Brain & Development xxx (2013) xxx–xxx www.elsevier.com/locate/braindev
Original article
Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations Xiaojing Xu a, Yuehua Zhang a,⇑, Huihui Sun b, Xiaoyan Liu a, Xiaoling Yang a, Hui Xiong a, Yuwu Jiang a, Xinhua Bao a, Shuang Wang a, Zhixian Yang a, Ye Wu a, Jiong Qin a, Qing Lin a, Xiru Wu a a
Department of Pediatrics, Peking University First Hospital, China b Department of Pediatrics, Beijing Ji Shui Tan Hospital, China
Received 5 May 2013; received in revised form 23 August 2013; accepted 9 October 2013
Abstract Objective: To summarize the early clinical features of Dravet syndrome (DS) patients with SCN1A gene mutations before the age of one. Methods: SCN1A gene mutation screening was performed by PCR–DNA sequencing and multiple ligation-dependent probe amplication (MLPA). The early clinical features of DS patients with SCN1A mutations were reviewed with attention to the seizures induced by fever and other precipitating factors before the first year of life. Results: The clinical data of 138 DS patients with SCN1A gene mutations were reviewed. The median seizure onset age was 5.3 months. Ninety-nine patients (71.7%) experienced seizures with duration more than 15 min in the first year of life. Two or more seizures induced by fever within 24 h or the same febrile illness were observed in 93 patients (67.4%). 111 patients (80.4%) had hemi-clonic and (or) focal seizures. Seizures had been triggered by fever of low degree (T < 38 °C) in 62.3% (86/138) before the first year of life. Vaccine-related seizures were observed in 34.8% (48/ 138). Seizures in 22.5% (31/138) of patients were triggered by hot bath. Carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin showed either no effect or exacerbating the seizures in our group. Conclusion: The seizure onset age in DS patients was earlier than that was in common febrile seizures. When a baby exhibits two or more features of complex febrile seizures in the first year of life, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Dravet syndrome; SCN1A gene; Mutation; Febrile seizures; Diagnosis
1. Introduction Dravet syndrome (DS) is a severe epileptic encephalopathy, previously known as severe myoclonic epilepsy of infancy (SMEI) [1]. DS is characterized by convulsions appearing in the first year of life, often prolonged, ⇑ Corresponding author. Address: Department of Pediatrics, Peking University First Hospital, No. 1, Xi’an Men Street, Xicheng District, Beijing 100034, China. Tel.: +86 010 83573238, fax: +86 010 66134261. E-mail addresses: [email protected], [email protected] (Y. Zhang).
generalized, or unilateral clonic seizures triggered by fever. Subsequently, other seizure types usually present including myoclonic seizures, atypical absences, and partial seizures with psychomotor slowing. Treatment options for patients are rather limited. Mutations of SCN1A gene coding for the a1 subunit of the sodium channel were associated with approximately 75% of DS patients [2,3]. The presence of an SCN1A mutation provides strong evidence in diagnosis of DS. Commercial testing for SCN1A gene mutations is now available in some countries.
