- Email: [email protected]
Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation
Accepted Manuscript Title: Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation Author: Xiaoping Du You Chen Yongxiong Zhao Wei Luo Zhidong Cen Weicheng Hao PII: DOI: Reference:
S1059-1311(16)30377-6 http://dx.doi.org/doi:10.1016/j.seizure.2016.12.020 YSEIZ 2882
To appear in:
Seizure
Received date: Revised date: Accepted date:
27-9-2016 26-12-2016 27-12-2016
Please cite this article as: Du Xiaoping, Chen You, Zhao Yongxiong, Luo Wei, Cen Zhidong, Hao Weicheng.Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.12.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title Page Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation Xiaoping Dua, You Chenb, Yongxiong Zhaoa, Wei Luob, Zhidong Cenc,1, Weicheng Haoa,1 a
Department of Neurology, West District of Second Affiliated Hospital, Shanxi Medical
University, Taiyuan, Shanxi, China b
Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang
University, Hangzhou, Zhejiang, China c
Department of Pediatrics, Second Affiliated Hospital, School of Medicine, Zhejiang
University, Hangzhou, Zhejiang, China 1
These authors contributed equally to the study and both should be considered as
corresponding authors. Correspondence to: Weicheng Hao, MD, Department of Neurology, West District of Second Affiliated Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030000, China. Tel: +86 13403696803 Email: [email protected] AND Zhidong Cen, MD, Department of Pediatrics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310000, China. Tel: +86 13735805744 Fax: +86 571 87784538 E-Mail: [email protected]
Key words: Absence epilepsy with ataxia, CACNA1A, pyridoxine, dramatic response
Mutations in ion channel genes can cause a diverse group of phenotypes and play important roles in the filed of monogenic neurological diseases.1 With the application of Next-generation sequencing, more and more genetic and clinical heterogeneity in monogenic neurological diseases were reported, which improved our understanding of the pathophysiologic mechanisms in different monogenic neurological diseases. Herein, we report a girl presenting with intractable absence epilepsy, which had a dramatic response to pyridoxine. Using a panel containing 153 epilepsy-related genes based on Next-generation sequencing, a de novo CACNA1A mutation was found coincidentally. Our report expands the clinical spectrum of CACNA1A-related disorders and the genetic spectrum of pyridoxine dependent epilepsy (PDE).
Case Report The patient was born at term after an unremarkable pregnancy and had nearly normal early psychomotor development, although the parents reported that the patient could not run fast like other normal children or speak smoothly. At the age of 3 years, she presented blank episode lasting for 2-3 seconds several times per day. The postural tone was not lost and she was able to resume normal activities immediately. Absence epilepsy was considered after attending to a local hospital and valproic acid (VPA) was used (200mg per day). However, no improvement was observed and the absence seizure still occured 2-3 times per day. At the age of 5 years, the patient came to our hospital. VPA (500mg per day) and lamotrigine (LTG) (150mg per day) were used and the frequency of absence seizure decreased. It only happened when the patient’s temperature was above 38℃. At the age of 6 years, the frequency of absence seizure increased without obvious inducement. It occured 20-30 times per day, accompanying with partial seizures for 3 times in one year, which all presented as right upper limb hold up, eyes looked toward right side and unconsciousness for about 1 minute. No episodic attack of ataxia was complained. An ataxic gait was observed, which was considered as antiepileptic drugs (AEDs) induced ataxia at first. On EEG examination, a typical 2.5-3 Hz spike-wave was observed. (Fig. 1A) The diagnosis of absence epilepsy was made based on clinical features and EEG result. Brain MRI at the age of 3 years revealed hippocampal sclerosis on the left side and no obvious cerebellar atrophy. At the age of 10 years, cerebellar atrophy was observed on the sagittal view in the brain MRI (Supplemental data 1). Metabolic tests of blood and urine were all normal, which included normal level of proline in blood. Other blood tests including alkaline phosphatase and Ca2+ were all within normal range. As
