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GLUT1 deficiency syndrome in clinical practice
Epilepsy Research (2012) 100, 272—277
journal homepage: www.elsevier.com/locate/epilepsyres
GLUT1 deficiency syndrome in clinical practice Joerg Klepper ∗ Childrens’ Hospital Aschaffenburg, Am Hasenkopf, D-63739 Aschaffenburg, Germany Received 6 January 2011; accepted 6 February 2011 Available online 5 March 2011
KEYWORDS GLUT1; GLUT1 deficiency syndrome; Intractable epilepsy; Ketogenic diet; SLC2A1; CSF glucose
Summary GLUT1 deficiency syndrome (GLUT1DS) is caused by impaired glucose transport into brain and is effectively treated by means of a ketogenic diet. In clinical practice the diagnosis of GLUT1DS often is challenging due to the increasing complexity of symptoms, diagnostic cut-offs for hypoglycorrhachia and genetic heterogeneity. In terms of treatment alternative ketogenic diets and their long-term side effects as well as novel compounds such as alpha-lipoic acid and triheptanoin have raised a variety of issues. The current diagnostic and therapeutic approach to GLUT1DS is discussed in this review in view of these recent developments. © 2011 Published by Elsevier B.V.
Introduction In 1991 GLUT1 deficiency syndrome (GLUTDS) was first described as an early-onset childhood epileptic encephalopathy caused by impaired glucose transport across the blood—brain barrier and into brain cells (De Vivo et al., 1991). Defects in the facilitated glucose transporter GLUT1 resulted in low CSF glucose levels termed hypoglycorrhachia. The majority of patients carry mutations in the SLC2A1 gene encoding the GLUT1 transporter. To date close to 200 patients have been identified worldwide (Klepper and Leiendecker, 2007; Rotstein and De Vivo, 2010). The classical phenotype of an early-onset epileptic encephalopathy rapidly expanded. To date the complex clinical pheno-
Abbreviations: GLUT1DS, GLUT1 deficiency syndrome; PED, paroxysmal exercise-induced dystonia; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography; MADm, odified Atkins Diet. ∗ Corresponding author. Tel.: +49 6021 32 3601/3600; fax: +49 6021 32 3699. E-mail address: [email protected] 0920-1211/$ — see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.eplepsyres.2011.02.007
type includes an epileptic encephalopathy with complex movement disorders in variable combinations, paroxysmal events, specific seizure types, and adult manifestations. The low glucose concentration in the cerebrospinal fluid (CSF) termed hypoglycorrhachia represents the biochemical hallmark of the disease and thus the diagnostic gold standard. This gold standard has been challenged by an increasing number of clinical subtypes with moderate if all hypoglycorrhachia who clinically and genetically clearly carry a definite diagnosis of GLUT1DS. Also, the spectrum of SLC2A1-mutations has rapidly expanded with several hot spots arising (Klepper and Leiendecker, 2007; Leen et al., 2010). However, patients sharing identical mutations often do not have identical clinical manifestations indicating that there are additional mechanisms such as modifying genes and proteins that alter phenotype and potentially contribute to the pathophysiology of this complex entity (Nickels and Wirrell, 2010). Within the setting of an increasing complexity of symptoms, mutations, and therapeutic regimens, diagnosing and treating GLUT1DS has become a challenge. Here we outline the clinical practice of GLUT1DS in view of the current literature.