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.10.004
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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Early recognition of DS is crucial for appropriate management and focused treatment. Given that seizures during the first year in DS are often associated with fever, distinguishing from common febrile seizures (FS) is critical in selecting antiepileptic drugs (AEDs). Some AEDs, such as carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin, have no positive effect and even exacerbate the seizures in DS patients [4–6]. The aim of our study was to identify the clinical features of DS patients with SCN1A mutations before the first year of life that can prompt an early diagnosis and targeted treatment. 2. Participants and methods 2.1. Participants DS patients were recruited from outpatient and neural units of Peking University First Hospital from June 2005 to December 2011. The study protocol and informed consent were approved by the Ethics Committee of Peking University First Hospital. Participants or parents provided written informed consent before enrollment. All patients fulfilled the following diagnostic criteria [7,8]: (1) Seizure onset within one year of age (around 6 months), first event is often seizures induced by fever; (2) Normal early development; (3) Prolonged generalized or hemi-clonic seizures, often triggered by fever; (4) Multiple seizure types (myoclonic, focal, atypical absences) after the second year of life; (5) Frequent persistence of sensitivity to fever; (6) Psychomotor slowing after the second year of life, ataxia and pyramidal signs evolve; (7) Interictal electroencephalography were normal in the first year of life, followed by generalized, focal or multifocal discharges; (8) Seizures are rather pharmacoresistance. 2.2. Detection of SCN1A mutations Genomic DNA was extracted from peripheral blood lymphocytes of the patients and their available parents by a simple salting-out procedure [9]. The 26 exons of SCN1A gene were amplified by PCR using primers as previously described [10]. Samples with mutations were sequenced in both directions from two independent PCR products. The novel SCN1A missense substitutions were not found in a cohort of 100 controls. If no mutation was identified in the DS patient by PCR-sequencing, multiple ligation-dependent probe amplication (MLPA) kit P137 (MRC-Holland, Amsterdam, the Netherlands) was used to screen for large deletions or duplications. The MLPA reactions were carried out following the instructions provided by the manufacturer. Finally, the PCR products were separated by capillary electrophoresis using an ABI 3100 automated sequencer
and size standards (Perkin-Elmer Applied Biosystems, Foster City, CA, USA). We used Genescan analysis software (version 3.7) and Genotype software (version 3.6) to analyze these data, which we then exported to a Microsoft Excel spreadsheet. The resulting values were approximately 1 for every wild-type peak, 1.3 for heterozygous duplications [8]. 2.3. Early clinical features evaluation Of 180 DS patients, 138 with SCN1A gene mutations were enrolled in our study group, and the remaining 42 patients were excluded. All 138 DS patients were longitudinally followed up after initial clinical examinations ranging from 6 months to 6 years and 5 months. The last follow-up ages were from 18 months to 17 years and 5 months, and the median age was 55 months. Detailed histories of epilepsy before the age of one were reviewed focusing on measurements including the age of seizure onset, the longest duration of fever induced seizures, number of seizures induced by fever within 24 h or the same febrile illness, partial seizures and the precipitating factors. 3. Results The series consists of 138 patients (78 males and 60 females), including two siblings. A positive family history of convulsive disorders in first or second degree relatives, including FS or epilepsy, was reported in 34.8% (48/138) of DS patients. 3.1. SCN1A mutations Among 138 (76.7%, 138/180) patients with SCN1A mutations, 125 mutation types were discovered. Missense mutations accounted for 42.4% (53/125). Truncation mutations were also common, including nonsense mutations (22.4%, 28/125), small deletions (17.6%, 22/ 125) and insertions (8.8%, 11/125). The remaining comprised splice site mutations (7.2%. 9/125) and duplications (1.6%, 2/125). The distribution of 125 types of SCN1A mutations in 138 DS patients was shown in Fig. 1. Two siblings shared the same mutations at D1755G and R1886X locations. Two sporadic patients separately shared the same mutation F90S, R101W, W738L, R1245X, R1213X, and R222X. Three sporadic patients shared the same mutation at R393H, and four shared mutation at A1783T. 3.2. Seizures induced by fever before one year of age In our group, the onset age of seizure ranged from 2 to 11 months (median: 5.3). Seizures began before 7 months of age in 76.8% (106/138) of patients.
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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occurred in a setting of vaccination, 26 of which were induced by DPT vaccine. The remaining 4 were induced by measles vaccine and 2 by hepatitis B vaccine. Seizures in 31 patients were triggered by hot bath. These stimuli are summarized in Table 2. Forty-five patients had a history of afebrile seizures, and 13 of those had afebrile seizure at the first attack. 3.4. Seizures aggravated by antiepileptic drugs
Fig. 1. The distribution of 125 types of SCN1A mutations in 138 DS patients.
