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Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet
Epilepsy & Behavior 32 (2014) 76–78
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet Anette Ramm-Pettersen a,⁎, Karl O. Nakken a, Kathrine Cammermeyer Haavardsholm a, Kaja Kristine Selmer b,c a b c
Department of Refractory Epilepsy-SSE, Oslo University Hospital, Norway Department of Medical Genetics, University of Oslo and Oslo University Hospital, Norway National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, Norway
a r t i c l e
i n f o
Article history: Received 19 December 2013 Revised 10 January 2014 Accepted 12 January 2014 Available online 6 February 2014 Keywords: Epilepsy GLUT1-DS Ketogenic diet SLC2A1
a b s t r a c t Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood–brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (N 50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of N 50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a metabolic encephalopathy most often caused by a mutation in the SLC2A1 gene. This gene encodes the glucose transporter protein GLUT1, and a mutation in this gene may compromise transport of glucose across the blood–brain barrier [1,2]. The syndrome was first described in 1991 [3], and the first SLC2A1 mutation was identified in 1998 [4]. The initially described patients had a phenotype characterized by epilepsy, movement disorders, developmental delay, and acquired microcephaly [3]. Recent studies of patients with this syndrome have shown great variability, both phenotypically and genetically [5,6]. Other studies indicate that about 10% of a cohort with early-onset absence epilepsy (EOAE) has GLUT1-DS [7,8]. Almost 5% of myoclon-astatic epilepsy (MAE) in patients is caused by a mutation in SLC2A1 [9]. The syndrome is probably underdiagnosed, and diagnosis is often delayed [10]. Proposals have been made to classify GLUT1-DS into different subgroups, but
⁎ Corresponding author at: Department of Refractory Epilepsy-SSE (Formerly National Centre for Epilepsy), Section for Children and Youth, Oslo University Hospital, P.O. Box 853, 1306 Sandvika, Norway. Fax: +47 67 54 04 96. E-mail address: [email protected] (A. Ramm-Pettersen). 1525-5050/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2014.01.003
no consensus has been reached [10,11]. The clinical heterogeneity may be due to various degrees of cerebral hypometabolism [12]. Treatment of choice for GLUT1-DS is the classical 4:1 or 3:1 (fat:carbohydrate and protein) ketogenic diet (KD) [2,13,14]. A modified Atkins diet (MAD) might be an alternative in cases of dietary non-adherence or concerns regarding long-term adverse effects, although the evidence is limited [15,16]. Both diets produce ketosis, and ketone bodies serve as an alternative fuel for the brain in the absence of glucose. Other treatment options have been suggested, but there are currently no reports on the effect of medium-chain ketogenic diet or low glycemic index treatment for GLUT1-DS [15], nor is there convincing evidence for the effect of an alpha-lipoic acid diet [2,17]. At the National Centre for Epilepsy in Norway, the classical ketogenic diet has been a treatment option for patients with difficult-to-treat epilepsy since 2005 and modified Atkins diet since 2009. The epilepsy center is the only Norwegian institution offering follow-up of patients treated with ketogenic diets. Since 2006, we have identified 17 patients with GLUT1-DS. The clinical and genetic characteristics of the first ten patients have been previously reported [18]. As KD or MAD has an excellent seizure-reducing effect on most patients with this syndrome, we hypothesized that among those who respond well to treatment with ketogenic diets, there could be patients with undiagnosed GLUT1-DS. Thus, the aim of this study was to test whether good response to dietary treatment was a suitable clinical clue for identifying patients with GLUT1-DS.
A. Ramm-Pettersen et al. / Epilepsy & Behavior 32 (2014) 76–78
77
Dietary treatment: 177 patients 47 treated < 3 months
130 patients 72 had < 50 % seizure reduction
58 patients
40 patients on KD
18 patients on MAD 6 GLUT1-DS 1 other mutation 3 resigned
5 GLUT1-DS 5 PDH 5 resigned
25 patients
8 patients
Fig. 1. The process of inclusion.
