diagnostic criterion of Dravet syndrome has not yet been established.
In this study, we reviewed the electroclinical features of SCN1A mutation positive patients to observe the key points that need to be considered in diagnosing Dravet syndrome.
2. Materials and Methods
2.1 Patients
This study was approved by the Institutional Review Board of Seoul National University Hospital. This was a retrospective study of 55 patients confirmed with SCN1Agene mutation through genetic analysis at Seoul National University Hospital and Asan Medical Center Children’s Hospital.
2.2 Data abstraction
Clinical and demographic data were collected from electronic medical records. We particularly focused on the clinical data accepted as the core features of Dravet syndrome according to the ILAE classification14. Data including age, type of seizure, presence of fever/illness, duration of seizure (prolonged seizure defined that have the duration > 15min or repetitive seizures without the recovery of consciousness > 15min), developmental delay, and interictal electroencephalography (EEG) at initial seizure were collected.
Seizures that appeared during the steady state (over 1 years old) were reviewed and categorized into focal, myoclonic, atypical absence and hemi- clonic seizures based on the medical records and video electroencephalography monitoring. Focal seizures included focal motor and dyscognitive focal seizures. Interictal electroencephalography (EEG) performed during the follow up period were collected. EEG that showed focal or generalized epileptiform discharges were confirmed. Because younger patients do not show myoclonic or atypical absence seizures or generalized epileptiform discharges, we included only 40 patients who were at least 3 years old at the last follow up to analyze generalized seizures and epileptiform
4
discharges. In addition, information on the developmental delay after 2 years old and treatment response for antiepileptic drugs were collected. The developmental status of 43 patients who have sufficient information were evaluated. Fourteen patients were examined by Wechsler Intelligence Scale for Children or Bayley Scales of Infant Development and others were evaluated by clinical observation. Patients were classified into three group, mild, moderate or severe degree according to severity.
2.3 SCN1A direct sequencing and MLPA
Genetic analysis was performed on genomic DNA extracted from peripheral blood using g a QIAamp® DNA Blood Midi Kit, according to the manufacturer’s instructions (Qiagen, Valencia, CA, USA). Direct sequencing of all coding exons and flanking intronic sequences of the SCN1A gene was performed using primer pairs designed by the corresponding authors.
Polymerase chain reaction amplification was conducted in a thermal cycler (Model 9700; Applied Biosystems, Foster City, CA, USA), and cycle sequencing was performed on an ABI Prism 3730xl DNA Analyzer using the BigDye Terminator Sequencing Ready Reaction Kit (Applied Biosystems).
Sequence variations were analyzed via comparison with the wild-type sequence (NM_001165963). Pathogenic mutations were determined by the following criteria: 1) previously reported mutation 2) novel truncation (nonsense, frame-shift, canonical splice sites). Novel missense variant was regarded as pathogenic when confirmed as de novo or segregated through the affected family members by family study16. We confirmed intragenic deletion and duplication in patients without mutations by MLPA analysis. MLPA
analysis was conducted using the SALSA MLPA kit P137-A2 SCN1A (MRC Holland, Amsterdam, the Netherlands), according to the manufacturer’s instructions. MLPA samples have 50-100ng of genomic DNA. Fragment analysis of PCR products were performed using capillary electrophoresis on an ABI 3130xl Genetic Analyzer (Applied Biosystems). Data were analyzed using the geneMarker software, version 1.6 (Soft-Genetics, Stage College, PA, USA). The reference range was set from 0.75 for deletion to 1.3 for duplication.
6
3. Results
The study population consisted of 29 males and 26 females. Their mean age at last follow up was 89.9 months (SD = 92.8, range 7.6 – 270.1 months). The mean follow up duration was 73.2 months (SD = 72.6, range 1.9 – 270.8).
3.1 SCN1Amutations
Fifty-five patients with confirmed SCN1A mutation were recruited. There is no identical mutation among them. Twenty-three mutations were novel mutations, and others were previously reported. Missense mutations were seen in 24/55 (48%). Truncation mutations were detected in 26/55 (46%) consisting of 14 frame shifts and 12 nonsense mutations. Two patients had splice site mutation. Large deletions were seen in 3 patients. Trio sample including parents were done in 37 patients. De novo mutation was confirmed in 34 patients. Of the remaining 3 patients, patients 9, 19, 42 had mutations inherited from their parents. The father of patient 9 had frequent febrile seizures during childhood and is currently and epilepsy patient with no intellectual disability. The father of patient 19 had a febrile seizure history, but was seizure free after adolescence. Finally, the mother of patient 42 had a mosaic mutation of the same region, but without a history of seizure. The distribution of SCN1A mutations is shown in Figure 1. More detailed information regarding mutations is summarized in Table 1.