GLUT1 deficiency syndrome in clinical practice
Suspecting GLUT1DS There is a classical manifestation of GLUT1DS: intractable epilepsy within the first six months of life followed by global developmental delay and a complex movement disorder (Klepper and Leiendecker, 2007; Leen et al., 2010). Symptoms may increase on fasting and improve on carbohydrate intake reflecting the cerebral energy deficit — in fact an adult patient was served honey at bedside in the morning by his wife to improve his alertness and neurological functioning (Brockmann et al., 2001). Seizures are of various types and often not controlled by anticonvulsant medication (Klepper et al., 2005). The past 20 years have shown an increasingly complex clinical presentation with several variants to the classical presentation outlined above. Atypical variants may present with choreoathetosis (Friedman et al., 2006), paroxysmal events (Zorzi et al., 2008; Urbizu et al., 2010), without seizures (Joshi et al., 2008; Overweg-Plandsoen et al., 2003; Wang et al., 2005), with early-onset absence epilepsy (Mullen et al., 2010; Suls et al., 2008; Urbizu et al., 2010), alternating hemiplegia (Rotstein et al., 2009), as adults with GLUT1DS or paroxysmal exertion-induced dystonia (PED) (Weber et al., 2008; Suls et al., 2008; Schneider et al., 2009). Today this entity should be suspected in children of any age presenting with single features or a combination of: • any form of intractable epilepsy, in particular early onset absence epilepsy; • global developmental delay, particularly in speech; • complex movement disorders; • paroxysmal events triggered by exercise, exertion, or fasting. The diagnosis: If GLUT1DS is suspected, the essential diagnostic step is to perform a controlled lumbar puncture. Patients should fast for 4—6 h to achieve a glucose steady state within the CSF compartment. The diagnosis of GLUT1DS by means of a lumbar puncture is confirmed if: CSF glucose concentration is < 2.2 mmol/l (<40 mg/dl) (Rotstein and De Vivo, 2010) (exclude prolonged seizures/status epilepticus or hypoglycemia) concentrations of CSF cells, protein, and CSF lactate are normal (exclude CSF infection). CSF lactate is never elevated in GLUT1DS! (Klepper and Leiendecker, 2007; Leen et al., 2010) The ratio of CSF glucose vs. blood glucose concentration can be an additional biomarker and should be <0.45. Blood glucose should be determined immediately before the lumbar puncture to avoid stress-related hyperglycemia (Klepper and Leiendecker, 2007) (see Fig. 1). Of note: • In patients on a ketogenic diet suspected with GLUT1DS a lumbar puncture is still diagnostic and will show hypoglycorrhachia (Klepper et al., 2004). • CSF samples taken from ventriculo-peritoneal shunt systems often show significant hypoglycorrhachia in an otherwise healthy patient. This is presumably an artefact
273 due to CSF stasis in the shunt system and should not be used to diagnose GLUT1DS (Klepper, personal communications). There has been increasing controversy about evaluating CSF glucose levels (De Vivo and Wang, 2008; Nickels and Wirrell, 2010; Rotstein and De Vivo, 2010). When unsure of the diagnosis, consider to repeat the lumbar puncture in a controlled setting as outlined above. In a comprehensive review of 84 patients we determined a mean CSF glucose of <1.7 ± 0.3 mmol/l (range 0.9—2.7 mmol/l). The CSF vs. blood glucose ratio was <0.35 ± 0.07 (range 0.19—0.49) (Klepper and Leiendecker, 2007). Relying on hypoglycorrhachia alone might be unhelpful for a definite diagnosis in individual cases. In mild variants of GLUT1DS, early-onset absence epilepsy, and paroxysmal exertion-induced dystonia the diagnosis might be missed — even absent hypoglycorrhachia has been reported (Mullen et al., 2010). This carries the risk that some patients might even remain undiagnosed and untreated. Consequently, the molecular analysis of the SLC2A1 gene has become the alternative gold standard for the diagnosis of GLUT1DS. Approximately 70—80% of patients carry SLC2A1 mutations (Klepper and Leiendecker, 2007; Wang et al., 2000). Genetic testing is commercially available at several centers worldwide. It should include PCR sequencing of all 10 exons, splice sites, and the promoter region (Leen et al., 2010; Seidner et al., 1998; Wang et al., 2000). If negative, deletions/duplications within the SLC2A1 gene can be detected by multiplex ligation-dependent probe amplification (Leen et al., 2010) or by SNP oligonucleotide microarray analysis (Levy et al., 2010). In SLC2A1-negative patients the diagnosis of GLUT1DS can only be considered affirmative if definite hypoglycorrhachia has been shown. This subset of patients is particularly interesting as they might carry defects in GLUT1 assembly, threedimensional GLUT1-folding, GLUT1-trafficking to the cell membrane, or GLUT1 activation (Klepper and Leiendecker, 2007). In SLC2A1-negative patients without clear hypoglycorrhachia it seems adequate to suspect GLUT1DS and initiate a ketogenic diet — an immediate and response to the diet will support the diagnosis. If ineffective, the diet can be discontinued within four to six weeks. EEG recordings in the fasting and the postprandial state can helpful diagnostic tools. If the fasting EEG is abnormal, a postprandial EEG might show improvement of EEG abnormalities indicating reversible brain energy impairment caused by the GLUT1 defect (Leary et al., 2003; von Moers et al., 2002). Cerebral magnetic resonance imaging (MRI) is unhelpful for the diagnosis. Positron emission tomography (PET) may show a characteristic metabolic footprint of GLUT1DS (Pascual et al., 2002) but is not readily available at many centers. Sedation, radiation exposure, and limited reference values in young children represent further limitations of this method. Glucose uptake studies into erythrocytes of suspected patients represent another reliable laboratory standard for the diagnosis of GLUT1DS (Klepper et al., 1999). However, these studies are not commercially available and they are demanding in terms of protocol, time, sample size and sample quality. False negative results in patients carrying pathogenic SLC2A1 mutations have been described (Fujii et al., in press).