Ninety-nine patients (71.7%) experienced seizures longer than 15 min (median: 30 min). Status epilepticus (SE) occurred in 46.4% (64/138) of cases, and the longest one lasted 3 h. In 67.4% (93/138) of cases, FS occurred more than once (median: 3) within 24 h or the same febrile illness. Even 21.0% (29/138) of patients had experienced three or more attacks, one of which experienced 35 attacks within the same febrile illness. Eighty-nine (64.5%) patients experienced hemi-clonic seizures and 50.7% (70/138) of patients had focal seizures. Hemi-clonic and (or) focal seizures occurred in 80.4% (111/138). The incidence rate of hemi-clonic and focal seizures in the same patient was 34.0% (47/138). Among the three clinical manifestations (FS P 15 min, P2 times FS within 24 h or the same febrile illness, hemi-clonic or focal seizures) of complex febrile seizures (CFS) in DS patients, one item was discovered in 20 cases (14.5%), two items in 58 (42.0%) and three items in 56 (40.6%). The clinical features of 138 patients are summarized in Table 1. 3.3. Seizure precipitating factors before one year of age Eighty-six patients had seizures induced by low-grade fever (T < 38 °C). Forty-eight (34.8%) patients experienced seizures within 72 h of administration of vaccines, 68.8% (33/48) of which were victims with induced seizures after diptheria, pertussis and tetanus (DPT). The seizure onset of DS in 23.2% (32/138) of patients Table 1 The clinical features of FS in the first year of life in 138 DS patients. Characteristics
DS patients (n = 138)
Onset 15 min); (3) a focal onset or showing focal features during the seizure [14,15]. In the two previous FS studies [16,17], more than one seizure per episode of fever were found in 14% and 19%, seizures prolonged >15 min in 8% and 13% and focal seizures in 4% and 20% of the FS patients. The seizure onset age of DS was always before the first year of life. Our data indicate that one of the most striking features is the early onset of seizures in DS patients. In our study the first seizure occurred within the 7 months of age in 76.8% of infants. Risk factors for the development of epilepsy in FS patients include: (1) onset of FS before one year of age; (2) CFS; (3) positive family history of epilepsy; (4) antecedent neurologic
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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Table 2 Seizure precipitating factors before one year of age in 138 DS patients. Factors
DS patients (n = 138)
Low-grade fever Vaccine DPT vaccine Measles vaccine Epidemic meningitis vaccine Influenza vaccine Hepatitis B vaccine Hot bath
86 (62.3%) 48 (34.8%) 33 8 4 1 2 31 (22.5%)
or developmental abnormality [18–20]. In one study, children with one CFS feature had a risk of epilepsy from 6% to 8%; with two or three CFS features, the risk was 17% to 22% and 49% respectively [11]. Seizures induced by fever tend to be prolonged in DS patients. Of our 138 patients, 46.4% of patients experienced SE before one year of age. It is reported that the incidence of SE in DS patients is estimated from 40.7% to 80% before one year old [21–23]. Children with DS often have recurrent FS before one year old. Our data suggested that 67.4% of patients had two or more seizures within 24 h or the same febrile illness. Hemi-clonic seizures and focal seizures were very common seizure types in children with DS, and this characteristic was apparent before the first year of life, noted by 80.4% of children experienced hemi-clonic and (or) focal seizures in our study. Ragona et al. [23] reported that the incidence of hemi-clonic was 37.8% (14/37) and focal seizure was 40.5% (15/37) in their DS patients before the first year of life. Hattori et al. [22] reported that 72% (33/46) of children with DS had hemi-clonic and 37% (17/46) of them had focal seizures. In our study, two CFS features were found in 42.0% and three CFS features in 40.6% of patients before one year old. These suggested the more CFS features appeared the higher possibility of DS. Our studies, therefore, provide a clue for clinicians to diagnose DS in children with seizures in the first year of life. When two or more features of CFS are found in a baby, it is necessary to perform a genetic test of SCN1A to confirm the diagnosis of DS. In the first year of life, psychomotor development is usually normal in DS patients. Their fever induced seizures are easily diagnosed as CFS. Between age 1 and 4 years, various seizures appear in patients, such as generalized tonic-clonic, alternating unilateral clonic, myoclonic, absence and partial seizures. These often lead to developmental problems and seriously affect the life quality of their families. Therefore it is necessary to treat DS patients as early as possible. Although clinical characteristics are not apparent in the first year of life, the seizure onset age and other features of CFS are important clues in early diagnosis. Importantly, SCN1A mutation screening provides strong evidence. Hattori et al. [22] proposed a diagnostic screening test using risk