pyridoxine was proposed in some intractable epilepsy, 500mg pyridoxine (Vitamin B6, 20mg/kg) daily was added to current treatment of 750mg (30mg/kg) VPA and 150mg (6mg/kg) LTG daily. A dramatic improvement was observed that the frequency of absence seizure was less than 10 times on the first day and no absence seizure was observed on the next five days. The pyridoxine withdraw test was positive as the frequency of absence seizure increased (about 30-40 times per day) when we reduced the dose of pyridoxine. After the use of pyridoxine, the background of EEG was also better than that before the use of pyridoxine. (Fig. 1B and 1C) The patient was discharged with oral drugs containing 750mg (30mg/kg) pyridoxine, 500mg (20mg/kg) VPA and 50mg (2mg/kg) LTG daily. In the next year, with oral drugs containing 200mg (7.4mg/kg) pyridoxine, 500mg (18mg/kg) VPA and 50mg (1.9mg/kg) LTG daily, she only had absence seizure for 2-3 times per day and one generalized tonic-clonic seizure in this year. The ataxia did not improve or progress and no episodic progress of ataxia was complained. Using a panel containing 153 epilepsy-related genes (Supplemental data 3) based on Next-generation sequencing, a heterozygous missense variant c. 410A>G (p. E137G) in CACNA1A gene was detected in this patient. This variant was further confirmed by Sanger sequencing and not detected in either of the healthy parents, which indicated that this variant was de novo (Supplemental data 2). According to the standards and guidelines of ACMG and MacArthur et al, this variant was evaluated as pathogenic mutation (Supplemental data 4). No pathogenic variant in genes (ALDH7A1, PNPO and PIGV were contained in the panel) responsible for PDE was detected in this patient. Although other two genes (TNSALP and ALDH4A1) responsible for PDE were not sequenced, the normal level of proline and alkaline phosphatase did not support this patient had their responsible phenotypes of hypophosphatasia and hyperprolinemia type 2.2 Based on these clinical and genetic studies, we concluded that the mutation c. 410A>G (p. E137G) in CACNA1A gene was the causative mutation in this patient. Discussion Mutations in CACNA1A have complicated phenotypic heterogeneity, and mainly cause three allelic disorders: episodic ataxia type 2 (OMIM: 108500), familial hemiplegic migraine type 1 (OMIM: 141500) and spinocerebellar ataxia type 6 (OMIM: 183086).1 Epilepsy was reported in about 7% patients of episodic ataxia type 2.3 Absence epilepsy with a 3 Hz spike-wave EEG pattern was reported as the core symptom in several patients with mutations
in CACNA1A. The clinical phenotype of absence epilepsy with ataxia (AEA) was proposed in these patients.4 According to the clinical features and EEG result of this patient, a diagnosis of AEA should be considered. To our knowledge, there were a total of ten patients with CACNA1A gene mutations experienced absence seizure reported. We reviewed these patients’ clinical phenotypes, EEG, brain MRI and drug response of absence seizure (Table 1). The response to AEDs in these patients with absence seizure was variable from “seizure-free with VPA and LTG” and “successively treated with VPA, topiramate and levetiracetam” to intractable absence seizure even with two or three conventional AEDs (like VPA and ethosuximide) for absence seizure. It seems that the absence seizure was not easy to be controlled as this type of seizure used to be. This patient presented frequent absence seizure, which was intractable to several AEDs (VPA and LTG). As pyridoxine was proposed in some intractable epilepsy, pyridoxine was used in this patient and a dramatic response was observed clinically and electroencephalographically. The positive result of the pyridoxine withdraw test supported the pyridoxine dependence of the absence epilepsy in this patient. PDE is characterized by intractable seizures that are not controlled with conventional AEDs but that respond clinically and electroencephalographically to pharmacologic doses of pyridoxine.2 Autosomal recessive inherited mutations in ALDH7A1 gene were the main genetic defects of PDE. Four other autosomal recessive conditions with seizures responsive to pyridoxine or its vitamers are known: pyridoxal phosphate responsive epileptic encephalopathy (OMIM: 610090, PNPO gene), neonatal/infantile hypophosphatasia (OMIM: 241500, TNSALP gene), familial hyperphosphatasia (OMIM: 239300, PIGV gene) and hyperprolinemia type 2 (OMIM: 239510, ALDH4A1 gene). In this patient, no mutation of ALDH7A1, PNPO and PIGV genes was detected and the tests in blood and urine did not support a clinical diagnosis of neonatal/infantile hypophosphatasia or hyperprolinemia type 2. However, it is a limitation that we did not sequence TNSALP and ALDH4A1 genes. Although some AEA patients with CACNA1A mutations reported intractable absence seizure, pyridoxine was not used in these patients. We suggested that pyridoxine could be tried as the choice in such patients. Our report expands the clinical spectrum of CACNA1A-related disorders and the genetic spectrum of PDE and more observation was needed to get a more reliable conclusion. Conflict of interest The authors declare no competing financial interests.
