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Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy
Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy Afnan Alhakeem, Faisal Alshibani, Brahim Tabarki ⇑ Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Received 16 February 2018; accepted 26 May 2018
Abstract Introduction: SLC13A5-related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus. Methods and results: We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness. Conclusion: These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Stiripentol; Epilepsy; SLC13A5
1. Introduction Recently, loss-of-function mutations in SLC13A5 have been found to cause severe epileptic encephalopathy starting early in life, developmental delay, and teeth hypoplasia [1,2]. Status epilepticus is common in the course of the disease, and it is mainly triggered by febrile illness. Seizures are usually refractory to antiepileptic drugs, and the use of a ketogenic diet remains controversial [1–5]. Stiripentol, a second-generation antiepileptic, enhances central GABA neurotransmission by increasing the duration of GABA-A receptor channel opening ⇑ Corresponding author at: Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, PO Box 7889, 11159 Riyadh, Saudi Arabia. E-mail address: [email protected] (B. Tabarki).
and interferes with GABA reuptake and metabolism [6]. The efficacy of stiripentol is currently well established in Dravet syndrome, which is mainly associated with the SCN1A gene [7,8]. The use of stiripentol in other epilepsies, mainly genetic epilepsy, is limited, but some benefit has been demonstrated [9–11]. We report three siblings with SLC13A5 transporter deficiency with intractable seizures and frequent admission for status epilepticus with favorable outcomes on stiripentol. 2. Case report The clinical features, EEG, MRI, gene mutation, and response to stiripentol of the three affected siblings are summarized in Table 1. Whole-exome sequencing showed a novel homozygous frameshift insertion mutation in the SLC13A5
https://doi.org/10.1016/j.braindev.2018.05.020 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020
2
A. Alhakeem et al. / Brain & Development xxx (2018) xxx–xxx
Table 1 The main features of the patients with SLC13A5. Patient 1
Patient 2
Patient 3
Seizure onset Seizure sociology
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizures and generalized toni-clonic seizures
Frequency EEG pattern
10 times/day Multifocal epileptiform discharges
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizure and generalized toni-clonic seizures 10 times/day Focal left temporal discharges
Antiepileptic drugs used before stiripentol Response to Stiripentol
Topiramate, Clonazepam Carbamazepine, Levetiracetam
Topiramate, Clonazepam Carbamazepine, Levetiracetam
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizure and generalized toni-clonic seizures 13 times/day Many sharp wave and poly spikes in the left side Phenobarbitone, Clonazepam Carbamazepine, Levetiracetam
1 brief focal seizure/month No status or clusters of seizures, even during febrile illness Psychomotor delay Can sit down, roll over
1 brief focal seizure/month No status or clusters of seizures, even during febrile illness Psychomotor delay Can sit down, roll over Unremarkable
1 brief focal seizure/2months No status or clusters of seizures, even during febrile illness Psychomotor delay Hypotonic, sits without support Unremarkable
p.(Ile410Hisfs*13) (Homozygous)
p.(Ile410Hisfs*13) (Homozygous)
Developmental status MRI brain
SLC13A5 mutation
Posterior periventricular/peritrigone hyperintensity with reduction in the volume of white matter p.(Ile410Hisfs*13) (Homozygous)
gene: c.1227_1228insC (p.(Ile410Hisfs*13)). Segregation of the mutation was confirmed by Sanger sequencing as homozygous in the three affected children and heterozygous in their parents. This homozygous variant is absent in 1500 Saudi exomes and scored as pathogenic according to ACMG guidelines. No pathogenic rare variant has been identified in any of the genes known to cause other recessive early onset epileptic encephalopathy. The pregnancy and birth history were unremarkable for the 3 siblings from this consanguineous family. The 3 patients presented with seizures in the first 24 h of life. The seizure semiology varied with most having focal motor seizures with secondary generalization and eye blinking. The seizure frequency was more than 10 times per day. The EEG showed multifocal or focal discharges in 2 patients and burst suppression in one patient. With age, the 3 patients reported episodes of prolonged seizures evolving to status epilepticus that were mainly triggered by febrile illness. In addition to their daily seizures, the prolonged seizures led to emergency room visits and frequent admissions (more than 6 times per year). All patients reported severely delayed psychomotor development. The brain MRI showed mild brain atrophy. All of the patients had been placed on numerous antiseizure medications, including Phenobarbitone, Clonazepam, Topiramate, Carbamazepine, and Levetiracetam, with only partial seizure control and no effect on the prolonged seizure/status epilepticus. No patient was reported as being successfully weaned off antiepileptic drugs. After starting stiripentol and reaching 40 mg/kg/day within 1 month, in combination with Topiramate and Carbamazepine, there was a dramatic response: only a