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J. Klepper
Figure 1 A practical approach to GLUT1DS. On suspicion, a fasting lumbar puncture (LP) and the genetic analysis of the SLC2A1 gene should be performed applying polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification (MLPA), or SNP oligonucleotide microarray analysis (SNP). In SLC2A1-negative patients definite hypoglycorrhachia in the LP is essential for diagnosis of GLUT1DS. In addition, glucose uptake studies into erythrocytes are available on a research basis only. If GLUT1DS is diagnosed, a ketogenic diet (4:1 or 3:1 fat:carbohydrate and protein), MAD modified Atkins Diet; LGID low-glycemic index diet) should be introduced according to age (indicated as bars).
Genetics: To date, SLC2A1 (OMIM 138140) is the only gene linked to GLUT1DS (OMIM 606777). Several hot spots within the SLC2A1 gene have been identified. Transmission may be sporadic, autosomal dominant (Brockmann et al., 2001; Klepper et al., 2001), or autosomal recessive (Klepper et al., 2009). Generally patients with missense mutations often present with moderate to mild symptoms, but no clear-cut phenotype—genotype correlations have been established. Interestingly, patients sharing the same mutation present often present with remarkable different phenotypes (Klepper and Leiendecker, 2007; Leen et al., 2010) indicating that the pathogenetic mechanisms in this entity are complex. GLUT1DS may also be a part of a genetic syndrome as shown in microdeletion syndromes involving the SLC2A1 gene (Aktas et al., 2010; Vermeer et al., 2007). Treatment: The ketogenic diet remains the therapy of choice for GLUT1DS. It mimicks the metabolic state of fasting but maintains ketosis by the utilization of nutritional fat rather than body fat. In the setting of hypoglycorrhachia ketones serve as an alternative fuel to the brain and effectively reverse the cerebral ‘‘energy crisis’’. The response to a classical 4:1 or 3:1 (fat:carbohydrate and protein) ketogenic diet in most patients will be impressive
with immediate seizure control and improvement motor and cognitive function (Klepper and Leiendecker, 2007; Klepper et al., 2005; Leen et al., 2010). Initiating and maintaining the ketogenic diet in GLUT1DS does not substantially differ from the diet used for treating intractable childhood epilepsy. Support by a team of pediatrician and dietician is essential as are supplements — for details on initiating and maintaining a ketogenic diet see (Kossoff et al., 2009; Neal et al., 2009). Recently novel ketogenic diets for the treatment of intractable childhood epilepsy have been developed. The modified Atkins Diet (MAD) represents restricts carbohydrates to 10 g/day (15 g/day in adults) while encouraging high fat foods (Kossoff and Dorward, 2008). It is similar in fat composition to a 0.9:1 ketogenic ratio (fat:carbohydrate and protein) diet, with approximately 65% of the calories from fat sources. In GLUT1DS MAD has been used successfully (Ito et al., 2008). The low glycemic index diet liberalizes the extreme carbohydrate restriction of the KD but restricts the type of carbohydratecontaining foods to those that produce relatively small changes in blood glucose (Pfeifer et al., 2008). This diet provides even less ketones than the MAD and has not been applied in GLUT1DS. Deciding which diet to use we favour an individual, pragmatic approach in order to maintain com-
GLUT1 deficiency syndrome in clinical practice pliance in the affected children and families. In general a 3:1 diet is sufficient for adequate ketosis and seizures control (personal communications) — in infants it is certainly recommended as a 4:1 diet will not provide adequate amounts of protein for growth. In schoolchildren and adolescents with difficulties maintaining a classical ketogenic diet the MAD offers a good alternative. Whether adults with PED or classical GLUT1DS should be started on a ketogenic diet currently remains unclear. Adults achieve adequate ketosis on a classical ketogenic diet but