2. Materials and methods
boundaries of the SLC2A1 gene were sequenced (NCBI reference sequence: NM_006516.2). Primer information and polymerase chain reaction (PCR) conditions are available upon request. Multiplex ligation-dependent probe amplification (MLPA) was also performed on all samples.
2.1. Clinical We retrospectively reviewed the medical records of all children (0–16 years) treated with KD and MAD at the epilepsy center in the period of February 2005–February 2012. All patients diagnosed with GLUT1-DS in Norway during the study period were treated and followed at the epilepsy center. We did not include patients treated for less than 3 months and those treated with KD for pyruvate dehydrogenase (PDH) deficiency. We evaluated the effect of KD after 1.5 and 4 months and the effect of MAD after 3 and 6 months. Compared with the pre-diet seizure situation, we defined as responders those who achieved N 50% reduction in seizure frequency after 4 months on KD and after 6 months on MAD. The responders were invited to participate in the study. From the patients' medical records, we collected demographic data, information about seizure type and frequency, developmental status, exerciseinduced movement disorders, and results from EEG and cerebral MRI. All participants or their relatives gave written informed consent.
2.2. Genetic analysis Deoxyribonucleic acid was extracted from venous blood using Autopure LS from Qiagen, Cologne, Germany (http://www.qiagen.com/ Products/Automation/AutopureLS.aspx). All 12 exons and exon−intron
3. Results During the period in question, 177 patients started with KD and MAD at the center. The process of inclusion is illustrated in Fig. 1. The clinical characteristics of the studied cohort are summarized in Table 1. Of the 177 patients, 130 children were treated for more than 3 months. Of these, 58 (44%) were defined as responders. However, 11 were already diagnosed with GLUT1-DS. Six children had other mutations explaining their phenotype, and eight declined to participate. In the remaining 33 children, no SLC2A1 mutations were identified. Only three of the 33 patients became completely seizure-free. Two were treated with KD and one with MAD. The epilepsy etiology was unknown in all three. One had myoclonic-astatic epilepsy with seizure onset at five months of age in addition to severe mental retardation. The other patient had seizure onset at two years, and she gradually developed a Lennox−Gastaut-like syndrome with atypical absence, generalized tonic − clonic, atonic, and tonic seizures. After starting KD treatment, she has had a normal cognitive development. The third patient had seizure onset when she was four years old, and the epilepsy
Table 1 Clinical features, EEG and MRI findings in patients with N50% seizure reduction on KD (n = 25) and MAD (n = 8) and known GLUT1-DS (n = 11). Patient cohort (# of patients)
Seizure freedom after dietary treatment
Seizure types
Epileptic syndromes frequently seen in GLUT1-DS
Cognitive function
EEG
MRI
Exercise-induced movement disorders
KD (25)
2/25
GTC, tonic, atonic, absences
EOAE: 0 MAE: 2
Pathological: 25
Pathological: 14 Normal: 11
0
MAD (8)
1/8
Absences, myoclonias
EOAE: 3 MAE: 0
Pathological: 8
Pathological: 0 Normal: 7 Not tested: 1
0
GLUT1-DS (11)
9/10 (10 with seizures)
Cyanotic spells, myoclonias, absences
EOAE: 6 MAE: 0
Severe MR: 18 Moderate MR: 5 Mild MR: 1 Normal: 1 Severe MR: 1 Moderate MR:1 Mild MR: 4 Normal: 2 Moderate MR: 4 Mild MR: 4 Normal: 3
Pathologic: 4 Normal: 7
Pathological: 1 Normal: 8 Not tested: 2
8
Abbreviations: KD: ketogenic diet; MAD: modified Atkins diet; GLUT1-DS: glucose transporter 1 deficiency syndrome; GTC: generalized tonic–clonic convulsions, EOAE: early-onset absence epilepsy, MAE: myoclonic-astatic epilepsy, MR: mental retardation.