brief attack every month initially and no prolonged seizures or status epilepticus or visits to the emergency department for seizures even during febrile illness after 18 months of follow-up. Currently, the three patients are weaned off Topiramate and remain stable. The family also noticed some improvement in their alertness, and repeated EEG showed only slow background activity without any epileptiform discharges. 3. Discussion Nonsense and missense mutations in SLC13A5 gene cause early infantile epileptic encephalopathies characterized by severe, neonatal onset seizures, psychomotor retardation, and in some patients teeth hypoplasia (microdontia) [1,2]. Weeke et al. [12] showed that the neonatal MRI exhibits a characteristic MRI pattern with punctate white matter lesions that were no longer visible at the age of 6 months but led to gliotic scarring visible on the MRI at the age of 18 months. Mass spectrometry of the plasma, cerebrospinal fluid and urine showed distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle metabolism [13]. Currently, there is no effective treatment for this disorder. Triheptanoin may benefit patients with neuronal citrate transporter deficiency because it increases the metabolism of oddchain fatty acids in neuronal mitochondria and thereby increases the levels of succinyl-CoA, subsequently leading to an increase in citrate concentrations [5]. SLC13A5-associated epilepsy manifests mainly in the form of focal motor seizures, complex partial seizures or
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020
A. Alhakeem et al. / Brain & Development xxx (2018) xxx–xxx
myoclonic seizures. As in Dravet syndrome or PCDH19-related epilepsy, the seizures are mainly induced by fever and occur mainly in clusters lasting from hours to days, sometimes evolving into status epilepticus and leading to frequent emergency department visits and admissions [1–5,12]. The seizures are refractory, requiring the use of multiple antiepileptic drugs; however, some improvement in response to drugs that affect the GABA system, including diazepam, lorazepam, clonazepam, clobazam, and phenobarbital, have been observed. In addition, several patients have reported improvement with phenytoin and lamotrigine, drugs that target sodium channels. In one patient, however, phenytoin was mentioned as worsening myoclonus. Acetazolamide was tried in four patients, with improved seizure control. The use of the ketogenic diet in SLC13A5-epileptic encephalopathy is controversial. It was reported to be beneficial for seizure control or the level of alertness and development in three patients and non-effective or even worsening the seizures in other studies [3–5]. Stiripentol is a new-generation antiepileptic drug that enhances GABAergic transmission, and it was first used to treat Dravet syndrome. It has multiple mechanisms of action, including the following: i) augmenting GABAergic activity by extending the mean open time of GABAA receptors and increases GABA levels by interfering with its reuptake by acting as a positive allosteric modulator of these receptors, ii) inhibiting lactate dehydrogenase, an enzyme that increases neuron activity by stimulating ATP-sensitive potassium channels, and iii) increasing the concentration of antiepileptic drugs and the duration of their effects by inhibiting cytochrome P450 enzymes [6]. Stiripentol as an adjunctive therapy to valproate and clobazam is particularly effective in reducing the frequency and severity of seizures and status epilepticus in patients with Dravet syndrome, mainly those caused by the SNC1A mutation [7,8]. Stiripentol has also been used in other drug-resistant epilepsies [9,11], including genetic epileptic encephalopathy, with some success. Trivisano et al. [10] reported good improvement in PCDH19-related epileptic encephalopathy in response to stiripentol. Post-marketing surveys reported a good safety and tolerability profile. The mechanism of improvement of SLC13A5epilepsy by stiripentol and other GABA system antiepileptic drugs is not fully understood. One possible mechanism is that the loss-of-function mutations in SLC13A5 decrease cytoplasmic levels of citrate and consequently decrease the synthesis of the inhibitory neurotransmitter GABA. The dysfunction of this GABA-generating enzyme is associated with epilepsy in mice. On the other hand, alterations in acetylation status of metabolic enzymes in the cytoplasm resulting from decreased citrate and acetyl CoA might also contribute to the pathogenesis of epilepsy [3,4].
