Accepted Manuscript Title: Do Glut1 (Glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet? Author: Felicitas Becker Julian Schubert Sarah Weckhuysen Arvid Suls Steffen Gr¨uninger Elisabeth Korn-Merker Anne Hofmann-Peters J¨urgen Sperner Helen Cross Kerstin Hallmann Christian E. Elger Wolfram S. Kunz Ren´e Madeleyen Holger Lerche Yvonne G. Weber PII: DOI: Reference:
S0920-1211(15)00085-6 http://dx.doi.org/doi:10.1016/j.eplepsyres.2015.04.012 EPIRES 5365
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
17-11-2014 7-4-2015 23-4-2015
Please cite this article as: Becker, Felicitas, Schubert, Julian, Weckhuysen, Sarah, Suls, Arvid, Gr¨uninger, Steffen, Korn-Merker, Elisabeth, Hofmann-Peters, Anne, Sperner, J¨urgen, Cross, Helen, Hallmann, Kerstin, Elger, Christian E., Kunz, Wolfram S., Madeleyen, Ren´e, Lerche, Holger, Weber, Yvonne G., Do Glut1 (Glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2015.04.012 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.
Epilepsy research: Short Communication
Do Glut1 (Glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?
Felicitas Becker,1$ Julian Schubert,1$ Sarah Weckhuysen2, Arvid Suls2, Steffen Grüninger1, Elisabeth Korn-Merker3#, Anne Hofmann-Peters3, Jürgen Sperner4, Helen Cross5, Kerstin Hallmann6, Christian E. Elger6, Wolfram S. Kunz6, René Madeleyen7, Holger Lerche1, Yvonne G. Weber1* *corresponding author $ equally contributed
1
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research,
University of Tübingen, Tübingen, Germany; 2Neurogenetics Group, Department of Molecular Genetics, VIB and Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium, Epilepsy Centre Kempenhaeghe, Oosterhout, the Netherlands 3Epilepsy Centre
Bethel,
Bielefeld,
Germany;
since
October
1st
2013:
#
Klinik
Hochried, Murnau, Germany; 4Department of Pediatrics, University of Luebeck, Luebeck, Germany; 5AG UCL-Institute of Child Health, Great Ormond Street Hospital, London and National Centre for Young people with Epilepsy, Lingfield, UK; 6Department of Epileptology and Life&Brain Centre, University of Bonn, Bonn, Germany; 7Abteilung Kinder- und Jugendmedizin, Filderklinik Stuttgart, Stuttgart, Germany.
emails: [email protected], [email protected], [email protected], [email protected], [email protected],
[email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected].
Corresponding author: Prof. Dr. Y. Weber, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076 Tübingen, Germany. T +49-7071-29-80443, F +49-7071-29-4488, email [email protected] WORD COUNTS Title (characters including spaces):
89
Running title (max. 40 characters including spaces):
46
Summary (max. 200 words):
172
Manuscript including the summary (max. 1500 words):
1402
References (max. 20):
17
Figures and Tables (max. 2):
1
Key words (3-6):
6
KEY WORDS SLC2A1, epilepsy, pharmacoresistance, antiepileptic drugs, glut1 deficiency syndrome, genetics.
RUNNING TITLE Glut1 defects in ketogenic diet responders?
Highlights
• GLUT1 deficiency syndromes are known to respond to ketogenic diet. • Ketogenic diet is an established treatment for pharmaco-resistant epilepsies. • Sequencing of resistant patients responding well to a ketogenic diet. • No GLUT1 mutation was found in the examined cohort. • The Glut1 transporter seems not to be a relevant mechanism of ketogenic diet. ABSTRACT In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (PED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of KD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role. The glucose transporter type 1 (Glut1) facilitates the transport of the most important energy source of the brain across the blood-brain-barrier. In the early nineties, the first genetic defect in
SLC2A1, coding for Glut1, was described, as a cause of the Glut1 deficiency syndrome (Glut1DS) (De Vivo et al., 1991; Seidner et al., 1998). Glut1-DS is characterized by early developmental delay, microcephaly, ataxia and pharmaco-resistant infantile epilepsy. Recently, the clinical picture of Glut1 defects and the pathophysiological knowledge about the disease has been significantly enlarged. A Glut1 defect can cause a special type of movement disorder, namely paroxysmal exercise-induced dyskinesia (PED) (Suls et al., 2008; Weber et al., 2008), different forms of absence epilepsies, particularly the childhood absence epilepsy (CAE) (Striano et al., 2012) and the early-onset absence epilepsy (EOAE) (Suls et al., 2009), as well as the choreoathetosis/spasticity syndrome (CSE) (Weber et al., 2011). All Glut1 syndromes respond well to a ketogenic diet (KD). Most of the patients show a rapid seizure control and a positive influence on alertness, psychomotor development and the movement disorder (for review see Klepper 2008). Mutations found in the SLC2A1 lead to a reduced glucose transport over the cell membrane, as seen in functional studies (Weber et al., 2008), and to a reduced glucose metabolism in the basal ganglia, as seen in positron emission tomography (PET) studies (Suls et al., 2008). Despite the rarity of Glut1 diseases, their early diagnosis is of high clinical relevance since a very effective therapy, the ketogenic diet (KD), can improve or reverse symptoms, especially if started early in the course of the disease. KD circumvents the glucose transport by providing ketone bodies as the alternative energy source, mimicking conditions as they occur under starvation. KD can also be very effective as an add-on therapy in patients with different forms of severe pharmaco-resistant epilepsies (Neal et al., 2008; Neal et al., 2009; Nei et al., 2014). Several forms of KD have been established since the 1920s, such as the classical type (CD) with a ratio of fat to carbohydrate and protein of 3:1, the modified form with a ratio of 4:1, the modified
Atkins diet (MAD, 1.5:1 vs. normal nutrition 0.3:1) or the MCT (medium-chain triglycerides, 1.2:1) diet. All types of KD can reduce seizure frequency but none of the studies could prove a superior effect of one KD form (Neal et al., 2008; for review see Payne et al., 2011 and Lee et al. 2011). Since the clinical presentation of Glut1 defects are very variable, we tested the hypothesis that KD responsive patients with severe pharmaco-resistant epilepsy may actually have an undiagnosed Glut1 deficiency.