factors and a scoring system. In our study, we expanded the sample number, and all the participants harbored SCN1A gene mutations. We investigated the most common features of CFS in DS to help early diagnosis before SCN1A screening. In our 138 DS patients, 17 children were diagnosed as DS before the age of one, of whom 16 had a seizure onset age younger than 7 months. Two features of CFS were found in 7 cases and three in 10 cases. All these 17 patients were confirmed with SCN1A mutations before the first year of life. In fact, early diagnosis of DS will help clinicians avoid using drugs that exacerbate episodes of DS. In DS patients, seizure induction is sensitive to temperature variations. This study provides more evidence to support this feature. Seizures in 62.3% of patients were triggered by low-grade fever. Fountain-Capal et al. [21] reported that 94% of children with SCN1A mutation would be aggravated by hyperthermia. Hot bath is also an important factor responsible for triggering seizures. In our series, 22.5% of children experienced seizures resulting from hot bath. Hattori et al. [22] reported that seizures induced by hot bath were observed in 59% (27/46) of patients with DS in Japan. . In recent years, many observations and data have discussed a relationship of vaccines with seizures. Several studies described up to 50% of patients with DS having their first seizure in a setting of vaccination [24,25]. Vaccine-related onset was defined as seizures beginning within 72 h of vaccination. Berkovic et al. [26] reported 12 DS patients having seizure onset following vaccinations within 72 h, 91.7% (11/12) of which were associated with SCN1A mutations. The majority of seizures occurred after DPT vaccinations. McIntosh et al. [27] reported 30% (12/40) of DS patients with SCN1A mutations were identified having seizure onset within 48 hours after vaccination. Our retrospective study found that 34.8% of patients had seizures within 72 h after vaccinations. The first seizures in 23.2% of patients occurred in a setting of vaccination. Several large studies have established an increased risk of FS following DPT, showing 6–9 cases of induced FS per 100,000 vaccine doses [28,29]. In this study, 34.8% of patients had a history of seizure after vaccination, 68.8% (33/48) of which were victims with induced seizures after DPT vaccine. DPT vaccination was a high risk factor increasing seizures. The remaining patients had seizures after measles, epidemic meningitis, influenza and hepatitis B vaccines. It is possible that these vaccines cause fever resulting in seizures [30]. We found that the DS patients experiencing seizures induced by vaccination often have different degree of fever. Most of them had low-degree fever (T < 38 °C), but many parents can not recall a specific temperature. This supports the argument that children carrying a SCN1A mutation are destined to develop seizures, which in turn can be precipitated by low-grade fever from vaccination or a hot bath. The vaccination
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is only the trigger in the inevitable onset of DS, and it would have happened anyway. The gating kinetics of Na+ channels in DS-associated SCN1A missense and nonsense mutations were analyzed by Sugawara et al. [31]. These mutant channels exhibited a drastic attenuation of the peak Na+ current, and even lead to loss of function. Therefore, drugs that reduce sodium currents are inappropriate in DS. The focal features in DS may tempt the clinician to prescribe carbamazepine, oxcarbazepine, lamotrigine, or phenytoin, which are sodium channel blockers [32]. In our patients, some of them had a history of receiving above drugs in the local hospitals, and their seizures were aggravated. When these drugs are used early in the course of the disease, the diagnosis of DS should be considered if an aggravation in seizure activity is noted. Valproic acid, levetiracetam, topiramate, clonbazam and stiripentol may be beneficial for some patients. Ketogenic diet is also a choice for patients with no response to medication [33]. In summary, the seizure onset age in DS patients was earlier than that in common FS. When a baby exhibits two or more features of CFS, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis.