Acknowledgements We are indebted to the patient and parents for their generous participation in this study. This study was supported by the National Natural Science Foundation of China (Proj. No. 81600850, 81571089 and 81371266). The authors have stated that they had no interests which might be perceived as posing a conflict or bias. References 1. Rajakulendran S, Kaski D, Hanna MG. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 2012;8:86-96. 2. Stockler S, Plecko B, Gospe SM, Jr., et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011;104:48-60. 3. Rajakulendran S, Graves TD, Labrum RW, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 2010;588:1905-1913. 4. Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 2004;127:2682-2692.
Fig. 1. Ictal EEG and interictal EEG before and after the treatment of pyridoxine indicated the response to pyridoxine. (A) ictal EEG of this patient revealed a typical 3 Hz spike-wave. (B) Wake epoch before the treatment of pyridoxine showed an abnormal background with diffuse delta and theta rhythm. (C) Wake epoch after the treatment of pyridoxine showed almost normal background for her age.
Table 1. Patients with CACNA1A mutations presenting absence seizure Reference
Jouvenceau et al. 2001
Imbrici et al. 2004
Patie nt ID
no
II:6
III:3
I:2
CACNA1A mutation
c.5733C>T, p.R1820X
c.439G>A, p.E147K
c.439G>A, p.E147K
c.439G>A, p.E147K
EEG
MRI
Generalized polyspike and
Normal
wave Generalized 3 Hz spike-wave
Generalized 3 Hz spike-wave Generalized 3 Hz spike-wave
Drugs for absence seizure No response to
GTCS, EA, cognitive
LTG
impairment
Cerebellar
Symptoms remitted
vermian
on acetazolamide
atrophy
and CBZ
n.a.
n.a.
Other phenotypes
No response to CZP and PHT
EA, AEDs induced cerebellar ataxia. EA, cognitive impairment, AEDs induced cerebellar ataxia.
n.a.
EA
n.a.
EA
n.a.
EA
n.a.
EA, learning difficulties
Slight Strupp et. al.
Patie
c.5733C>T,
2004
nt 2
p.R1820X
n.a.
cerebellar atrophy (vermis) Cerebellar
Labrum et al. 2009
F6
Deletion of exons
Generalized 3 Hz
atrophy, in
39–47
spike-wave
particular the
c.3313G>A, p.
Generalized 3 Hz
G1105S
spike-wave
vermis Rajakulendran et al. 2010
6
n.a. Severe
Jung et al. 2010
III:1
c.1063dupG, p.
Generalized 3 Hz
cerebellar
Seizure-free with
V355Gfs*32
spike-wave
vermian
VPA and LTG
Migraine
atrophy Diffuse slowing, generalized theta Damaj et al. 2015
F1-4.
c.3832C>T,
bursts
1
p.R1278X
interspersed with spikes,
Hippocampal
Successively
asymmetry
treated with VPA
(L>R)
TPM and LEV.
EA, GTCS, global developmental delay
bi-occipital spikes Refractory to VAP F2-4.
c.2867_2869del,
Generalized 3 Hz
1
p.R957Dfs113
spike-wave
Normal
and ESM but partially responsive to VPA and LEV
EA, global developmental delay, learning difficulties, ADHD
ADHD: attention deficit hyperactivity disorder; AEDs: antiepileptic drugs; CBZ, carbamazepine; CZP, clonazepam; EA: episodic ataxia; ESM: ethosuximide; F: family; GTCS: generalized tonic-clonic seizure; LEV, levetiracetam; LTG: lamotrigine; n.a.: not available; PHT, phenytoin; PMT, primidome; TPM, topiramate; VPA, valproic acid.