METHODS All procedures were in accordance with the declaration of Helsinki and approved by the local Ethical Committees. Patients responsive to KD were contacted by their treating physicians and included in the study. First, written informed consent was obtained from the patients or their legal guardians. Afterwards, clinical details were collected from the medical files and via a telephone interview, including age of onset, epilepsy and seizure classification, additional neurological features such as neuropsychological deficits or ataxia, previous anticonvulsant medication, type of KD, and the seizure frequency before and under KD. Responders to KD were defined as patients with a seizure reduction of more than 50% compared to baseline or with improvement of psychomotor development. The epilepsy and seizures were classified according to the classification scheme of the International League Against Epilepsy from 1989 (Commission on Classification and Terminology of the International League Against Epilepsy 1989). DNA was extracted from peripheral blood using standard procedures. All exons and flanking intronic regions of SLC2A1 were sequenced as described previously (Weber et al., 2008). RESULTS
Twenty-eight patients (12 females and 16 males) responding to a KD were included in the study. Table 1 summarizes the clinical data of the patients. The cohort comprised 10 patients with cryptogenic focal epilepsy, 10 patients with symptomatic, 7 patients with idiopathic and 1 patient with unclassifiable epilepsy. All patients suffered from severe, pharmaco-resistant epilepsy with trials of 2 to maximum 16 anticonvulsant drugs prior to the KD. The seizure frequency before starting the KD was 583 per month on average. On the diet, it reduced to 86 seizures per month. This corresponds to an overall seizure reduction of 85 %. Only in 23 of 28 cases detailed information about seizure frequency was available but the response to KD was well documented. In one case (EP1700.01), the response consisted of a positive influence on behaviour and cognition and was visible in the EEG showing a strong reduction of the epileptic activity. Several forms of KD were used, but the classical KD with ratios of 2.5:1 up to 4:1 was preferred. Within the cohort, examined epileptic syndromes did not show any differences referred to response to KD. Sequencing of exons and intronic boundaries of the SLC2A1 gene in all patients did not reveal any mutations. The polymorphisms detected in our cohort were comparable to the databank dbSNP135 and 1000 Genomes dataset in healthy controls (http://www.ncbi.nlm.nih.gov/projects/SNP/, http://www.1000genomes.org/). DISCUSSION The response to KD in drug resistant epilepsy is highly variable and unpredictable, except in patients with mutations in SLC2A1, who typically respond very well. We therefore hypothesized that a good response to KD can be suggestive for mutations in SLC2A1. KD has been proven to be a well-tolerated add-on therapy in patients with pharmaco-resistant epilepsy. 38% to 52% of all patients (children and adults) showed a reduction in seizure
frequency under KD (Neal et al., 2008; Nei et al., 2014, for review see Payne et al. 2011). Since KD is usually started in patients with severe forms of epilepsy, it might be even more effective in milder epilepsy types. In general, KD is not used more frequently since the diet interferes with the daily family life dramatically. Long-term compliance with the diet is often an issue, especially for adult patients. Additionally, the diet should be started under inpatient settings to monitor possible side effects. With these constraints, our cohort of 28 patients responding to the diet represents a considerable selection of patients from Germany and the Netherlands. Most of our patients received the classical KD. All analyzed patient had early-onset pharmaco-resistant epilepsy, including cryptogenic, symptomatic and genetic forms showing that KD can be effective in all epilepsy types. We could not detect any differences referring to response and epilepsy syndrome. We sequenced the coding regions and adjacent splice sites of SLC2A1 in all patients but none of the patients carried a mutation in the gene. We did not exclude large deletions or promoter mutations in the SLC2A1, however both have been reported only rarely in Glut1 defects (Wang et al., 2000; Leen et al., 2010) with point mutations accounting for about 80% of all cases. Therefore, we do not expect to have missed a major genetic alteration in SLC2A1. Although the exact mechanisms of action of KD are unknown, an anticonvulsive effect of ketone bodies has been shown in various animal models (for review see Nally and Hartman, 2012). Ketone bodies seem to work on GABA (gamma-aminobutyric acid) signaling, inward-retifying potassium channels (KATP), the citric acid cycle and glutamate transporters (VGLUT). They also seem to have antioxidant effects (Nally and Hartman, 2012). Since we did not find mutations in SLC2A1 in our cohort, bypassing the Glut1 transport seems not to be relevant for the response to KD.