78
A. Ramm-Pettersen et al. / Epilepsy & Behavior 32 (2014) 76–78
was classified as EOAE. She had normal cognitive development. Before starting the diet, the seizures of all three patients had failed to improve with more than four AEDs.
disorders, complete seizure freedom on dietary treatment seems to be a hallmark of the disease. Acknowledgment
4. Discussion In this study, our hypothesis that children with undiagnosed GLUT1DS could be found among those who had responded well (N 50% seizure reduction) to KD or MAD was not supported. However, when comparing the clinical phenotypes between those with known GLUT1-DS and those who had responded well to KD or MAD, there were considerable clinical differences. One evident difference was that only three out of the 33 patients became completely seizure-free on the KD and MAD diets. These clinical differences might give important clues on how to identify patients with GLUT1-DS in the future. The patients with GLUT1-DS in this cohort are not severely mentally retarded; they have mostly absences with or without myoclonic jerks, the majority have paroxysmal exercise-induced dyskinesias, most of them are seizure-free on dietary treatment, and most of them have normal EEG and cerebral MRI. These characteristics are in contrast to what we observed in the other patients responding well to dietary treatment. When we started treating patients with KD in 2005, most of them had PEG (peritoneal enteral gastrostomy), which we assumed was necessary for good compliance. The majority of the patients treated with KD had several physical disabilities, had severe mental retardation, had seizures that showed a considerable diversity, and often had pronounced pathology on MRI and EEG. Later on, we have also treated cognitively normal patients, and these were most often treated with the MAD. The patients in the MAD group had clinical features more similar to the patients with GLUT1-DS, but only one became completely seizure-free. Additionally, paroxysmal exercise-induced dyskinesias were not reported in the medical records of any of the patients treated with MAD and KD. Another interesting difference was the occurrence of the two epileptic syndromes frequently seen in GLUT1-DS, EOAE, and MAE [8,19]. These syndromes were less frequent among patients treated with KD and MAD than among patients with known GLUT1-DS (Table 1). As a negative genetic test does not exclude GLUT1-DS in all patients and since neither standardized lumbar puncture with measurement of CSF to serum glucose ratio nor glucose uptake tests have been performed in all our cases, we cannot exclude the possibility that we might have overlooked some mutation-negative cases. In conclusion, our study illustrates the known dramatic effect of dietary treatment on seizure frequency in patients with GLUT1-DS. Furthermore, the clear difference in effect in patients with GLUT1-DS versus patients with epilepsy with other etiologies shows that seizure freedom is an important clue in the diagnosis of GLUT1-DS, while seizure reduction of N50% is too unspecific. As many clinicians are still not familiar with the disorder, a diagnostic delay of more than ten years has been reported [18]. Knowing that the syndrome is treatable if diagnosed early makes it particularly important to be aware of the most common symptoms. In addition to difficult-to-treat epilepsy, increasing cognitive problems with age, and exercise-induced movement
The authors would like to thank colleague Elena Kvan for helpful assistance in preparing the patient forms. Disclosure The authors declare no conflict of interest. References [1] Klepper J, Leiendecker B. GLUT1 deficiency syndrome—2007 update. Dev Med Child Neurol 2007;49:707–16. [2] Klepper J. GLUT1 deficiency syndrome in clinical practice. Epilepsy Res 2012;100: 272–7. [3] De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood–brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325: 703–9. [4] Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J, Stump TS, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood–brain barrier hexose carrier. Nat Genet 1998;18:188–91. [5] Tzadok M, Nissenkorn A, Porper K, Matot I, Marcu S, Anikster Y, et al. The many faces of Glut1 deficiency syndrome. J Child Neurol 2013 Jan 22 (Electronic publication ahead of print). [6] Pearson TS, Akman C, Hinton VJ, Engelstad K, De V. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep 2013;13:342. [7] Suls A, Mullen SA, Weber YG, Verhaert K, Ceulemans B, Guerrini R, et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 2009;66:415–9. [8] Arsov T, Mullen SA, Damiano JA, Lawrence KM, Huh LL, Nolan M, et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 2012;53:e204–7. [9] Mullen SA, Marini C, Suls A, Mei D, Della GE, Buti D, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011;68: 1152–5. [10] Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 2009;31:545–52. [11] Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010;133:655–70. [12] Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57:111–8. [13] Klepper J, Diefenbach S, Kohlschutter A, Voit T. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids 2004;70:321–7. [14] Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M, et al. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 2005;36:302–8. [15] Klepper J, Leiendecker B. Glut1 deficiency syndrome and novel ketogenic diets. J Child Neurol 2013;28:1045–8. [16] Ito Y, Oguni H, Ito S, Oguni M, Osawa M. A modified Atkins diet is promising as a treatment for glucose transporter type 1 deficiency syndrome. Dev Med Child Neurol 2011;53:658–63. [17] Verrotti A, D'Egidio C, Agostinelli S, Gobbi G. Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 2012;16:3–9. [18] Ramm-Pettersen A, Nakken KO, Skogseid IM, Randby H, Skei EB, Bindoff LA, et al. Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol 2013;55:440–7. [19] Mullen SA, Marini C, Suls A, Mei D, Della GE, Buti D, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011;68: 1152–5.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet Anette Ramm-Pettersen a,⁎, Karl O. Nakken a, Kathrine Cammermeyer Haavardsholm a, Kaja Kristine Selmer b,c a b c
Department of Refractory Epilepsy-SSE, Oslo University Hospital, Norway Department of Medical Genetics, University of Oslo and Oslo University Hospital, Norway National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, Norway
a r t i c l e
i n f o
Article history: Received 19 December 2013 Revised 10 January 2014 Accepted 12 January 2014 Available online 6 February 2014 Keywords: Epilepsy GLUT1-DS Ketogenic diet SLC2A1
a b s t r a c t Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood–brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (N 50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of N 50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a metabolic encephalopathy most often caused by a mutation in the SLC2A1 gene. This gene encodes the glucose transporter protein GLUT1, and a mutation in this gene may compromise transport of glucose across the blood–brain barrier [1,2]. The syndrome was first described in 1991 [3], and the first SLC2A1 mutation was identified in 1998 [4]. The initially described patients had a phenotype characterized by epilepsy, movement disorders, developmental delay, and acquired microcephaly [3]. Recent studies of patients with this syndrome have shown great variability, both phenotypically and genetically [5,6]. Other studies indicate that about 10% of a cohort with early-onset absence epilepsy (EOAE) has GLUT1-DS [7,8]. Almost 5% of myoclon-astatic epilepsy (MAE) in patients is caused by a mutation in SLC2A1 [9]. The syndrome is probably underdiagnosed, and diagnosis is often delayed [10]. Proposals have been made to classify GLUT1-DS into different subgroups, but
⁎ Corresponding author at: Department of Refractory Epilepsy-SSE (Formerly National Centre for Epilepsy), Section for Children and Youth, Oslo University Hospital, P.O. Box 853, 1306 Sandvika, Norway. Fax: +47 67 54 04 96. E-mail address: [email protected] (A. Ramm-Pettersen). 1525-5050/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2014.01.003
no consensus has been reached [10,11]. The clinical heterogeneity may be due to various degrees of cerebral hypometabolism [12]. Treatment of choice for GLUT1-DS is the classical 4:1 or 3:1 (fat:carbohydrate and protein) ketogenic diet (KD) [2,13,14]. A modified Atkins diet (MAD) might be an alternative in cases of dietary non-adherence or concerns regarding long-term adverse effects, although the evidence is limited [15,16]. Both diets produce ketosis, and ketone bodies serve as an alternative fuel for the brain in the absence of glucose. Other treatment options have been suggested, but there are currently no reports on the effect of medium-chain ketogenic diet or low glycemic index treatment for GLUT1-DS [15], nor is there convincing evidence for the effect of an alpha-lipoic acid diet [2,17]. At the National Centre for Epilepsy in Norway, the classical ketogenic diet has been a treatment option for patients with difficult-to-treat epilepsy since 2005 and modified Atkins diet since 2009. The epilepsy center is the only Norwegian institution offering follow-up of patients treated with ketogenic diets. Since 2006, we have identified 17 patients with GLUT1-DS. The clinical and genetic characteristics of the first ten patients have been previously reported [18]. As KD or MAD has an excellent seizure-reducing effect on most patients with this syndrome, we hypothesized that among those who respond well to treatment with ketogenic diets, there could be patients with undiagnosed GLUT1-DS. Thus, the aim of this study was to test whether good response to dietary treatment was a suitable clinical clue for identifying patients with GLUT1-DS.