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Original article
Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations Xiaojing Xu a, Yuehua Zhang a,⇑, Huihui Sun b, Xiaoyan Liu a, Xiaoling Yang a, Hui Xiong a, Yuwu Jiang a, Xinhua Bao a, Shuang Wang a, Zhixian Yang a, Ye Wu a, Jiong Qin a, Qing Lin a, Xiru Wu a a
Department of Pediatrics, Peking University First Hospital, China b Department of Pediatrics, Beijing Ji Shui Tan Hospital, China
Received 5 May 2013; received in revised form 23 August 2013; accepted 9 October 2013
Abstract Objective: To summarize the early clinical features of Dravet syndrome (DS) patients with SCN1A gene mutations before the age of one. Methods: SCN1A gene mutation screening was performed by PCR–DNA sequencing and multiple ligation-dependent probe amplication (MLPA). The early clinical features of DS patients with SCN1A mutations were reviewed with attention to the seizures induced by fever and other precipitating factors before the first year of life. Results: The clinical data of 138 DS patients with SCN1A gene mutations were reviewed. The median seizure onset age was 5.3 months. Ninety-nine patients (71.7%) experienced seizures with duration more than 15 min in the first year of life. Two or more seizures induced by fever within 24 h or the same febrile illness were observed in 93 patients (67.4%). 111 patients (80.4%) had hemi-clonic and (or) focal seizures. Seizures had been triggered by fever of low degree (T < 38 °C) in 62.3% (86/138) before the first year of life. Vaccine-related seizures were observed in 34.8% (48/ 138). Seizures in 22.5% (31/138) of patients were triggered by hot bath. Carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin showed either no effect or exacerbating the seizures in our group. Conclusion: The seizure onset age in DS patients was earlier than that was in common febrile seizures. When a baby exhibits two or more features of complex febrile seizures in the first year of life, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Dravet syndrome; SCN1A gene; Mutation; Febrile seizures; Diagnosis
1. Introduction Dravet syndrome (DS) is a severe epileptic encephalopathy, previously known as severe myoclonic epilepsy of infancy (SMEI) [1]. DS is characterized by convulsions appearing in the first year of life, often prolonged, ⇑ Corresponding author. Address: Department of Pediatrics, Peking University First Hospital, No. 1, Xi’an Men Street, Xicheng District, Beijing 100034, China. Tel.: +86 010 83573238, fax: +86 010 66134261. E-mail addresses: [email protected], [email protected] (Y. Zhang).
generalized, or unilateral clonic seizures triggered by fever. Subsequently, other seizure types usually present including myoclonic seizures, atypical absences, and partial seizures with psychomotor slowing. Treatment options for patients are rather limited. Mutations of SCN1A gene coding for the a1 subunit of the sodium channel were associated with approximately 75% of DS patients [2,3]. The presence of an SCN1A mutation provides strong evidence in diagnosis of DS. Commercial testing for SCN1A gene mutations is now available in some countries.