ACKNOWLEDGMENTS We thank Yasemin Colakoglu and Ana Flugenico-Maisch for the help with the SLC2A1 sequencing and Sarah Rau and Snezana Maljevic for editing the manuscript. We thank also Danielle Lambrechts, Boudewijn Gunning (Epilepsy Center Kempenhaeghe, Heeze, the Netherlands) and Gerda Gravelands (Epilepsy Center Kempenhaeghe, Oostherhout, the Netherlands) for referring patients to the study. This project was supported by grants from the National Genome Network of the Federal Ministry for Education and Research (BMBF: NGFNplus/01GS08123, to HL) and the European Union (EpiPGX 279062, to HL and FZ). None of the authors has any conflict of interest to disclose.
REFERENCES Commission on Classification and Terminology of the International League against Epilepsy, 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389–399. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI, 1991. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 325:703-709. Klepper J, 2008. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 49(8):46-49. Lee PR, Kosshoff EH, 2011. Dietary treatments for epilepsy: management guidelines for the general practitioner. Epileppsy Behav. 21(2):115-21.
Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, Wevers RA, Arthur T, Bahi-Buisson N, Ballhausen D, Bekhof J, van Bogaert P, Carrilho I, Chabrol B, Champion MP, Coldwell J, Clayton P, Donner E, Evangeliou A, Ebinger F, Farrell K, Forsyth RJ, de Goede CG, Gross S, Grunewald S, Holthausen H, Jayawant S, Lachlan K, Laugel V, Leppig K, Lim MJ, Mancini G, Marina AD, Martorell L, McMenamin J, Meuwissen ME, Mundy H, Nilsson NO, Panzer A, Poll-The BT, Rauscher C, Rouselle CM, Sandvig I, Scheffner T, Sheridan E, Simpson N, Sykora P, Tomlinson R, Trounce J, Webb D, Weschke B, Scheffer H, Willemsen MA,2010. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 133:655-70. McNally MA, Hartman AL,2012. Ketone bodies in epilepsy. J Neurochem 121:28-35. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH, 2008. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7:500-6. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH, 2009. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50:1109-17. Nei M, Ngo L, Sirven JL, Sperling MR, 2014. Ketogenic diet in adolescents and adults with epilepsy. Seizure 23(6):439-42. Payne NE, Cross JH, Sander JW, Sisodiya SM, 2011. The ketogenic and related diets in adolescents and adults-a review. Epilepsia 52:1941-1948. Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum
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Striano P, Weber YG, Toliat MR, Schubert , Leu C, Chaimana R, Baulac S, Guerrero R. LeGuern G, Lehesjoki AE, Polvi A, Robbiano A, Serratosa JM, Epicure Consortium, Guerrini R, Nürnberg P, Sander T, Zara F, Lerche H, Marini C,2012. GLUT1-mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 78:557-62. Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P, Cassiman D, Kempfle J, Wuttke TV, Weber Y, Lerche H, Afawi Z, Vandenberghe W, Korczyn AD, Berkovic SF, Ekstein D, Kivity S, Ryvlin P, Claes LR, Deprez L, Maljevic S, Vargas A, Van Dyck T, Goossens D, Del-Favero J, Van Laere K, De Jonghe P, Van Paesschen W,2008. Paroxysmal exerciseinduced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 131:1831-44. Suls A, Mullen SA, Weber YG, Verhaert K, Ceulemans B, Guerrini R, Wuttke TV, SalvoVargas A, Deprez L, Claes LR, Jordanova A, Berkovic SF, Lerche H, De Jonghe P, Scheffer IE,2009. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 66:415-9. Wang D, Kranz-Eble P, De Vivo DC,2000. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum Mutat 16:224-231. Weber YG, Storch A, Wuttke TV, Brockmann K, Kempfle J, Maljevic S, Margari L, Kamm C, Schneider SA, Huber SM, Pekrun A, Roebling R, Seebohm G, Koka S, Lang C, Kraft E, Blazevic D, Salvo-Vargas A, Fauler M, Mottaghy FM, Münchau A, Edwards MJ, Presicci A, Margari F, Gasser T, Lang F, Bhatia KP, Lehmann-Horn F, Lerche H,2008. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118:2157-68. Weber YG, Kamm C, Suls A, Kempfle J, Kotschet K, Schüle R, Wuttke TV, Maljevic S, Liebrich J, Gasser T, Ludolph AC, Van Paesschen W, Schöls L, De Jonghe P, Auburger G,
Lerche H,2011. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 77:959-64.