3
In conclusion, stiripentol showed remarkable improvement in terms of the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness in 3 siblings with SLC13A5-related epilepsy. These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted. 4. Standard protocol approvals, registration, and patient consent This study was approved by the Ethics Committee of the Prince Sultan Military Medical City, Riyadh, Saudi Arabia (IRB: RC 943/2017). Informed consent was obtained from all patients. References [1] Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Juge´ C, et al. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet 2014;95:113–20. [2] Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, et al. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 2015;138:3238–50. [3] Klotz J, Porter BE, Colas C, Schlessinger A, Pajor AM. Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med 2016;22:310–21. [4] Bhutia YD, Kopel JJ, Lawrence JJ, Neugebauer V, Ganapathy V. Plasma membrane Na+-coupled citrate transporter (SLC13A5) and neonatal epileptic encephalopathy. Molecules 2017;22(3) Pii: E378. [5] Anselm I, MacCuaig M, Prabhu SB, Berry GT. Disease heterogeneity in Na+/citrate cotransporter deficiency. JIMD Rep 2017;31:107–11. [6] Chiron C. Stiripentol. Neurotherapeutics 2007;4:123–5. [7] Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356:1638–42. [8] Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP, et al. Stiripentol in Dravet syndrome: results of a retrospective U. S. study. Epilepsia 2013;54:1595–604. [9] Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: a randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol 2006;21:496–502. [10] Trivisano M, Specchio N, Vigevano F. Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19related epilepsy. Eur J Paediatr Neurol 2015;19:248–50. [11] Merdariu D, Delanoe D, Mahfoufi N, Bellavoine V, Auvin S. Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam. Brain Dev 2013;35:177–80. [12] Weeke LC, Brilstra E, Braun KP, Zonneveld-Huijssoon E, Salomons GS, Koeleman BP, et al. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. Eur J Paediatr Neurol 2017;21:396–403. [13] Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, et al. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Mol Genet Metab 2017;121:314–9.
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020
Case Report
Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy Afnan Alhakeem, Faisal Alshibani, Brahim Tabarki ⇑ Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Received 16 February 2018; accepted 26 May 2018
Abstract Introduction: SLC13A5-related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus. Methods and results: We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness. Conclusion: These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Stiripentol; Epilepsy; SLC13A5
1. Introduction Recently, loss-of-function mutations in SLC13A5 have been found to cause severe epileptic encephalopathy starting early in life, developmental delay, and teeth hypoplasia [1,2]. Status epilepticus is common in the course of the disease, and it is mainly triggered by febrile illness. Seizures are usually refractory to antiepileptic drugs, and the use of a ketogenic diet remains controversial [1–5]. Stiripentol, a second-generation antiepileptic, enhances central GABA neurotransmission by increasing the duration of GABA-A receptor channel opening ⇑ Corresponding author at: Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, PO Box 7889, 11159 Riyadh, Saudi Arabia. E-mail address: [email protected] (B. Tabarki).