A. Ramm-Pettersen et al. / Epilepsy & Behavior 32 (2014) 76–78
77
Dietary treatment: 177 patients 47 treated < 3 months
130 patients 72 had < 50 % seizure reduction
58 patients
40 patients on KD
18 patients on MAD 6 GLUT1-DS 1 other mutation 3 resigned
5 GLUT1-DS 5 PDH 5 resigned
25 patients
8 patients
Fig. 1. The process of inclusion.
2. Materials and methods
boundaries of the SLC2A1 gene were sequenced (NCBI reference sequence: NM_006516.2). Primer information and polymerase chain reaction (PCR) conditions are available upon request. Multiplex ligation-dependent probe amplification (MLPA) was also performed on all samples.
2.1. Clinical We retrospectively reviewed the medical records of all children (0–16 years) treated with KD and MAD at the epilepsy center in the period of February 2005–February 2012. All patients diagnosed with GLUT1-DS in Norway during the study period were treated and followed at the epilepsy center. We did not include patients treated for less than 3 months and those treated with KD for pyruvate dehydrogenase (PDH) deficiency. We evaluated the effect of KD after 1.5 and 4 months and the effect of MAD after 3 and 6 months. Compared with the pre-diet seizure situation, we defined as responders those who achieved N 50% reduction in seizure frequency after 4 months on KD and after 6 months on MAD. The responders were invited to participate in the study. From the patients' medical records, we collected demographic data, information about seizure type and frequency, developmental status, exerciseinduced movement disorders, and results from EEG and cerebral MRI. All participants or their relatives gave written informed consent.
2.2. Genetic analysis Deoxyribonucleic acid was extracted from venous blood using Autopure LS from Qiagen, Cologne, Germany (http://www.qiagen.com/ Products/Automation/AutopureLS.aspx). All 12 exons and exon−intron
3. Results During the period in question, 177 patients started with KD and MAD at the center. The process of inclusion is illustrated in Fig. 1. The clinical characteristics of the studied cohort are summarized in Table 1. Of the 177 patients, 130 children were treated for more than 3 months. Of these, 58 (44%) were defined as responders. However, 11 were already diagnosed with GLUT1-DS. Six children had other mutations explaining their phenotype, and eight declined to participate. In the remaining 33 children, no SLC2A1 mutations were identified. Only three of the 33 patients became completely seizure-free. Two were treated with KD and one with MAD. The epilepsy etiology was unknown in all three. One had myoclonic-astatic epilepsy with seizure onset at five months of age in addition to severe mental retardation. The other patient had seizure onset at two years, and she gradually developed a Lennox−Gastaut-like syndrome with atypical absence, generalized tonic − clonic, atonic, and tonic seizures. After starting KD treatment, she has had a normal cognitive development. The third patient had seizure onset when she was four years old, and the epilepsy
Table 1 Clinical features, EEG and MRI findings in patients with N50% seizure reduction on KD (n = 25) and MAD (n = 8) and known GLUT1-DS (n = 11). Patient cohort (# of patients)
Seizure freedom after dietary treatment
Seizure types
Epileptic syndromes frequently seen in GLUT1-DS
Cognitive function
EEG
MRI
Exercise-induced movement disorders
KD (25)
2/25
GTC, tonic, atonic, absences
EOAE: 0 MAE: 2
Pathological: 25
Pathological: 14 Normal: 11
0
MAD (8)
1/8
Absences, myoclonias
EOAE: 3 MAE: 0
Pathological: 8
Pathological: 0 Normal: 7 Not tested: 1
0
GLUT1-DS (11)
9/10 (10 with seizures)
Cyanotic spells, myoclonias, absences
EOAE: 6 MAE: 0
Severe MR: 18 Moderate MR: 5 Mild MR: 1 Normal: 1 Severe MR: 1 Moderate MR:1 Mild MR: 4 Normal: 2 Moderate MR: 4 Mild MR: 4 Normal: 3
Pathologic: 4 Normal: 7
Pathological: 1 Normal: 8 Not tested: 2
8
Abbreviations: KD: ketogenic diet; MAD: modified Atkins diet; GLUT1-DS: glucose transporter 1 deficiency syndrome; GTC: generalized tonic–clonic convulsions, EOAE: early-onset absence epilepsy, MAE: myoclonic-astatic epilepsy, MR: mental retardation.