6w
4
5
4
13
6. EP M 1741.01
20
35
3. EP M 1697.01 4. EP M 1663.01 5. EP M 1658.01
4m
2
13
2. EP M 1700.01
1
9
Sex Age Onset of (f/m) (y) epilepsy (y)
1. EP F 1048.01
Cases Patient
CPS GTCS CPS
SPS CPS GTCS MS GTCS CSWS
Seizure type
symptomatic focal, Spasms, T, multiple, bilateral GTCS, MS, intracerebral bleedings CPS symptomatic focal CPS (temporal dysplasia, L) AS
cryptogenic focal
cryptogenic focal
cryptogenic focal
cryptogenic focal
Epilepsy syndrome
MC PMR
PMR autism PMR
/
PMR ADHD ASD
ADHD
Additional features
CLB, LEV, OXC, PB, PHT, TPM, VPA,
CBZ, LEV, LTG, PB, VGB
CLB, GBP, LEV, LTG, OXC, VPA CBZ, CLB, LTG
CLB, ETX, immunoglobulines, LEV, LTG, steroids, STM, VGB, VPA
CBZ, CLB, LEV, LTG, TPM, VPA
Previous anticonvulsive medications
CD (3.75:1)
CD (4:1)
MAD MCT MCT
MCT
MCT
KD type
20/d
several per day
several per day
4-12
CSWS, but rare seizures (< 1/y). Cognitive regression related to degree of epileptic activity during sleep
10-30
Seizure frequency before KD (per m)
0-10/d
only FS
4/y
0 Positive influence on alertness, behavior and cognition. Strong reduction of epileptic activity in EEG 2
Seizure frequency during KD (per m) 1-7
Table1. Clinical details of patients included in the study. sex: f female, m male; age and onset of epilepsy: y years, m month, w weeks; localization: L left, R right; epilepsy syndrome: SMEI severe myoclonic epilepsy of infancy; seizure type: CPS complex-partial seizures, SPS simple partial seizures, GTCS generalized tonic-clonic seizures, AS atonic seizures, MS myoclonic seizures, SE status epilepticus, FS febrile seizures, CSWS continuous spike-waves during sleep, ES epileptics spasms; additional features: MC microcephaly, PMR psychomotor retardation, ADHD attention deficit hyperactivity syndrome, ASD atrial septum defect, MCT medium-chain triglycerides; ketogenic diet (KD): MAD modified Atkins diet, CD classical diet, BRO bromide, CBZ carbamazepine, CLB clobazam, GBP gabapentin, ETX ethosuximide, FBM felbamate, LCM lacosamide, LEV levetiracetam, LTG lamotrigine, OXC oxcarbamazepin, PHT phenytoin, PB phenobarbital, PRM primidone, RUF rufinamide, STM sultiam, TPM topiramate, TGB tiagabine, VGB vigabatrin, VPA valproate, ZON zonisamide, / not available.
M
F
F
F
F
14. KD8 L1945
15. KD9 L2035
16. KD10 L2063
17. KD11
9
29
7
9
16
7
M
13. KD7 L2004
14
13
F
M
/
M
11. KD5 L1905 12. KD6 L1924
10
M
8. KD2 L1869 9. KD3 L1859 10. KD4 L1891
4
F
7. KD1 L1818
2
8
6m
5m
6w
1.5
8
1
/
/
/
cryptogenic focal
cryptogenic focal
idiopathic epileptic encephalopathy (SMEI)
unclassifiable (probable cryptogenic focal
symptomatic focal
cryptogenic focal
cryptogenic focal
unclassifiable (probable myoclonic astatic epilepsy) symptomatic focal (lissencephaly) symptomatic focal (pachygyria) symptomatic focal (hemisphere bleeding, L)
FS
FS MS CPS GTCS SE SPS CPS GTCS
fear Aura CPS GTCS MS CPS GTCS
AS GTCS
GTCS
GTCS, CPS CPS GTCS
/
MS GTCS SE /
PMR
/
MC tetraparesis chromosomal translocation chr5/14 PMR SCN1A mutation c.677C>A
PMR
/
PMR
PMR
PMR
/
/
CBZ, ETX, FBM, GBP, LCM, LEV, LTG, OXC, PB, PHT, PRM, RUF, STM, TGB, TPM, ZON CLB, PB, TPM, VPA
LEV, LTG, PB, STM, TPM
CBZ, LEV, LTG, OXC, STM, TPM, VPA LEV, LTG, STM, VPA
CBZ, LEV, LTG, PB, steroids, STM, TPM, VPA CBZ, LEV, LTG, OXC, PB, TPM, VPA LTG, VPA
VPA, TPM, LTG,
/
/
ZON
CD
probable Classical diet
CD (4:1)
/
/
/
/
CD
/
/
MCT
8-12
4/d
8-12 GTCS many MS per day
100/d
8-12
/
10-15/week
1-3
/
/
/
0
4
0 MS 1/d
30/d
seizure free for 2y Unclear, seizure free without KD 06/2007 4
1/y
1-2
/
/
M
M
F
M
F
F
F
M
M
F
20. KD16 L2993
21. KD18 L2997
22. KD19 L3000
23. KD21 L3079
24. KD17 L2998
25. KD22 L3061
26. KD24 L3060
27. KD25 L3222
28. KD26 L3221
M
19. KD15 L2991
L2431 18. KD13 L3186
5
7
7
15
12
16
8
23
28
4
4m
/
1
2
1.5w
1.5m
4m
1m
6m
1w
5m
idiopathic epileptic encephalopathy
idiopathic epileptic encephalopathy
symptomatic focal (frontal dysplasia, R)
idiopathic epileptic encephalopathy
symptomatic focal (pachygyria)
idiopathic epileptic encephalopathy