find it extremely difficult to maintain — again alternative ketogenic diets might be beneficial and practical (Kossoff et al., 2008). Although suggestive, it remains to be proven that a higher ketogenic ratio will be more effective in treating GLUT1DS. Adverse effects of the ketogenic diet resemble those observed in children treated for intractable epilepsy (Vining, 2008). However, the ketogenic diet in GLUT1DS should be used until adolescence to meet the increased energy demand of the developing brain. Consequently, long-term effects of the diet such as growth impairment and atherosclerosis are of more concern in patients with GLUT1DS and should be carefully monitored.
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Outcome and perspectives Twenty years of experience have shown that GLUT1DS is a complex clinical entity encompassing various types of epilepsy, movement abnormalities, continuous and paroxysmal events, and intellectual impairment that may be highly variable. All patients will become ambulatory and acquire language with general improvement at their individual pace — GLUT1DS is never degenerative. The few adult patients identified within autosomal-dominant pedigrees or with PED also apparently follow a non-progressive course. The more it is essential that this entity should be diagnosed as early as possible as it responds very effectively to ketogenic diet(s). A controlled lumbar puncture, the analysis of the SLC2A1 gene, or the glucose uptake assay into erythrocytes can confirm the diagnosis — relying on one method only carries the risk of false negative results, especially in the mild subtypes and in manifestations as early-onset absence epilepsy or PED. Remaining questions are the underlying pathogenic mechanisms of different phenotypes and in SLC2A1-negative patients and the potential of novel supplemental therapies. Ongoing research in novel compounds, the GLUT1DS animal models available, and the increase in patient numbers and international awareness of this entity are encouraging means to this end.
Alternative compounds for treatment of GLUT1DS Recently two compounds, alpha lipoic acid and triheptanoin are discussed as a potential supplementary treatment of GLUT1DS. Alpha lipoic acid is an antioxidant that serves as a co-enzyme in energy metabolism. It neutralizes free radicals, improves cellular glucose uptake by stimulating the insulin signal cascade, reduces inflammation, and detains metals. It is an approved drug for treating diabetic neuropathy and has also been used ‘‘off label’’ in several neurological conditions such as multiple sclerosis, Parkinson’s Disease, Alzheimer’s Disease, and Diabetes mellitus type II (Shay et al., 2009). In GLUT1DS alpha lipoic acid supplementation was recommended based on the observation that it improves glucose transport in cultured muscle cells via mobilization of the GLUT4 transporter from intracellular pools (De Vivo et al., 2002). As yet there is no convincing clinical or experimental evidence that this supplementation will have similar effects on the GLUT1 transporter at the blood—brain barrier. In the few patients applied the appropriate dose taken by mouth remained experimental and the response to alpha lipoic acid had been modest at best (personal communications). Triheptanoin is a triglyceride that has been used as an anaplerotic substrate in humans to treat inherited metabolic diseases, such as Pyruvate carboxylase deficiency and Carnitine palmitoyltransferase II deficiency (Roe and Mochel, 2006). Since it is composed of odd-carbon fatty acids, it can produce ketone bodies with five carbon atoms (betaketopentanoate and beta-hydroxypentanoate) that easily cross the blood—brain barrier and may enhance the effect of the regular ketone bodies as an alternative fuel to the brain. Although a promising theory, there is currently no clinical data that supports the use of this compound in GLUT1DS. Recently a case report described an excellent response to acetazolamide in a patient with PED (Anheim et al., 2010).