78
A. Ramm-Pettersen et al. / Epilepsy & Behavior 32 (2014) 76–78
was classified as EOAE. She had normal cognitive development. Before starting the diet, the seizures of all three patients had failed to improve with more than four AEDs.
disorders, complete seizure freedom on dietary treatment seems to be a hallmark of the disease. Acknowledgment
4. Discussion In this study, our hypothesis that children with undiagnosed GLUT1DS could be found among those who had responded well (N 50% seizure reduction) to KD or MAD was not supported. However, when comparing the clinical phenotypes between those with known GLUT1-DS and those who had responded well to KD or MAD, there were considerable clinical differences. One evident difference was that only three out of the 33 patients became completely seizure-free on the KD and MAD diets. These clinical differences might give important clues on how to identify patients with GLUT1-DS in the future. The patients with GLUT1-DS in this cohort are not severely mentally retarded; they have mostly absences with or without myoclonic jerks, the majority have paroxysmal exercise-induced dyskinesias, most of them are seizure-free on dietary treatment, and most of them have normal EEG and cerebral MRI. These characteristics are in contrast to what we observed in the other patients responding well to dietary treatment. When we started treating patients with KD in 2005, most of them had PEG (peritoneal enteral gastrostomy), which we assumed was necessary for good compliance. The majority of the patients treated with KD had several physical disabilities, had severe mental retardation, had seizures that showed a considerable diversity, and often had pronounced pathology on MRI and EEG. Later on, we have also treated cognitively normal patients, and these were most often treated with the MAD. The patients in the MAD group had clinical features more similar to the patients with GLUT1-DS, but only one became completely seizure-free. Additionally, paroxysmal exercise-induced dyskinesias were not reported in the medical records of any of the patients treated with MAD and KD. Another interesting difference was the occurrence of the two epileptic syndromes frequently seen in GLUT1-DS, EOAE, and MAE [8,19]. These syndromes were less frequent among patients treated with KD and MAD than among patients with known GLUT1-DS (Table 1). As a negative genetic test does not exclude GLUT1-DS in all patients and since neither standardized lumbar puncture with measurement of CSF to serum glucose ratio nor glucose uptake tests have been performed in all our cases, we cannot exclude the possibility that we might have overlooked some mutation-negative cases. In conclusion, our study illustrates the known dramatic effect of dietary treatment on seizure frequency in patients with GLUT1-DS. Furthermore, the clear difference in effect in patients with GLUT1-DS versus patients with epilepsy with other etiologies shows that seizure freedom is an important clue in the diagnosis of GLUT1-DS, while seizure reduction of N50% is too unspecific. As many clinicians are still not familiar with the disorder, a diagnostic delay of more than ten years has been reported [18]. Knowing that the syndrome is treatable if diagnosed early makes it particularly important to be aware of the most common symptoms. In addition to difficult-to-treat epilepsy, increasing cognitive problems with age, and exercise-induced movement
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