cryptogenic focal
symptomatic focal (tuberous sclerosis)
idiopathic epileptic encephalopathy
idiopathic epileptic encephalopathy (West syndrome) symptomatic focal (occipital heterotopia, R)
MS AS
AS
CPS MS GTCS SPS CPS GTCS CPS GCTS SE AS MS CPS GTCS SE
SPS CPS GTCS FS MS GTCS SE SPS CPS MS SPS CPS GTCS MS
GTCS ES
PMR
PMR
PMR ataxia
PMR Dyskinesia
Deletion 3p26.1-3p25.2 PMR PMR
PMR tetraparesis blindness PMR Hemiparesis, L
/
PRM, STM, VPA
CLB, ETX, LEV, PB, RUF, STM, TPM,
/
BRO, CBZ, CLB, PHT, PRM, TPM, VPA ETX, LEV, steroids, STM, TPM, VPA, ZON
LEV, OXC, PHT, steroids, STM, TPM, VPA, ZON LTG, OXC , PB, STM, VGB, VPA
LEV, OXC, PB, TPM, VGB, vitamin B6, VPA CBZ, CLB, GBP, LCM, LEV, LTG, OXC, PB, PHT, RUF, STM, TPM, VGB, vitamin B6, VPA, ZON
BRO, CBZ, LEV, LTG, PB, PHT, VPA
PMR CBZ, LTG, OXC, PB, hemiparesis, L PHT, VGB,
/
/ CD (2:1)
CD (3:1)
CD (4:1)
CD (4:1, 5:1)
CD (4:1, 3:1)
CD (4:1, 3.5:1, 1:1)
CD (3:1, 2:1)
CD (2.5:1)
CD (4:1)
(4:1) CD (3,5:1)
/ 15-50/d
>1/d
1/2d
7-10/d
20/d
20/d
150
2-4/d
26/d
25-100/d
0
Seizure free
0
seizure free for 3 months 1-2
Seizure free for 7 months, later reduced seizure frequency 5-10/d
20
2-4/d (seizures shorter)
8-10/d
0
POLG mutation VGB, vitamin B6
S0920-1211(15)00085-6 http://dx.doi.org/doi:10.1016/j.eplepsyres.2015.04.012 EPIRES 5365
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
17-11-2014 7-4-2015 23-4-2015
Please cite this article as: Becker, Felicitas, Schubert, Julian, Weckhuysen, Sarah, Suls, Arvid, Gr¨uninger, Steffen, Korn-Merker, Elisabeth, Hofmann-Peters, Anne, Sperner, J¨urgen, Cross, Helen, Hallmann, Kerstin, Elger, Christian E., Kunz, Wolfram S., Madeleyen, Ren´e, Lerche, Holger, Weber, Yvonne G., Do Glut1 (Glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?.Epilepsy Research http://dx.doi.org/10.1016/j.eplepsyres.2015.04.012 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.
Epilepsy research: Short Communication
Do Glut1 (Glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?
Felicitas Becker,1$ Julian Schubert,1$ Sarah Weckhuysen2, Arvid Suls2, Steffen Grüninger1, Elisabeth Korn-Merker3#, Anne Hofmann-Peters3, Jürgen Sperner4, Helen Cross5, Kerstin Hallmann6, Christian E. Elger6, Wolfram S. Kunz6, René Madeleyen7, Holger Lerche1, Yvonne G. Weber1* *corresponding author $ equally contributed
1
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research,
University of Tübingen, Tübingen, Germany; 2Neurogenetics Group, Department of Molecular Genetics, VIB and Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium, Epilepsy Centre Kempenhaeghe, Oosterhout, the Netherlands 3Epilepsy Centre
Bethel,
Bielefeld,
Germany;
since
October
1st
2013:
#
Klinik
Hochried, Murnau, Germany; 4Department of Pediatrics, University of Luebeck, Luebeck, Germany; 5AG UCL-Institute of Child Health, Great Ormond Street Hospital, London and National Centre for Young people with Epilepsy, Lingfield, UK; 6Department of Epileptology and Life&Brain Centre, University of Bonn, Bonn, Germany; 7Abteilung Kinder- und Jugendmedizin, Filderklinik Stuttgart, Stuttgart, Germany.
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[email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected].
Corresponding author: Prof. Dr. Y. Weber, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076 Tübingen, Germany. T +49-7071-29-80443, F +49-7071-29-4488, email [email protected] WORD COUNTS Title (characters including spaces):
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Running title (max. 40 characters including spaces):
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Summary (max. 200 words):
172
Manuscript including the summary (max. 1500 words):
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References (max. 20):
17
Figures and Tables (max. 2):
1
Key words (3-6):
6
KEY WORDS SLC2A1, epilepsy, pharmacoresistance, antiepileptic drugs, glut1 deficiency syndrome, genetics.
RUNNING TITLE Glut1 defects in ketogenic diet responders?