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journal homepage: www.elsevier.com/locate/epilepsyres
GLUT1 deficiency syndrome in clinical practice Joerg Klepper ∗ Childrens’ Hospital Aschaffenburg, Am Hasenkopf, D-63739 Aschaffenburg, Germany Received 6 January 2011; accepted 6 February 2011 Available online 5 March 2011
KEYWORDS GLUT1; GLUT1 deficiency syndrome; Intractable epilepsy; Ketogenic diet; SLC2A1; CSF glucose
Summary GLUT1 deficiency syndrome (GLUT1DS) is caused by impaired glucose transport into brain and is effectively treated by means of a ketogenic diet. In clinical practice the diagnosis of GLUT1DS often is challenging due to the increasing complexity of symptoms, diagnostic cut-offs for hypoglycorrhachia and genetic heterogeneity. In terms of treatment alternative ketogenic diets and their long-term side effects as well as novel compounds such as alpha-lipoic acid and triheptanoin have raised a variety of issues. The current diagnostic and therapeutic approach to GLUT1DS is discussed in this review in view of these recent developments. © 2011 Published by Elsevier B.V.
Introduction In 1991 GLUT1 deficiency syndrome (GLUTDS) was first described as an early-onset childhood epileptic encephalopathy caused by impaired glucose transport across the blood—brain barrier and into brain cells (De Vivo et al., 1991). Defects in the facilitated glucose transporter GLUT1 resulted in low CSF glucose levels termed hypoglycorrhachia. The majority of patients carry mutations in the SLC2A1 gene encoding the GLUT1 transporter. To date close to 200 patients have been identified worldwide (Klepper and Leiendecker, 2007; Rotstein and De Vivo, 2010). The classical phenotype of an early-onset epileptic encephalopathy rapidly expanded. To date the complex clinical pheno-
Abbreviations: GLUT1DS, GLUT1 deficiency syndrome; PED, paroxysmal exercise-induced dystonia; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography; MADm, odified Atkins Diet. ∗ Corresponding author. Tel.: +49 6021 32 3601/3600; fax: +49 6021 32 3699. E-mail address: [email protected] 0920-1211/$ — see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.eplepsyres.2011.02.007
type includes an epileptic encephalopathy with complex movement disorders in variable combinations, paroxysmal events, specific seizure types, and adult manifestations. The low glucose concentration in the cerebrospinal fluid (CSF) termed hypoglycorrhachia represents the biochemical hallmark of the disease and thus the diagnostic gold standard. This gold standard has been challenged by an increasing number of clinical subtypes with moderate if all hypoglycorrhachia who clinically and genetically clearly carry a definite diagnosis of GLUT1DS. Also, the spectrum of SLC2A1-mutations has rapidly expanded with several hot spots arising (Klepper and Leiendecker, 2007; Leen et al., 2010). However, patients sharing identical mutations often do not have identical clinical manifestations indicating that there are additional mechanisms such as modifying genes and proteins that alter phenotype and potentially contribute to the pathophysiology of this complex entity (Nickels and Wirrell, 2010). Within the setting of an increasing complexity of symptoms, mutations, and therapeutic regimens, diagnosing and treating GLUT1DS has become a challenge. Here we outline the clinical practice of GLUT1DS in view of the current literature.