and interferes with GABA reuptake and metabolism [6]. The efficacy of stiripentol is currently well established in Dravet syndrome, which is mainly associated with the SCN1A gene [7,8]. The use of stiripentol in other epilepsies, mainly genetic epilepsy, is limited, but some benefit has been demonstrated [9–11]. We report three siblings with SLC13A5 transporter deficiency with intractable seizures and frequent admission for status epilepticus with favorable outcomes on stiripentol. 2. Case report The clinical features, EEG, MRI, gene mutation, and response to stiripentol of the three affected siblings are summarized in Table 1. Whole-exome sequencing showed a novel homozygous frameshift insertion mutation in the SLC13A5
https://doi.org/10.1016/j.braindev.2018.05.020 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020
2
A. Alhakeem et al. / Brain & Development xxx (2018) xxx–xxx
Table 1 The main features of the patients with SLC13A5. Patient 1
Patient 2
Patient 3
Seizure onset Seizure sociology
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizures and generalized toni-clonic seizures
Frequency EEG pattern
10 times/day Multifocal epileptiform discharges
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizure and generalized toni-clonic seizures 10 times/day Focal left temporal discharges
Antiepileptic drugs used before stiripentol Response to Stiripentol
Topiramate, Clonazepam Carbamazepine, Levetiracetam
Topiramate, Clonazepam Carbamazepine, Levetiracetam
First 24 h of life Focal lip smacking and facial twitching evolving to focal motor seizure and generalized toni-clonic seizures 13 times/day Many sharp wave and poly spikes in the left side Phenobarbitone, Clonazepam Carbamazepine, Levetiracetam
1 brief focal seizure/month No status or clusters of seizures, even during febrile illness Psychomotor delay Can sit down, roll over
1 brief focal seizure/month No status or clusters of seizures, even during febrile illness Psychomotor delay Can sit down, roll over Unremarkable
1 brief focal seizure/2months No status or clusters of seizures, even during febrile illness Psychomotor delay Hypotonic, sits without support Unremarkable
p.(Ile410Hisfs*13) (Homozygous)
p.(Ile410Hisfs*13) (Homozygous)
Developmental status MRI brain
SLC13A5 mutation
Posterior periventricular/peritrigone hyperintensity with reduction in the volume of white matter p.(Ile410Hisfs*13) (Homozygous)
gene: c.1227_1228insC (p.(Ile410Hisfs*13)). Segregation of the mutation was confirmed by Sanger sequencing as homozygous in the three affected children and heterozygous in their parents. This homozygous variant is absent in 1500 Saudi exomes and scored as pathogenic according to ACMG guidelines. No pathogenic rare variant has been identified in any of the genes known to cause other recessive early onset epileptic encephalopathy. The pregnancy and birth history were unremarkable for the 3 siblings from this consanguineous family. The 3 patients presented with seizures in the first 24 h of life. The seizure semiology varied with most having focal motor seizures with secondary generalization and eye blinking. The seizure frequency was more than 10 times per day. The EEG showed multifocal or focal discharges in 2 patients and burst suppression in one patient. With age, the 3 patients reported episodes of prolonged seizures evolving to status epilepticus that were mainly triggered by febrile illness. In addition to their daily seizures, the prolonged seizures led to emergency room visits and frequent admissions (more than 6 times per year). All patients reported severely delayed psychomotor development. The brain MRI showed mild brain atrophy. All of the patients had been placed on numerous antiseizure medications, including Phenobarbitone, Clonazepam, Topiramate, Carbamazepine, and Levetiracetam, with only partial seizure control and no effect on the prolonged seizure/status epilepticus. No patient was reported as being successfully weaned off antiepileptic drugs. After starting stiripentol and reaching 40 mg/kg/day within 1 month, in combination with Topiramate and Carbamazepine, there was a dramatic response: only a
brief attack every month initially and no prolonged seizures or status epilepticus or visits to the emergency department for seizures even during febrile illness after 18 months of follow-up. Currently, the three patients are weaned off Topiramate and remain stable. The family also noticed some improvement in their alertness, and repeated EEG showed only slow background activity without any epileptiform discharges. 3. Discussion Nonsense and missense mutations in SLC13A5 gene cause early infantile epileptic encephalopathies characterized by severe, neonatal onset seizures, psychomotor retardation, and in some patients teeth hypoplasia (microdontia) [1,2]. Weeke et al. [12] showed that the neonatal MRI exhibits a characteristic MRI pattern with punctate white matter lesions that were no longer visible at the age of 6 months but led to gliotic scarring visible on the MRI at the age of 18 months. Mass spectrometry of the plasma, cerebrospinal fluid and urine showed distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle metabolism [13]. Currently, there is no effective treatment for this disorder. Triheptanoin may benefit patients with neuronal citrate transporter deficiency because it increases the metabolism of oddchain fatty acids in neuronal mitochondria and thereby increases the levels of succinyl-CoA, subsequently leading to an increase in citrate concentrations [5]. SLC13A5-associated epilepsy manifests mainly in the form of focal motor seizures, complex partial seizures or