Highlights
• GLUT1 deficiency syndromes are known to respond to ketogenic diet. • Ketogenic diet is an established treatment for pharmaco-resistant epilepsies. • Sequencing of resistant patients responding well to a ketogenic diet. • No GLUT1 mutation was found in the examined cohort. • The Glut1 transporter seems not to be a relevant mechanism of ketogenic diet. ABSTRACT In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (PED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of KD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role. The glucose transporter type 1 (Glut1) facilitates the transport of the most important energy source of the brain across the blood-brain-barrier. In the early nineties, the first genetic defect in
SLC2A1, coding for Glut1, was described, as a cause of the Glut1 deficiency syndrome (Glut1DS) (De Vivo et al., 1991; Seidner et al., 1998). Glut1-DS is characterized by early developmental delay, microcephaly, ataxia and pharmaco-resistant infantile epilepsy. Recently, the clinical picture of Glut1 defects and the pathophysiological knowledge about the disease has been significantly enlarged. A Glut1 defect can cause a special type of movement disorder, namely paroxysmal exercise-induced dyskinesia (PED) (Suls et al., 2008; Weber et al., 2008), different forms of absence epilepsies, particularly the childhood absence epilepsy (CAE) (Striano et al., 2012) and the early-onset absence epilepsy (EOAE) (Suls et al., 2009), as well as the choreoathetosis/spasticity syndrome (CSE) (Weber et al., 2011). All Glut1 syndromes respond well to a ketogenic diet (KD). Most of the patients show a rapid seizure control and a positive influence on alertness, psychomotor development and the movement disorder (for review see Klepper 2008). Mutations found in the SLC2A1 lead to a reduced glucose transport over the cell membrane, as seen in functional studies (Weber et al., 2008), and to a reduced glucose metabolism in the basal ganglia, as seen in positron emission tomography (PET) studies (Suls et al., 2008). Despite the rarity of Glut1 diseases, their early diagnosis is of high clinical relevance since a very effective therapy, the ketogenic diet (KD), can improve or reverse symptoms, especially if started early in the course of the disease. KD circumvents the glucose transport by providing ketone bodies as the alternative energy source, mimicking conditions as they occur under starvation. KD can also be very effective as an add-on therapy in patients with different forms of severe pharmaco-resistant epilepsies (Neal et al., 2008; Neal et al., 2009; Nei et al., 2014). Several forms of KD have been established since the 1920s, such as the classical type (CD) with a ratio of fat to carbohydrate and protein of 3:1, the modified form with a ratio of 4:1, the modified
Atkins diet (MAD, 1.5:1 vs. normal nutrition 0.3:1) or the MCT (medium-chain triglycerides, 1.2:1) diet. All types of KD can reduce seizure frequency but none of the studies could prove a superior effect of one KD form (Neal et al., 2008; for review see Payne et al., 2011 and Lee et al. 2011). Since the clinical presentation of Glut1 defects are very variable, we tested the hypothesis that KD responsive patients with severe pharmaco-resistant epilepsy may actually have an undiagnosed Glut1 deficiency.
METHODS All procedures were in accordance with the declaration of Helsinki and approved by the local Ethical Committees. Patients responsive to KD were contacted by their treating physicians and included in the study. First, written informed consent was obtained from the patients or their legal guardians. Afterwards, clinical details were collected from the medical files and via a telephone interview, including age of onset, epilepsy and seizure classification, additional neurological features such as neuropsychological deficits or ataxia, previous anticonvulsant medication, type of KD, and the seizure frequency before and under KD. Responders to KD were defined as patients with a seizure reduction of more than 50% compared to baseline or with improvement of psychomotor development. The epilepsy and seizures were classified according to the classification scheme of the International League Against Epilepsy from 1989 (Commission on Classification and Terminology of the International League Against Epilepsy 1989). DNA was extracted from peripheral blood using standard procedures. All exons and flanking intronic regions of SLC2A1 were sequenced as described previously (Weber et al., 2008). RESULTS
Twenty-eight patients (12 females and 16 males) responding to a KD were included in the study. Table 1 summarizes the clinical data of the patients. The cohort comprised 10 patients with cryptogenic focal epilepsy, 10 patients with symptomatic, 7 patients with idiopathic and 1 patient with unclassifiable epilepsy. All patients suffered from severe, pharmaco-resistant epilepsy with trials of 2 to maximum 16 anticonvulsant drugs prior to the KD. The seizure frequency before starting the KD was 583 per month on average. On the diet, it reduced to 86 seizures per month. This corresponds to an overall seizure reduction of 85 %. Only in 23 of 28 cases detailed information about seizure frequency was available but the response to KD was well documented. In one case (EP1700.01), the response consisted of a positive influence on behaviour and cognition and was visible in the EEG showing a strong reduction of the epileptic activity. Several forms of KD were used, but the classical KD with ratios of 2.5:1 up to 4:1 was preferred. Within the cohort, examined epileptic syndromes did not show any differences referred to response to KD. Sequencing of exons and intronic boundaries of the SLC2A1 gene in all patients did not reveal any mutations. The polymorphisms detected in our cohort were comparable to the databank dbSNP135 and 1000 Genomes dataset in healthy controls (http://www.ncbi.nlm.nih.gov/projects/SNP/, http://www.1000genomes.org/). DISCUSSION The response to KD in drug resistant epilepsy is highly variable and unpredictable, except in patients with mutations in SLC2A1, who typically respond very well. We therefore hypothesized that a good response to KD can be suggestive for mutations in SLC2A1. KD has been proven to be a well-tolerated add-on therapy in patients with pharmaco-resistant epilepsy. 38% to 52% of all patients (children and adults) showed a reduction in seizure
frequency under KD (Neal et al., 2008; Nei et al., 2014, for review see Payne et al. 2011). Since KD is usually started in patients with severe forms of epilepsy, it might be even more effective in milder epilepsy types. In general, KD is not used more frequently since the diet interferes with the daily family life dramatically. Long-term compliance with the diet is often an issue, especially for adult patients. Additionally, the diet should be started under inpatient settings to monitor possible side effects. With these constraints, our cohort of 28 patients responding to the diet represents a considerable selection of patients from Germany and the Netherlands. Most of our patients received the classical KD. All analyzed patient had early-onset pharmaco-resistant epilepsy, including cryptogenic, symptomatic and genetic forms showing that KD can be effective in all epilepsy types. We could not detect any differences referring to response and epilepsy syndrome. We sequenced the coding regions and adjacent splice sites of SLC2A1 in all patients but none of the patients carried a mutation in the gene. We did not exclude large deletions or promoter mutations in the SLC2A1, however both have been reported only rarely in Glut1 defects (Wang et al., 2000; Leen et al., 2010) with point mutations accounting for about 80% of all cases. Therefore, we do not expect to have missed a major genetic alteration in SLC2A1. Although the exact mechanisms of action of KD are unknown, an anticonvulsive effect of ketone bodies has been shown in various animal models (for review see Nally and Hartman, 2012). Ketone bodies seem to work on GABA (gamma-aminobutyric acid) signaling, inward-retifying potassium channels (KATP), the citric acid cycle and glutamate transporters (VGLUT). They also seem to have antioxidant effects (Nally and Hartman, 2012). Since we did not find mutations in SLC2A1 in our cohort, bypassing the Glut1 transport seems not to be relevant for the response to KD.