GLUT1 deficiency syndrome in clinical practice
Suspecting GLUT1DS There is a classical manifestation of GLUT1DS: intractable epilepsy within the first six months of life followed by global developmental delay and a complex movement disorder (Klepper and Leiendecker, 2007; Leen et al., 2010). Symptoms may increase on fasting and improve on carbohydrate intake reflecting the cerebral energy deficit — in fact an adult patient was served honey at bedside in the morning by his wife to improve his alertness and neurological functioning (Brockmann et al., 2001). Seizures are of various types and often not controlled by anticonvulsant medication (Klepper et al., 2005). The past 20 years have shown an increasingly complex clinical presentation with several variants to the classical presentation outlined above. Atypical variants may present with choreoathetosis (Friedman et al., 2006), paroxysmal events (Zorzi et al., 2008; Urbizu et al., 2010), without seizures (Joshi et al., 2008; Overweg-Plandsoen et al., 2003; Wang et al., 2005), with early-onset absence epilepsy (Mullen et al., 2010; Suls et al., 2008; Urbizu et al., 2010), alternating hemiplegia (Rotstein et al., 2009), as adults with GLUT1DS or paroxysmal exertion-induced dystonia (PED) (Weber et al., 2008; Suls et al., 2008; Schneider et al., 2009). Today this entity should be suspected in children of any age presenting with single features or a combination of: • any form of intractable epilepsy, in particular early onset absence epilepsy; • global developmental delay, particularly in speech; • complex movement disorders; • paroxysmal events triggered by exercise, exertion, or fasting. The diagnosis: If GLUT1DS is suspected, the essential diagnostic step is to perform a controlled lumbar puncture. Patients should fast for 4—6 h to achieve a glucose steady state within the CSF compartment. The diagnosis of GLUT1DS by means of a lumbar puncture is confirmed if: CSF glucose concentration is < 2.2 mmol/l (<40 mg/dl) (Rotstein and De Vivo, 2010) (exclude prolonged seizures/status epilepticus or hypoglycemia) concentrations of CSF cells, protein, and CSF lactate are normal (exclude CSF infection). CSF lactate is never elevated in GLUT1DS! (Klepper and Leiendecker, 2007; Leen et al., 2010) The ratio of CSF glucose vs. blood glucose concentration can be an additional biomarker and should be <0.45. Blood glucose should be determined immediately before the lumbar puncture to avoid stress-related hyperglycemia (Klepper and Leiendecker, 2007) (see Fig. 1). Of note: • In patients on a ketogenic diet suspected with GLUT1DS a lumbar puncture is still diagnostic and will show hypoglycorrhachia (Klepper et al., 2004). • CSF samples taken from ventriculo-peritoneal shunt systems often show significant hypoglycorrhachia in an otherwise healthy patient. This is presumably an artefact
273 due to CSF stasis in the shunt system and should not be used to diagnose GLUT1DS (Klepper, personal communications). There has been increasing controversy about evaluating CSF glucose levels (De Vivo and Wang, 2008; Nickels and Wirrell, 2010; Rotstein and De Vivo, 2010). When unsure of the diagnosis, consider to repeat the lumbar puncture in a controlled setting as outlined above. In a comprehensive review of 84 patients we determined a mean CSF glucose of <1.7 ± 0.3 mmol/l (range 0.9—2.7 mmol/l). The CSF vs. blood glucose ratio was <0.35 ± 0.07 (range 0.19—0.49) (Klepper and Leiendecker, 2007). Relying on hypoglycorrhachia alone might be unhelpful for a definite diagnosis in individual cases. In mild variants of GLUT1DS, early-onset absence epilepsy, and paroxysmal exertion-induced dystonia the diagnosis might be missed — even absent hypoglycorrhachia has been reported (Mullen et al., 2010). This carries the risk that some patients might even remain undiagnosed and untreated. Consequently, the molecular analysis of the SLC2A1 gene has become the alternative gold standard for the diagnosis of GLUT1DS. Approximately 70—80% of patients carry SLC2A1 mutations (Klepper and Leiendecker, 2007; Wang et al., 2000). Genetic testing is commercially available at several centers worldwide. It should include PCR sequencing of all 10 exons, splice sites, and the promoter region (Leen et al., 2010; Seidner et al., 1998; Wang et al., 2000). If negative, deletions/duplications within the SLC2A1 gene can be detected by multiplex ligation-dependent probe amplification (Leen et al., 2010) or by SNP oligonucleotide microarray analysis (Levy et al., 2010). In SLC2A1-negative patients the diagnosis of GLUT1DS can only be considered affirmative if definite hypoglycorrhachia has been shown. This subset of patients is particularly interesting as they might carry defects in GLUT1 assembly, threedimensional GLUT1-folding, GLUT1-trafficking to the cell membrane, or GLUT1 activation (Klepper and Leiendecker, 2007). In SLC2A1-negative patients without clear hypoglycorrhachia it seems adequate to suspect GLUT1DS and initiate a ketogenic diet — an immediate and response to the diet will support the diagnosis. If ineffective, the diet can be discontinued within four to six weeks. EEG recordings in the fasting and the postprandial state can helpful diagnostic tools. If the fasting EEG is abnormal, a postprandial EEG might show improvement of EEG abnormalities indicating reversible brain energy impairment caused by the GLUT1 defect (Leary et al., 2003; von Moers et al., 2002). Cerebral magnetic resonance imaging (MRI) is unhelpful for the diagnosis. Positron emission tomography (PET) may show a characteristic metabolic footprint of GLUT1DS (Pascual et al., 2002) but is not readily available at many centers. Sedation, radiation exposure, and limited reference values in young children represent further limitations of this method. Glucose uptake studies into erythrocytes of suspected patients represent another reliable laboratory standard for the diagnosis of GLUT1DS (Klepper et al., 1999). However, these studies are not commercially available and they are demanding in terms of protocol, time, sample size and sample quality. False negative results in patients carrying pathogenic SLC2A1 mutations have been described (Fujii et al., in press).