S1059-1311(16)30377-6 http://dx.doi.org/doi:10.1016/j.seizure.2016.12.020 YSEIZ 2882
To appear in:
Seizure
Received date: Revised date: Accepted date:
27-9-2016 26-12-2016 27-12-2016
Please cite this article as: Du Xiaoping, Chen You, Zhao Yongxiong, Luo Wei, Cen Zhidong, Hao Weicheng.Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation.SEIZURE: European Journal of Epilepsy http://dx.doi.org/10.1016/j.seizure.2016.12.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title Page Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation Xiaoping Dua, You Chenb, Yongxiong Zhaoa, Wei Luob, Zhidong Cenc,1, Weicheng Haoa,1 a
Department of Neurology, West District of Second Affiliated Hospital, Shanxi Medical
University, Taiyuan, Shanxi, China b
Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang
University, Hangzhou, Zhejiang, China c
Department of Pediatrics, Second Affiliated Hospital, School of Medicine, Zhejiang
University, Hangzhou, Zhejiang, China 1
These authors contributed equally to the study and both should be considered as
corresponding authors. Correspondence to: Weicheng Hao, MD, Department of Neurology, West District of Second Affiliated Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030000, China. Tel: +86 13403696803 Email: [email protected] AND Zhidong Cen, MD, Department of Pediatrics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310000, China. Tel: +86 13735805744 Fax: +86 571 87784538 E-Mail: [email protected]
Key words: Absence epilepsy with ataxia, CACNA1A, pyridoxine, dramatic response
Mutations in ion channel genes can cause a diverse group of phenotypes and play important roles in the filed of monogenic neurological diseases.1 With the application of Next-generation sequencing, more and more genetic and clinical heterogeneity in monogenic neurological diseases were reported, which improved our understanding of the pathophysiologic mechanisms in different monogenic neurological diseases. Herein, we report a girl presenting with intractable absence epilepsy, which had a dramatic response to pyridoxine. Using a panel containing 153 epilepsy-related genes based on Next-generation sequencing, a de novo CACNA1A mutation was found coincidentally. Our report expands the clinical spectrum of CACNA1A-related disorders and the genetic spectrum of pyridoxine dependent epilepsy (PDE).
Case Report The patient was born at term after an unremarkable pregnancy and had nearly normal early psychomotor development, although the parents reported that the patient could not run fast like other normal children or speak smoothly. At the age of 3 years, she presented blank episode lasting for 2-3 seconds several times per day. The postural tone was not lost and she was able to resume normal activities immediately. Absence epilepsy was considered after attending to a local hospital and valproic acid (VPA) was used (200mg per day). However, no improvement was observed and the absence seizure still occured 2-3 times per day. At the age of 5 years, the patient came to our hospital. VPA (500mg per day) and lamotrigine (LTG) (150mg per day) were used and the frequency of absence seizure decreased. It only happened when the patient’s temperature was above 38℃. At the age of 6 years, the frequency of absence seizure increased without obvious inducement. It occured 20-30 times per day, accompanying with partial seizures for 3 times in one year, which all presented as right upper limb hold up, eyes looked toward right side and unconsciousness for about 1 minute. No episodic attack of ataxia was complained. An ataxic gait was observed, which was considered as antiepileptic drugs (AEDs) induced ataxia at first. On EEG examination, a typical 2.5-3 Hz spike-wave was observed. (Fig. 1A) The diagnosis of absence epilepsy was made based on clinical features and EEG result. Brain MRI at the age of 3 years revealed hippocampal sclerosis on the left side and no obvious cerebellar atrophy. At the age of 10 years, cerebellar atrophy was observed on the sagittal view in the brain MRI (Supplemental data 1). Metabolic tests of blood and urine were all normal, which included normal level of proline in blood. Other blood tests including alkaline phosphatase and Ca2+ were all within normal range. As