ACKNOWLEDGMENTS We thank Yasemin Colakoglu and Ana Flugenico-Maisch for the help with the SLC2A1 sequencing and Sarah Rau and Snezana Maljevic for editing the manuscript. We thank also Danielle Lambrechts, Boudewijn Gunning (Epilepsy Center Kempenhaeghe, Heeze, the Netherlands) and Gerda Gravelands (Epilepsy Center Kempenhaeghe, Oostherhout, the Netherlands) for referring patients to the study. This project was supported by grants from the National Genome Network of the Federal Ministry for Education and Research (BMBF: NGFNplus/01GS08123, to HL) and the European Union (EpiPGX 279062, to HL and FZ). None of the authors has any conflict of interest to disclose.
REFERENCES Commission on Classification and Terminology of the International League against Epilepsy, 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30:389–399. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI, 1991. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 325:703-709. Klepper J, 2008. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 49(8):46-49. Lee PR, Kosshoff EH, 2011. Dietary treatments for epilepsy: management guidelines for the general practitioner. Epileppsy Behav. 21(2):115-21.
Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, Wevers RA, Arthur T, Bahi-Buisson N, Ballhausen D, Bekhof J, van Bogaert P, Carrilho I, Chabrol B, Champion MP, Coldwell J, Clayton P, Donner E, Evangeliou A, Ebinger F, Farrell K, Forsyth RJ, de Goede CG, Gross S, Grunewald S, Holthausen H, Jayawant S, Lachlan K, Laugel V, Leppig K, Lim MJ, Mancini G, Marina AD, Martorell L, McMenamin J, Meuwissen ME, Mundy H, Nilsson NO, Panzer A, Poll-The BT, Rauscher C, Rouselle CM, Sandvig I, Scheffner T, Sheridan E, Simpson N, Sykora P, Tomlinson R, Trounce J, Webb D, Weschke B, Scheffer H, Willemsen MA,2010. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 133:655-70. McNally MA, Hartman AL,2012. Ketone bodies in epilepsy. J Neurochem 121:28-35. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH, 2008. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7:500-6. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH, 2009. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50:1109-17. Nei M, Ngo L, Sirven JL, Sperling MR, 2014. Ketogenic diet in adolescents and adults with epilepsy. Seizure 23(6):439-42. Payne NE, Cross JH, Sander JW, Sisodiya SM, 2011. The ketogenic and related diets in adolescents and adults-a review. Epilepsia 52:1941-1948. Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum
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Lerche H,2011. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 77:959-64.
6w
4
5
4
13
6. EP M 1741.01
20
35
3. EP M 1697.01 4. EP M 1663.01 5. EP M 1658.01
4m
2
13
2. EP M 1700.01
1
9
Sex Age Onset of (f/m) (y) epilepsy (y)
1. EP F 1048.01
Cases Patient
CPS GTCS CPS
SPS CPS GTCS MS GTCS CSWS
Seizure type
symptomatic focal, Spasms, T, multiple, bilateral GTCS, MS, intracerebral bleedings CPS symptomatic focal CPS (temporal dysplasia, L) AS
cryptogenic focal
cryptogenic focal
cryptogenic focal
cryptogenic focal
Epilepsy syndrome
MC PMR
PMR autism PMR
/
PMR ADHD ASD
ADHD
Additional features
CLB, LEV, OXC, PB, PHT, TPM, VPA,
CBZ, LEV, LTG, PB, VGB
CLB, GBP, LEV, LTG, OXC, VPA CBZ, CLB, LTG
CLB, ETX, immunoglobulines, LEV, LTG, steroids, STM, VGB, VPA
CBZ, CLB, LEV, LTG, TPM, VPA
Previous anticonvulsive medications
CD (3.75:1)
CD (4:1)
MAD MCT MCT
MCT
MCT
KD type
20/d
several per day
several per day
4-12
CSWS, but rare seizures (< 1/y). Cognitive regression related to degree of epileptic activity during sleep
10-30
Seizure frequency before KD (per m)
0-10/d
only FS
4/y
0 Positive influence on alertness, behavior and cognition. Strong reduction of epileptic activity in EEG 2
Seizure frequency during KD (per m) 1-7
Table1. Clinical details of patients included in the study. sex: f female, m male; age and onset of epilepsy: y years, m month, w weeks; localization: L left, R right; epilepsy syndrome: SMEI severe myoclonic epilepsy of infancy; seizure type: CPS complex-partial seizures, SPS simple partial seizures, GTCS generalized tonic-clonic seizures, AS atonic seizures, MS myoclonic seizures, SE status epilepticus, FS febrile seizures, CSWS continuous spike-waves during sleep, ES epileptics spasms; additional features: MC microcephaly, PMR psychomotor retardation, ADHD attention deficit hyperactivity syndrome, ASD atrial septum defect, MCT medium-chain triglycerides; ketogenic diet (KD): MAD modified Atkins diet, CD classical diet, BRO bromide, CBZ carbamazepine, CLB clobazam, GBP gabapentin, ETX ethosuximide, FBM felbamate, LCM lacosamide, LEV levetiracetam, LTG lamotrigine, OXC oxcarbamazepin, PHT phenytoin, PB phenobarbital, PRM primidone, RUF rufinamide, STM sultiam, TPM topiramate, TGB tiagabine, VGB vigabatrin, VPA valproate, ZON zonisamide, / not available.