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Figure 1 A practical approach to GLUT1DS. On suspicion, a fasting lumbar puncture (LP) and the genetic analysis of the SLC2A1 gene should be performed applying polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification (MLPA), or SNP oligonucleotide microarray analysis (SNP). In SLC2A1-negative patients definite hypoglycorrhachia in the LP is essential for diagnosis of GLUT1DS. In addition, glucose uptake studies into erythrocytes are available on a research basis only. If GLUT1DS is diagnosed, a ketogenic diet (4:1 or 3:1 fat:carbohydrate and protein), MAD modified Atkins Diet; LGID low-glycemic index diet) should be introduced according to age (indicated as bars).
Genetics: To date, SLC2A1 (OMIM 138140) is the only gene linked to GLUT1DS (OMIM 606777). Several hot spots within the SLC2A1 gene have been identified. Transmission may be sporadic, autosomal dominant (Brockmann et al., 2001; Klepper et al., 2001), or autosomal recessive (Klepper et al., 2009). Generally patients with missense mutations often present with moderate to mild symptoms, but no clear-cut phenotype—genotype correlations have been established. Interestingly, patients sharing the same mutation present often present with remarkable different phenotypes (Klepper and Leiendecker, 2007; Leen et al., 2010) indicating that the pathogenetic mechanisms in this entity are complex. GLUT1DS may also be a part of a genetic syndrome as shown in microdeletion syndromes involving the SLC2A1 gene (Aktas et al., 2010; Vermeer et al., 2007). Treatment: The ketogenic diet remains the therapy of choice for GLUT1DS. It mimicks the metabolic state of fasting but maintains ketosis by the utilization of nutritional fat rather than body fat. In the setting of hypoglycorrhachia ketones serve as an alternative fuel to the brain and effectively reverse the cerebral ‘‘energy crisis’’. The response to a classical 4:1 or 3:1 (fat:carbohydrate and protein) ketogenic diet in most patients will be impressive
with immediate seizure control and improvement motor and cognitive function (Klepper and Leiendecker, 2007; Klepper et al., 2005; Leen et al., 2010). Initiating and maintaining the ketogenic diet in GLUT1DS does not substantially differ from the diet used for treating intractable childhood epilepsy. Support by a team of pediatrician and dietician is essential as are supplements — for details on initiating and maintaining a ketogenic diet see (Kossoff et al., 2009; Neal et al., 2009). Recently novel ketogenic diets for the treatment of intractable childhood epilepsy have been developed. The modified Atkins Diet (MAD) represents restricts carbohydrates to 10 g/day (15 g/day in adults) while encouraging high fat foods (Kossoff and Dorward, 2008). It is similar in fat composition to a 0.9:1 ketogenic ratio (fat:carbohydrate and protein) diet, with approximately 65% of the calories from fat sources. In GLUT1DS MAD has been used successfully (Ito et al., 2008). The low glycemic index diet liberalizes the extreme carbohydrate restriction of the KD but restricts the type of carbohydratecontaining foods to those that produce relatively small changes in blood glucose (Pfeifer et al., 2008). This diet provides even less ketones than the MAD and has not been applied in GLUT1DS. Deciding which diet to use we favour an individual, pragmatic approach in order to maintain com-
GLUT1 deficiency syndrome in clinical practice pliance in the affected children and families. In general a 3:1 diet is sufficient for adequate ketosis and seizures control (personal communications) — in infants it is certainly recommended as a 4:1 diet will not provide adequate amounts of protein for growth. In schoolchildren and adolescents with difficulties maintaining a classical ketogenic diet the MAD offers a good alternative. Whether adults with PED or classical GLUT1DS should be started on a ketogenic diet currently remains unclear. Adults achieve adequate ketosis on a classical ketogenic diet but find it extremely difficult to