pyridoxine was proposed in some intractable epilepsy, 500mg pyridoxine (Vitamin B6, 20mg/kg) daily was added to current treatment of 750mg (30mg/kg) VPA and 150mg (6mg/kg) LTG daily. A dramatic improvement was observed that the frequency of absence seizure was less than 10 times on the first day and no absence seizure was observed on the next five days. The pyridoxine withdraw test was positive as the frequency of absence seizure increased (about 30-40 times per day) when we reduced the dose of pyridoxine. After the use of pyridoxine, the background of EEG was also better than that before the use of pyridoxine. (Fig. 1B and 1C) The patient was discharged with oral drugs containing 750mg (30mg/kg) pyridoxine, 500mg (20mg/kg) VPA and 50mg (2mg/kg) LTG daily. In the next year, with oral drugs containing 200mg (7.4mg/kg) pyridoxine, 500mg (18mg/kg) VPA and 50mg (1.9mg/kg) LTG daily, she only had absence seizure for 2-3 times per day and one generalized tonic-clonic seizure in this year. The ataxia did not improve or progress and no episodic progress of ataxia was complained. Using a panel containing 153 epilepsy-related genes (Supplemental data 3) based on Next-generation sequencing, a heterozygous missense variant c. 410A>G (p. E137G) in CACNA1A gene was detected in this patient. This variant was further confirmed by Sanger sequencing and not detected in either of the healthy parents, which indicated that this variant was de novo (Supplemental data 2). According to the standards and guidelines of ACMG and MacArthur et al, this variant was evaluated as pathogenic mutation (Supplemental data 4). No pathogenic variant in genes (ALDH7A1, PNPO and PIGV were contained in the panel) responsible for PDE was detected in this patient. Although other two genes (TNSALP and ALDH4A1) responsible for PDE were not sequenced, the normal level of proline and alkaline phosphatase did not support this patient had their responsible phenotypes of hypophosphatasia and hyperprolinemia type 2.2 Based on these clinical and genetic studies, we concluded that the mutation c. 410A>G (p. E137G) in CACNA1A gene was the causative mutation in this patient. Discussion Mutations in CACNA1A have complicated phenotypic heterogeneity, and mainly cause three allelic disorders: episodic ataxia type 2 (OMIM: 108500), familial hemiplegic migraine type 1 (OMIM: 141500) and spinocerebellar ataxia type 6 (OMIM: 183086).1 Epilepsy was reported in about 7% patients of episodic ataxia type 2.3 Absence epilepsy with a 3 Hz spike-wave EEG pattern was reported as the core symptom in several patients with mutations
in CACNA1A. The clinical phenotype of absence epilepsy with ataxia (AEA) was proposed in these patients.4 According to the clinical features and EEG result of this patient, a diagnosis of AEA should be considered. To our knowledge, there were a total of ten patients with CACNA1A gene mutations experienced absence seizure reported. We reviewed these patients’ clinical phenotypes, EEG, brain MRI and drug response of absence seizure (Table 1). The response to AEDs in these patients with absence seizure was variable from “seizure-free with VPA and LTG” and “successively treated with VPA, topiramate and levetiracetam” to intractable absence seizure even with two or three conventional AEDs (like VPA and ethosuximide) for absence seizure. It seems that the absence seizure was not easy to be controlled as this type of seizure used to be. This patient presented frequent absence seizure, which was intractable to several AEDs (VPA and LTG). As pyridoxine was proposed in some intractable epilepsy, pyridoxine was used in this patient and a dramatic response was observed clinically and electroencephalographically. The positive result of the pyridoxine withdraw test supported the pyridoxine dependence of the absence epilepsy in this patient. PDE is characterized by intractable seizures that are not controlled with conventional AEDs but that respond clinically and electroencephalographically to pharmacologic doses of pyridoxine.2 Autosomal recessive inherited mutations in ALDH7A1 gene were the main genetic defects of PDE. Four other autosomal recessive conditions with seizures responsive to pyridoxine or its vitamers are known: pyridoxal phosphate responsive epileptic encephalopathy (OMIM: 610090, PNPO gene), neonatal/infantile hypophosphatasia (OMIM: 241500, TNSALP gene), familial hyperphosphatasia (OMIM: 239300, PIGV gene) and hyperprolinemia type 2 (OMIM: 239510, ALDH4A1 gene). In this patient, no mutation of ALDH7A1, PNPO and PIGV genes was detected and the tests in blood and urine did not support a clinical diagnosis of neonatal/infantile hypophosphatasia or hyperprolinemia type 2. However, it is a limitation that we did not sequence TNSALP and ALDH4A1 genes. Although some AEA patients with CACNA1A mutations reported intractable absence seizure, pyridoxine was not used in these patients. We suggested that pyridoxine could be tried as the choice in such patients. Our report expands the clinical spectrum of CACNA1A-related disorders and the genetic spectrum of PDE and more observation was needed to get a more reliable conclusion. Conflict of interest The authors declare no competing financial interests.