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.10.004
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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Early recognition of DS is crucial for appropriate management and focused treatment. Given that seizures during the first year in DS are often associated with fever, distinguishing from common febrile seizures (FS) is critical in selecting antiepileptic drugs (AEDs). Some AEDs, such as carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin, have no positive effect and even exacerbate the seizures in DS patients [4–6]. The aim of our study was to identify the clinical features of DS patients with SCN1A mutations before the first year of life that can prompt an early diagnosis and targeted treatment. 2. Participants and methods 2.1. Participants DS patients were recruited from outpatient and neural units of Peking University First Hospital from June 2005 to December 2011. The study protocol and informed consent were approved by the Ethics Committee of Peking University First Hospital. Participants or parents provided written informed consent before enrollment. All patients fulfilled the following diagnostic criteria [7,8]: (1) Seizure onset within one year of age (around 6 months), first event is often seizures induced by fever; (2) Normal early development; (3) Prolonged generalized or hemi-clonic seizures, often triggered by fever; (4) Multiple seizure types (myoclonic, focal, atypical absences) after the second year of life; (5) Frequent persistence of sensitivity to fever; (6) Psychomotor slowing after the second year of life, ataxia and pyramidal signs evolve; (7) Interictal electroencephalography were normal in the first year of life, followed by generalized, focal or multifocal discharges; (8) Seizures are rather pharmacoresistance. 2.2. Detection of SCN1A mutations Genomic DNA was extracted from peripheral blood lymphocytes of the patients and their available parents by a simple salting-out procedure [9]. The 26 exons of SCN1A gene were amplified by PCR using primers as previously described [10]. Samples with mutations were sequenced in both directions from two independent PCR products. The novel SCN1A missense substitutions were not found in a cohort of 100 controls. If no mutation was identified in the DS patient by PCR-sequencing, multiple ligation-dependent probe amplication (MLPA) kit P137 (MRC-Holland, Amsterdam, the Netherlands) was used to screen for large deletions or duplications. The MLPA reactions were carried out following the instructions provided by the manufacturer. Finally, the PCR products were separated by capillary electrophoresis using an ABI 3100 automated sequencer
and size standards (Perkin-Elmer Applied Biosystems, Foster City, CA, USA). We used Genescan analysis software (version 3.7) and Genotype software (version 3.6) to analyze these data, which we then exported to a Microsoft Excel spreadsheet. The resulting values were approximately 1 for every wild-type peak, 1.3 for heterozygous duplications [8]. 2.3. Early clinical features evaluation Of 180 DS patients, 138 with SCN1A gene mutations were enrolled in our study group, and the remaining 42 patients were excluded. All 138 DS patients were longitudinally followed up after initial clinical examinations ranging from 6 months to 6 years and 5 months. The last follow-up ages were from 18 months to 17 years and 5 months, and the median age was 55 months. Detailed histories of epilepsy before the age of one were reviewed focusing on measurements including the age of seizure onset, the longest duration of fever induced seizures, number of seizures induced by fever within 24 h or the same febrile illness, partial seizures and the precipitating factors. 3. Results The series consists of 138 patients (78 males and 60 females), including two siblings. A positive family history of convulsive disorders in first or second degree relatives, including FS or epilepsy, was reported in 34.8% (48/138) of DS patients. 3.1. SCN1A mutations Among 138 (76.7%, 138/180) patients with SCN1A mutations, 125 mutation types were discovered. Missense mutations accounted for 42.4% (53/125). Truncation mutations were also common, including nonsense mutations (22.4%, 28/125), small deletions (17.6%, 22/ 125) and insertions (8.8%, 11/125). The remaining comprised splice site mutations (7.2%. 9/125) and duplications (1.6%, 2/125). The distribution of 125 types of SCN1A mutations in 138 DS patients was shown in Fig. 1. Two siblings shared the same mutations at D1755G and R1886X locations. Two sporadic patients separately shared the same mutation F90S, R101W, W738L, R1245X, R1213X, and R222X. Three sporadic patients shared the same mutation at R393H, and four shared mutation at A1783T. 3.2. Seizures induced by fever before one year of age In our group, the onset age of seizure ranged from 2 to 11 months (median: 5.3). Seizures began before 7 months of age in 76.8% (106/138) of patients.
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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occurred in a setting of vaccination, 26 of which were induced by DPT vaccine. The remaining 4 were induced by measles vaccine and 2 by hepatitis B vaccine. Seizures in 31 patients were triggered by hot bath. These stimuli are summarized in Table 2. Forty-five patients had a history of afebrile seizures, and 13 of those had afebrile seizure at the first attack. 3.4. Seizures aggravated by antiepileptic drugs
Fig. 1. The distribution of 125 types of SCN1A mutations in 138 DS patients.