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020
A. Alhakeem et al. / Brain & Development xxx (2018) xxx–xxx
myoclonic seizures. As in Dravet syndrome or PCDH19-related epilepsy, the seizures are mainly induced by fever and occur mainly in clusters lasting from hours to days, sometimes evolving into status epilepticus and leading to frequent emergency department visits and admissions [1–5,12]. The seizures are refractory, requiring the use of multiple antiepileptic drugs; however, some improvement in response to drugs that affect the GABA system, including diazepam, lorazepam, clonazepam, clobazam, and phenobarbital, have been observed. In addition, several patients have reported improvement with phenytoin and lamotrigine, drugs that target sodium channels. In one patient, however, phenytoin was mentioned as worsening myoclonus. Acetazolamide was tried in four patients, with improved seizure control. The use of the ketogenic diet in SLC13A5-epileptic encephalopathy is controversial. It was reported to be beneficial for seizure control or the level of alertness and development in three patients and non-effective or even worsening the seizures in other studies [3–5]. Stiripentol is a new-generation antiepileptic drug that enhances GABAergic transmission, and it was first used to treat Dravet syndrome. It has multiple mechanisms of action, including the following: i) augmenting GABAergic activity by extending the mean open time of GABAA receptors and increases GABA levels by interfering with its reuptake by acting as a positive allosteric modulator of these receptors, ii) inhibiting lactate dehydrogenase, an enzyme that increases neuron activity by stimulating ATP-sensitive potassium channels, and iii) increasing the concentration of antiepileptic drugs and the duration of their effects by inhibiting cytochrome P450 enzymes [6]. Stiripentol as an adjunctive therapy to valproate and clobazam is particularly effective in reducing the frequency and severity of seizures and status epilepticus in patients with Dravet syndrome, mainly those caused by the SNC1A mutation [7,8]. Stiripentol has also been used in other drug-resistant epilepsies [9,11], including genetic epileptic encephalopathy, with some success. Trivisano et al. [10] reported good improvement in PCDH19-related epileptic encephalopathy in response to stiripentol. Post-marketing surveys reported a good safety and tolerability profile. The mechanism of improvement of SLC13A5epilepsy by stiripentol and other GABA system antiepileptic drugs is not fully understood. One possible mechanism is that the loss-of-function mutations in SLC13A5 decrease cytoplasmic levels of citrate and consequently decrease the synthesis of the inhibitory neurotransmitter GABA. The dysfunction of this GABA-generating enzyme is associated with epilepsy in mice. On the other hand, alterations in acetylation status of metabolic enzymes in the cytoplasm resulting from decreased citrate and acetyl CoA might also contribute to the pathogenesis of epilepsy [3,4].
3
In conclusion, stiripentol showed remarkable improvement in terms of the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness in 3 siblings with SLC13A5-related epilepsy. These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted. 4. Standard protocol approvals, registration, and patient consent This study was approved by the Ethics Committee of the Prince Sultan Military Medical City, Riyadh, Saudi Arabia (IRB: RC 943/2017). Informed consent was obtained from all patients. References [1] Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Juge´ C, et al. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet 2014;95:113–20. [2] Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, et al. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 2015;138:3238–50. [3] Klotz J, Porter BE, Colas C, Schlessinger A, Pajor AM. Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med 2016;22:310–21. [4] Bhutia YD, Kopel JJ, Lawrence JJ, Neugebauer V, Ganapathy V. Plasma membrane Na+-coupled citrate transporter (SLC13A5) and neonatal epileptic encephalopathy. Molecules 2017;22(3) Pii: E378. [5] Anselm I, MacCuaig M, Prabhu SB, Berry GT. Disease heterogeneity in Na+/citrate cotransporter deficiency. JIMD Rep 2017;31:107–11. [6] Chiron C. Stiripentol. Neurotherapeutics 2007;4:123–5. [7] Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356:1638–42. [8] Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP, et al. Stiripentol in Dravet syndrome: results of a retrospective U. S. study. Epilepsia 2013;54:1595–604. [9] Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: a randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol 2006;21:496–502. [10] Trivisano M, Specchio N, Vigevano F. Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19related epilepsy. Eur J Paediatr Neurol 2015;19:248–50. [11] Merdariu D, Delanoe D, Mahfoufi N, Bellavoine V, Auvin S. Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam. Brain Dev 2013;35:177–80. [12] Weeke LC, Brilstra E, Braun KP, Zonneveld-Huijssoon E, Salomons GS, Koeleman BP, et al. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. Eur J Paediatr Neurol 2017;21:396–403. [13] Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, et al. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Mol Genet Metab 2017;121:314–9.
Please cite this article in press as: Alhakeem A et al. Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.05.020