maintain — again alternative ketogenic diets might be beneficial and practical (Kossoff et al., 2008). Although suggestive, it remains to be proven that a higher ketogenic ratio will be more effective in treating GLUT1DS. Adverse effects of the ketogenic diet resemble those observed in children treated for intractable epilepsy (Vining, 2008). However, the ketogenic diet in GLUT1DS should be used until adolescence to meet the increased energy demand of the developing brain. Consequently, long-term effects of the diet such as growth impairment and atherosclerosis are of more concern in patients with GLUT1DS and should be carefully monitored.
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Outcome and perspectives Twenty years of experience have shown that GLUT1DS is a complex clinical entity encompassing various types of epilepsy, movement abnormalities, continuous and paroxysmal events, and intellectual impairment that may be highly variable. All patients will become ambulatory and acquire language with general improvement at their individual pace — GLUT1DS is never degenerative. The few adult patients identified within autosomal-dominant pedigrees or with PED also apparently follow a non-progressive course. The more it is essential that this entity should be diagnosed as early as possible as it responds very effectively to ketogenic diet(s). A controlled lumbar puncture, the analysis of the SLC2A1 gene, or the glucose uptake assay into erythrocytes can confirm the diagnosis — relying on one method only carries the risk of false negative results, especially in the mild subtypes and in manifestations as early-onset absence epilepsy or PED. Remaining questions are the underlying pathogenic mechanisms of different phenotypes and in SLC2A1-negative patients and the potential of novel supplemental therapies. Ongoing research in novel compounds, the GLUT1DS animal models available, and the increase in patient numbers and international awareness of this entity are encouraging means to this end.
Alternative compounds for treatment of GLUT1DS Recently two compounds, alpha lipoic acid and triheptanoin are discussed as a potential supplementary treatment of GLUT1DS. Alpha lipoic acid is an antioxidant that serves as a co-enzyme in energy metabolism. It neutralizes free radicals, improves cellular glucose uptake by stimulating the insulin signal cascade, reduces inflammation, and detains metals. It is an approved drug for treating diabetic neuropathy and has also been used ‘‘off label’’ in several neurological conditions such as multiple sclerosis, Parkinson’s Disease, Alzheimer’s Disease, and Diabetes mellitus type II (Shay et al., 2009). In GLUT1DS alpha lipoic acid supplementation was recommended based on the observation that it improves glucose transport in cultured muscle cells via mobilization of the GLUT4 transporter from intracellular pools (De Vivo et al., 2002). As yet there is no convincing clinical or experimental evidence that this supplementation will have similar effects on the GLUT1 transporter at the blood—brain barrier. In the few patients applied the appropriate dose taken by mouth remained experimental and the response to alpha lipoic acid had been modest at best (personal communications). Triheptanoin is a triglyceride that has been used as an anaplerotic substrate in humans to treat inherited metabolic diseases, such as Pyruvate carboxylase deficiency and Carnitine palmitoyltransferase II deficiency (Roe and Mochel, 2006). Since it is composed of odd-carbon fatty acids, it can produce ketone bodies with five carbon atoms (betaketopentanoate and beta-hydroxypentanoate) that easily cross the blood—brain barrier and may enhance the effect of the regular ketone bodies as an alternative fuel to the brain. Although a promising theory, there is currently no clinical data that supports the use of this compound in GLUT1DS. Recently a case report described an excellent response to acetazolamide in a patient with PED (Anheim et al., 2010).
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