Ninety-nine patients (71.7%) experienced seizures longer than 15 min (median: 30 min). Status epilepticus (SE) occurred in 46.4% (64/138) of cases, and the longest one lasted 3 h. In 67.4% (93/138) of cases, FS occurred more than once (median: 3) within 24 h or the same febrile illness. Even 21.0% (29/138) of patients had experienced three or more attacks, one of which experienced 35 attacks within the same febrile illness. Eighty-nine (64.5%) patients experienced hemi-clonic seizures and 50.7% (70/138) of patients had focal seizures. Hemi-clonic and (or) focal seizures occurred in 80.4% (111/138). The incidence rate of hemi-clonic and focal seizures in the same patient was 34.0% (47/138). Among the three clinical manifestations (FS P 15 min, P2 times FS within 24 h or the same febrile illness, hemi-clonic or focal seizures) of complex febrile seizures (CFS) in DS patients, one item was discovered in 20 cases (14.5%), two items in 58 (42.0%) and three items in 56 (40.6%). The clinical features of 138 patients are summarized in Table 1. 3.3. Seizure precipitating factors before one year of age Eighty-six patients had seizures induced by low-grade fever (T < 38 °C). Forty-eight (34.8%) patients experienced seizures within 72 h of administration of vaccines, 68.8% (33/48) of which were victims with induced seizures after diptheria, pertussis and tetanus (DPT). The seizure onset of DS in 23.2% (32/138) of patients Table 1 The clinical features of FS in the first year of life in 138 DS patients. Characteristics
DS patients (n = 138)
Onset 15 min); (3) a focal onset or showing focal features during the seizure [14,15]. In the two previous FS studies [16,17], more than one seizure per episode of fever were found in 14% and 19%, seizures prolonged >15 min in 8% and 13% and focal seizures in 4% and 20% of the FS patients. The seizure onset age of DS was always before the first year of life. Our data indicate that one of the most striking features is the early onset of seizures in DS patients. In our study the first seizure occurred within the 7 months of age in 76.8% of infants. Risk factors for the development of epilepsy in FS patients include: (1) onset of FS before one year of age; (2) CFS; (3) positive family history of epilepsy; (4) antecedent neurologic
Please cite this article in press as: Xu X et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.004
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Table 2 Seizure precipitating factors before one year of age in 138 DS patients. Factors
DS patients (n = 138)
Low-grade fever Vaccine DPT vaccine Measles vaccine Epidemic meningitis vaccine Influenza vaccine Hepatitis B vaccine Hot bath
86 (62.3%) 48 (34.8%) 33 8 4 1 2 31 (22.5%)
or developmental abnormality [18–20]. In one study, children with one CFS feature had a risk of epilepsy from 6% to 8%; with two or three CFS features, the risk was 17% to 22% and 49% respectively [11]. Seizures induced by fever tend to be prolonged in DS patients. Of our 138 patients, 46.4% of patients experienced SE before one year of age. It is reported that the incidence of SE in DS patients is estimated from 40.7% to 80% before one year old [21–23]. Children with DS often have recurrent FS before one year old. Our data suggested that 67.4% of patients had two or more seizures within 24 h or the same febrile illness. Hemi-clonic seizures and focal seizures were very common seizure types in children with DS, and this characteristic was apparent before the first year of life, noted by 80.4% of children experienced hemi-clonic and (or) focal seizures in our study. Ragona et al. [23] reported that the incidence of hemi-clonic was 37.8% (14/37) and focal seizure was 40.5% (15/37) in their DS patients before the first year of life. Hattori et al. [22] reported that 72% (33/46) of children with DS had hemi-clonic and 37% (17/46) of them had focal seizures. In our study, two CFS features were found in 42.0% and three CFS features in 40.6% of patients before one year old. These suggested the more CFS features appeared the higher possibility of DS. Our studies, therefore, provide a clue for clinicians to diagnose DS in children with seizures in the first year of life. When two or more features of CFS are found in a baby, it is necessary to perform a genetic test of SCN1A to confirm the diagnosis of DS. In the first year of life, psychomotor development is usually normal in DS patients. Their fever induced seizures are easily diagnosed as CFS. Between age 1 and 4 years, various seizures appear in patients, such as generalized tonic-clonic, alternating unilateral clonic, myoclonic, absence and partial seizures. These often lead to developmental problems and seriously affect the life quality of their families. Therefore it is necessary to treat DS patients as early as possible. Although clinical characteristics are not apparent in the first year of life, the seizure onset age and other features of CFS are important clues in early diagnosis. Importantly, SCN1A mutation screening provides strong evidence. Hattori et al. [22] proposed a diagnostic screening test using risk