Acknowledgements We are indebted to the patient and parents for their generous participation in this study. This study was supported by the National Natural Science Foundation of China (Proj. No. 81600850, 81571089 and 81371266). The authors have stated that they had no interests which might be perceived as posing a conflict or bias. References 1. Rajakulendran S, Kaski D, Hanna MG. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 2012;8:86-96. 2. Stockler S, Plecko B, Gospe SM, Jr., et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011;104:48-60. 3. Rajakulendran S, Graves TD, Labrum RW, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 2010;588:1905-1913. 4. Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 2004;127:2682-2692.
Fig. 1. Ictal EEG and interictal EEG before and after the treatment of pyridoxine indicated the response to pyridoxine. (A) ictal EEG of this patient revealed a typical 3 Hz spike-wave. (B) Wake epoch before the treatment of pyridoxine showed an abnormal background with diffuse delta and theta rhythm. (C) Wake epoch after the treatment of pyridoxine showed almost normal background for her age.
Table 1. Patients with CACNA1A mutations presenting absence seizure Reference
Jouvenceau et al. 2001
Imbrici et al. 2004
Patie nt ID
no
II:6
III:3
I:2
CACNA1A mutation
c.5733C>T, p.R1820X
c.439G>A, p.E147K
c.439G>A, p.E147K
c.439G>A, p.E147K
EEG
MRI
Generalized polyspike and
Normal
wave Generalized 3 Hz spike-wave
Generalized 3 Hz spike-wave Generalized 3 Hz spike-wave
Drugs for absence seizure No response to
GTCS, EA, cognitive
LTG
impairment
Cerebellar
Symptoms remitted
vermian
on acetazolamide
atrophy
and CBZ
n.a.
n.a.
Other phenotypes
No response to CZP and PHT
EA, AEDs induced cerebellar ataxia. EA, cognitive impairment, AEDs induced cerebellar ataxia.
n.a.
EA
n.a.
EA
n.a.
EA
n.a.
EA, learning difficulties
Slight Strupp et. al.
Patie
c.5733C>T,
2004
nt 2
p.R1820X
n.a.
cerebellar atrophy (vermis) Cerebellar
Labrum et al. 2009
F6
Deletion of exons
Generalized 3 Hz
atrophy, in
39–47
spike-wave
particular the
c.3313G>A, p.
Generalized 3 Hz
G1105S
spike-wave
vermis Rajakulendran et al. 2010
6
n.a. Severe
Jung et al. 2010
III:1
c.1063dupG, p.
Generalized 3 Hz
cerebellar
Seizure-free with
V355Gfs*32
spike-wave
vermian
VPA and LTG
Migraine
atrophy Diffuse slowing, generalized theta Damaj et al. 2015
F1-4.
c.3832C>T,
bursts
1
p.R1278X
interspersed with spikes,
Hippocampal
Successively
asymmetry
treated with VPA
(L>R)
TPM and LEV.
EA, GTCS, global developmental delay
bi-occipital spikes Refractory to VAP F2-4.
c.2867_2869del,
Generalized 3 Hz
1
p.R957Dfs113
spike-wave
Normal
and ESM but partially responsive to VPA and LEV
EA, global developmental delay, learning difficulties, ADHD
ADHD: attention deficit hyperactivity disorder; AEDs: antiepileptic drugs; CBZ, carbamazepine; CZP, clonazepam; EA: episodic ataxia; ESM: ethosuximide; F: family; GTCS: generalized tonic-clonic seizure; LEV, levetiracetam; LTG: lamotrigine; n.a.: not available; PHT, phenytoin; PMT, primidome; TPM, topiramate; VPA, valproic acid.