Figure 1. The distribution of SCN1A mutations
24
14 12
2 3
missense frame shift nonsense splice site large deletion
8
Table 1. Summary of SCN1A mutations
Patient No Nucleotide change Amino acid change Inheritance Novel Type
1 c.1276 T>C p.Tyr426His De novo Novel Missense
2 c.5176T>G p.Trp1726Gly De novo Novel Missense
3 c.4822G>T p.Asp1608Tyr De novo PR Missense
4 c.3340_3343del(ACTG) p. Thr1114Tyrfs*5 Not determined1 Novel Truncation
5 c.4188C>A p.Cys1396* Not determined Novel Truncation
6 c.3106C>T p.Gln1036X De novo Novel Truncation
7 c.302G>A p.Arg101Gln De novo PR Missense
8 c.2911G>A p.Val971lle Not determined Novel Missense
9 c.4216G>A p.Ala1406Thr Father PR Missense
10 c.1630delA p.Thr544HisfsX14 De novo Novel Truncation
11 c.1837C>T p.Arg613X De novo PR Truncation
12 c.2854T>C p.Trp952Arg De novo Novel Missense
13 c.3946A>T p.Arg1316Trp De novo PR Missense
14 c.4821_4827dupTGATTTT p.Val1610X De novo Novel Truncation
15 c.3968C>G p.Pro1323Arg De novo PR Missense
16 c.4906C>T p.Arg1636X De novo PR Truncation
17 c.1633_1634insAC p.Glu546MetfsX13 Not determined Novel Truncation
18 c.3384delC p.Asn1128LysfsX18 De novo PR Truncation
19 c.4296delA p.Gly1433AspfsX5 Father PR Truncation
20 c.4127_4128delGT p.Cys1376TyrfsX2 De novo PR Truncation
21 exon 1–20 deletion Not determined PR
22 c.596_602+3del p.Thr199Serfs*15 De novo Novel Truncation
23 exon1-exon26 Not determined PR
24 c.3598T>C p.Cys1200Arg Not determined Novel Missense
25 c.1315delC p.Gln439ArgfsX9 De novo Novel Truncation
26 c.4539dupA p.Leu1514IlefsX23 De novo PR Truncation
27 c.4219C>T p.Arg1407X Not determined PR Truncation
28 c.1177C>T p.Arg393Cys Not determined PR Missense
29 c.694+2delT De novo Novel
30 c.1624C>T p.Arg542* De novo PR Truncation
31 c.7C>T p p.Gln3X De novo PR Truncation
32 c.1142A>G p.Gln381Arg De novo Novel Missense
33 c.2947-1G>A Not determined PR Truncation
34 whole exon deletion (exon 1-
26) Not determined PR
35 c.2593C>T p.Arg865X Not determined PR Truncation
36 c.4662delC p.Asn1554LysfsX5 De novo PR Truncation
37 c.5734C>T p.Arg1912* Not determined PR Truncation
38 c.4488delA p.Asp1497ThrfsX4 De novo PR Truncation
39 c.5029C>T p.Leu1677Phe Not determined PR Missense
40 c.2088_2091delTTTC p.Phe697ThrfsX7 De novo PR Truncation
41 c.2686G>C p.Val896Leu De novo PR Missense
42 c.1187G>A p.Gly396Glu Mother PR Missense
43 c.4502C>T p.Thr1501Ile Not determined Novel Missense
44 c.4907G>C p.Arg1636Pro De novo Novel Missense
45 c.557T>C p.Leu186Pro De novo Novel Missense
46 c.1186G>A p.Gly396Arg De novo Novel Missense
47 c.248A>C p.Tyr83Ser De novo Novel Missense
48 c.833T>A p.Ile278Lys De novo Novel Missense
49 c.5674C>T p.Arg1892* De novo PR Truncation
50 c.5126C>T p.Thr1709Ile De novo PR Truncation
51 c.4286C>A p.Ala1429Asp Not determined PR Missense
52 c.del2851_2872 p.E951Thr fs*16 De novo Novel Truncation
53 c.992dupT p.Leu331Phe fs*8 De novo PR Truncation
54 c.4933C>G p.Arg1645Gly De novo Novel Missense
55 c.272T>C p.Ile91Thr Not determined PR Missense
Abbreviations: PR previously reported
1Parents were not analyzed
10 3.2 At onset
The mean age at seizure onset was 5.8 months (SD = 3.3, range 1day – 12.0 months). Fever was observed with seizure onset in 28 of 53 (53%) patients.