M
F
F
F
F
14. KD8 L1945
15. KD9 L2035
16. KD10 L2063
17. KD11
9
29
7
9
16
7
M
13. KD7 L2004
14
13
F
M
/
M
11. KD5 L1905 12. KD6 L1924
10
M
8. KD2 L1869 9. KD3 L1859 10. KD4 L1891
4
F
7. KD1 L1818
2
8
6m
5m
6w
1.5
8
1
/
/
/
cryptogenic focal
cryptogenic focal
idiopathic epileptic encephalopathy (SMEI)
unclassifiable (probable cryptogenic focal
symptomatic focal
cryptogenic focal
cryptogenic focal
unclassifiable (probable myoclonic astatic epilepsy) symptomatic focal (lissencephaly) symptomatic focal (pachygyria) symptomatic focal (hemisphere bleeding, L)
FS
FS MS CPS GTCS SE SPS CPS GTCS
fear Aura CPS GTCS MS CPS GTCS
AS GTCS
GTCS
GTCS, CPS CPS GTCS
/
MS GTCS SE /
PMR
/
MC tetraparesis chromosomal translocation chr5/14 PMR SCN1A mutation c.677C>A
PMR
/
PMR
PMR
PMR
/
/
CBZ, ETX, FBM, GBP, LCM, LEV, LTG, OXC, PB, PHT, PRM, RUF, STM, TGB, TPM, ZON CLB, PB, TPM, VPA
LEV, LTG, PB, STM, TPM
CBZ, LEV, LTG, OXC, STM, TPM, VPA LEV, LTG, STM, VPA
CBZ, LEV, LTG, PB, steroids, STM, TPM, VPA CBZ, LEV, LTG, OXC, PB, TPM, VPA LTG, VPA
VPA, TPM, LTG,
/
/
ZON
CD
probable Classical diet
CD (4:1)
/
/
/
/
CD
/
/
MCT
8-12
4/d
8-12 GTCS many MS per day
100/d
8-12
/
10-15/week
1-3
/
/
/
0
4
0 MS 1/d
30/d
seizure free for 2y Unclear, seizure free without KD 06/2007 4
1/y
1-2
/
/
M
M
F
M
F
F
F
M
M
F
20. KD16 L2993
21. KD18 L2997
22. KD19 L3000
23. KD21 L3079
24. KD17 L2998
25. KD22 L3061
26. KD24 L3060
27. KD25 L3222
28. KD26 L3221
M
19. KD15 L2991
L2431 18. KD13 L3186
5
7
7
15
12
16
8
23
28
4
4m
/
1
2
1.5w
1.5m
4m
1m
6m
1w
5m
idiopathic epileptic encephalopathy
idiopathic epileptic encephalopathy
symptomatic focal (frontal dysplasia, R)
idiopathic epileptic encephalopathy
symptomatic focal (pachygyria)
idiopathic epileptic encephalopathy
cryptogenic focal
symptomatic focal (tuberous sclerosis)
idiopathic epileptic encephalopathy
idiopathic epileptic encephalopathy (West syndrome) symptomatic focal (occipital heterotopia, R)
MS AS
AS
CPS MS GTCS SPS CPS GTCS CPS GCTS SE AS MS CPS GTCS SE
SPS CPS GTCS FS MS GTCS SE SPS CPS MS SPS CPS GTCS MS
GTCS ES
PMR
PMR
PMR ataxia
PMR Dyskinesia
Deletion 3p26.1-3p25.2 PMR PMR
PMR tetraparesis blindness PMR Hemiparesis, L
/
PRM, STM, VPA
CLB, ETX, LEV, PB, RUF, STM, TPM,
/
BRO, CBZ, CLB, PHT, PRM, TPM, VPA ETX, LEV, steroids, STM, TPM, VPA, ZON
LEV, OXC, PHT, steroids, STM, TPM, VPA, ZON LTG, OXC , PB, STM, VGB, VPA
LEV, OXC, PB, TPM, VGB, vitamin B6, VPA CBZ, CLB, GBP, LCM, LEV, LTG, OXC, PB, PHT, RUF, STM, TPM, VGB, vitamin B6, VPA, ZON
BRO, CBZ, LEV, LTG, PB, PHT, VPA
PMR CBZ, LTG, OXC, PB, hemiparesis, L PHT, VGB,
/
/ CD (2:1)
CD (3:1)
CD (4:1)
CD (4:1, 5:1)
CD (4:1, 3:1)
CD (4:1, 3.5:1, 1:1)
CD (3:1, 2:1)
CD (2.5:1)
CD (4:1)
(4:1) CD (3,5:1)
/ 15-50/d
>1/d
1/2d
7-10/d
20/d
20/d
150
2-4/d
26/d
25-100/d
0
Seizure free
0
seizure free for 3 months 1-2
Seizure free for 7 months, later reduced seizure frequency 5-10/d
20
2-4/d (seizures shorter)
8-10/d
0
POLG mutation VGB, vitamin B6