factors and a scoring system. In our study, we expanded the sample number, and all the participants harbored SCN1A gene mutations. We investigated the most common features of CFS in DS to help early diagnosis before SCN1A screening. In our 138 DS patients, 17 children were diagnosed as DS before the age of one, of whom 16 had a seizure onset age younger than 7 months. Two features of CFS were found in 7 cases and three in 10 cases. All these 17 patients were confirmed with SCN1A mutations before the first year of life. In fact, early diagnosis of DS will help clinicians avoid using drugs that exacerbate episodes of DS. In DS patients, seizure induction is sensitive to temperature variations. This study provides more evidence to support this feature. Seizures in 62.3% of patients were triggered by low-grade fever. Fountain-Capal et al. [21] reported that 94% of children with SCN1A mutation would be aggravated by hyperthermia. Hot bath is also an important factor responsible for triggering seizures. In our series, 22.5% of children experienced seizures resulting from hot bath. Hattori et al. [22] reported that seizures induced by hot bath were observed in 59% (27/46) of patients with DS in Japan. . In recent years, many observations and data have discussed a relationship of vaccines with seizures. Several studies described up to 50% of patients with DS having their first seizure in a setting of vaccination [24,25]. Vaccine-related onset was defined as seizures beginning within 72 h of vaccination. Berkovic et al. [26] reported 12 DS patients having seizure onset following vaccinations within 72 h, 91.7% (11/12) of which were associated with SCN1A mutations. The majority of seizures occurred after DPT vaccinations. McIntosh et al. [27] reported 30% (12/40) of DS patients with SCN1A mutations were identified having seizure onset within 48 hours after vaccination. Our retrospective study found that 34.8% of patients had seizures within 72 h after vaccinations. The first seizures in 23.2% of patients occurred in a setting of vaccination. Several large studies have established an increased risk of FS following DPT, showing 6–9 cases of induced FS per 100,000 vaccine doses [28,29]. In this study, 34.8% of patients had a history of seizure after vaccination, 68.8% (33/48) of which were victims with induced seizures after DPT vaccine. DPT vaccination was a high risk factor increasing seizures. The remaining patients had seizures after measles, epidemic meningitis, influenza and hepatitis B vaccines. It is possible that these vaccines cause fever resulting in seizures [30]. We found that the DS patients experiencing seizures induced by vaccination often have different degree of fever. Most of them had low-degree fever (T < 38 °C), but many parents can not recall a specific temperature. This supports the argument that children carrying a SCN1A mutation are destined to develop seizures, which in turn can be precipitated by low-grade fever from vaccination or a hot bath. The vaccination
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is only the trigger in the inevitable onset of DS, and it would have happened anyway. The gating kinetics of Na+ channels in DS-associated SCN1A missense and nonsense mutations were analyzed by Sugawara et al. [31]. These mutant channels exhibited a drastic attenuation of the peak Na+ current, and even lead to loss of function. Therefore, drugs that reduce sodium currents are inappropriate in DS. The focal features in DS may tempt the clinician to prescribe carbamazepine, oxcarbazepine, lamotrigine, or phenytoin, which are sodium channel blockers [32]. In our patients, some of them had a history of receiving above drugs in the local hospitals, and their seizures were aggravated. When these drugs are used early in the course of the disease, the diagnosis of DS should be considered if an aggravation in seizure activity is noted. Valproic acid, levetiracetam, topiramate, clonbazam and stiripentol may be beneficial for some patients. Ketogenic diet is also a choice for patients with no response to medication [33]. In summary, the seizure onset age in DS patients was earlier than that in common FS. When a baby exhibits two or more features of CFS, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis.
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