Forty-four patients (85%) showed generalized tonic-clonic seizure (GTCS) or hemi-clonic seizure as the first seizure. Fourteen patients (29%) among 48 had prolonged seizure. Six patients experienced their first seizure in association with vaccination. Among these 6 patients, 4 had fever within 48 hours after vaccination (2 PCV, 1 HBV, and 1 DPT) and the other 2 patients were without fever (2 DPT). All patients show normal development before initial seizure.
Initial interictal EEG recordings performed within one-year-old were available for 30 patients. Twenty-five (83%) of these cases showed normal findings. (Table 2)
Table 2. Characteristics of first seizure
n/N (%)
The presence of fever 28/53 (53)
The prolonged seizure (>15min) 14/48 (29) The seizure onset with vaccination 6/43 (14) Seizure type
GTCS 26/52 (52)
Hemi-clonic 18/52 (32)
Dyscognitive focal seizure 5/52 (12)
Others (focal motor 1, myoclonic 1) 2/52 (4)
Normal EEG 25/30 (83)
GTCS: generalized tonic-clonic seizure, N: the number of patients who have accessible medical data.
12 3.3 Steady state
Sixteen patients (40%) among 40 that were over 3 years old presented with myoclonic seizure, and 11 (28%) showed atypical absence seizure, while 23 (58%) patients had neither. Meanwhile, 45 (78%) of 54 patients had focal seizures including focal motor and dyscognitive focal seizure, and 32 patients (59%) had hemi-clonic seizure. Thirty-two patients with hemi-clonic seizure showed alternating hemi-clonic seizure. Generalized epileptiform discharges were detected in 16 (39%) of 40 patients, and focal epileptiform discharges were confirmed in 36 (65%) of 55 patients. Among patients with focal epileptiform discharges, 17 showed multifocal epileptiform discharges. Both focal and generalized epileptiform discharges were seen in 11 patients (20%), and 16 patients (32%) showed no epileptiform discharges in their interictal EEG during follow up period. All patients who can be evaluated were resistant to antiepileptic drugs and showed developmental delay or regression after 2 years old. Intellectual disability was mild in thirteen cases, moderate in 17 and severe in 13.
4. Discussion
We investigated the electroclinical features of SCN1A mutations positive Dravet patients in regards to the core features of Dravet syndrome. The mean age of at seizure onset was 5.8 months. Previous studies report that the mean age of their patients was from 5.3 months to 6.0 months8,18-20. Also, one study stated that 93% of Dravet syndrome patients showed first seizure within 7 months21. These results are similar in our present study. Up to 53% of the patients in our study presented with fever or illness at seizure onset. Earlier studies reported that 55~59% of the patients had fever or illness at initial seizure8,19,20,22. Therefore, this result is also closely similar to the findings in our study.
Dravet syndrome patients are known to present typically generalized tonic clonic or unilateral clonic seizure as the initial seizure. Two studies also found that generalized tonic clonic or unilateral seizures were the initial seizure types, observed in 73% and 100%, respectively, in SCN1A mutation positive Dravet patients19,23. Our study also showed findings consistent with the reported studies, showing similar proportions of the patients with fever at seizure onset.
Furthermore, we found that 83% of the patients showed a normal interictal EEG pattern. Several earlier studies show similar results with findings of normal EEG recording detected in up to 70~80% patients19,22,24. We confirmed that prolonged seizure was detected in 29% of the patients at seizure onset.
One earlier study reported that 25% of the patients had prolonged initial seizure, and another study reported prolonged initial seizures in 71%
14
patients19,25. The time of seizure onset was usually determined by the report of a parent. But, the report of a parent may be imprecise due to the lack of information and knowledge about seizures at first seizure onset. In addition, precise measures of the end point of seizures was difficult to determine for physician who did not have enough experience in observing epilepsy patients.
These factors may contribute to the variations on the proportion of patients with prolonged seizures between the studies.
At steady state, we found that patients frequently showed focal seizures and hemi-clonic seizures rather than generalized seizures, including myoclonic and atypical absence seizures. Previous studies stated that focal seizures were detected in 61~78% patients, hemi-clonic seizures in about 70%, myoclonic seizures in 43~82% patients, and atypical absence seizures in 38-67%19-22,26. These findings suggest that focal seizures are as common as generalized seizures in patients despite considering significant variations between the studies.
Upon analysis of the interictal EEG findings, 65% of the patients in our cohort showed focal epileptiform discharges and 39% had generalized epileptiform discharges. Previous studies reported inconsistent findings on interictal EEG patterns in Dravet syndrome. Some studies showed that focal or multifocal epileptifrom discharges were frequently seen in Dravet syndrome22,26,27, whereas others reported contradicting results20,28. In addition, two studies stated that the dominant seizure semiology or interictal EEG can be changed according to the age of patients within even one study. One study stated that generalized epileptiform discharges were seen in 44% of the
patients and focal epileptiform discharges in 53% at first visit. But, generalized epileptiform discharges were detected in only 9% of the patients and focal epileptiform discharges in 69% of the patients at last visit;
furthermore, myoclonic seizures and atypical absence seizures decreased compared to the first visit26. Another study reported that generalized epileptiform discharges were decreased from 60% at onset to 14% at end of the study22. The significant differences between studies in seizure semiology and interictal EEG at steady state suggest that the spectrum of Dravet syndrome is wide and variations between the patients is large. Therefore, defining the dominant seizure semiology and EEG patterns is difficult, even until now.
In summary, the mode of seizure onset is consistent between studies including our cohort, except the proportion of patients with prolonged seizure.
In particular, the results in most of the studies on the age, type of seizure, and interictal EEG patterns at seizure onset was closely similar. The consistent findings between the studies suggest that patients show similar presentation at early stages of the disease. In contrast, at steady state patients may show various seizure types and interictal EEG patterns.
Early genetic diagnosis has benefits on various aspects such as 1) reducing additional diagnostic testing, 2) avoiding antiepileptic medication that may aggravating seizures (Na channel blocker), and 3) selecting antiepileptic drugs or comprehensive treatment strategies that are known to have effects on Dravet syndrome. However, there are several obstacles for early diagnosis of Dravet syndrome. Firstly, Dravet syndrome does not have strict diagnostic
16
criteria. Secondly, several features among criteria can be apparent over time and some of them may not even appear. Thirdly, the electroclinical spectrum of Dravet syndrome is expanding according to finding patients without one or more core features of Dravet syndrome. Because of these facts, selecting proper candidates for SCN1A genetic testing is challenging. Fortunately, Dravet syndrome patients show relatively consistent presentations. Therefore, we suggest that findings at seizure onset can give help in the early diagnosis of Dravet syndrome.
In conclusion, we confirm that Dravet syndrome patients with SCN1A mutation present consistent characteristics including age, absence of development delay, interictal EEG finding, and the type of seizure at seizure onset. But, at steady state, the seizure semiology and EEG patterns have significant variations between patients. Therefore, carful investigation on the mode of seizure onset is crucial for diagnosing Dravet syndrome.
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Epilepsy Res 2006;70 Suppl 1:S231-8.
국 문 초 록
SCN1A 유전자 검사의 이용 증가와 더불어 Dravet 증후군의 주
요한 특징이 부족한 환자들이 지속적으로 발견되고 있다. 따라서 Dravet 증후군의 임상적 범위는 확장되고 있다. 본 연구에서는 SCN1A 돌연변이가 확인된 Dravet 증후군 환자의 임상적 특징과 뇌파를 분석하여 Dravet 증후군환자의 진단에 고려하여 할 측면을 알아보고자 한다.
SCN1A 돌연변이가 확인된 55명의 환자를 Dravet 증후군의 주요한 특징에 초점을 두고 임상 양상을 분석하였다. SCN1A 돌연변이 분 석에는 Sanger sequencing과 multiple ligation dependent probe amplification을 사용하였다.
총 55명의 환자 중 남자는 29명이었다. 첫 발작 발생 시 환자들의 평균 나이는 5.8개월 이었다. 53%의 환자들이 첫 발작 시 발열을 보였으며 29% 환자들은 15분 이상의 발작 시간을 보였다. 85%의 환자들이 첫 발작의 형태로 전신경직간대 발작 혹은 단측 간대 발 작을 보였다. 모든 환자들은 첫 발작 발생 전에 정상적인 발달을 보 였다. 83%의 환자들은 발작간기 뇌파에서 정상 소견을 보였다. 2세 이후의 안정 단계에서 78%의 환자들은 국소 발작을 보였고 59%의 환자들은 단측 간대 발작을 보였으며, 40%의 환자들은 간대성 근 경련 발작을 그리고 28% 환자들은 비전형적 소 발작을 보였다. 발 작간기 뇌파에서 39% 환자들은 전신 간질 모양파를 보였으며 65%
환자들은 국소 간질 모양파를 보였다. 모든 환자들은 항경련제에 대 해서 약물 저항성을 보였으며 2세 이후에는 뚜렷한 발달 지연 및
22 퇴행을 보였다.
본 연구에서는 첫 발작 시 환자들의 연령, 발작간기 뇌파 소견 그 리고 발작의 형태는 환자 간에 큰 차이를 보이지 않는다. 반면 2세 이후 안정기의 환자 간에 경련의 형태 및 뇌파 소견은 큰 편차를 보인다. 따라서 초기 임상 양상에 대한 관찰이 Dravet 증후군의 진 단에 중요하다.
주요어: 드라벳 증후군,SCN1A 돌연변이, 진단 학번: 2015-20024
