Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet
Address correspondence to Joerg Klepper, P.D. Dr. Med., Department of Pediatrics and Pediatric Neurology, Klinikum Aschaffenburg, D-63739 Aschaffenburg, Germany. E-mail email@example.com
Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1DS, OMIM 606777) is caused by impaired glucose transport into brain mediated by GLUT1, the glucose transporter at the blood–brain barrier. The condition is diagnosed by hypoglycorrhachia, impaired glucose uptake into erythrocytes, and heterozygous mutations in the SLC2A1 gene (OMIM 138140, gene map locus 1p35-31.3). Patients present with early-onset epilepsy, developmental delay, and a complex movement disorder. The phenotype is highly variable and several atypical variants have been described. The ketogenic diet (KD) provides ketones as an alternative fuel to the brain. Calculation, administration, supplements, and adverse effects of the KD in GLUT1DS do not differ from patients treated for intractable childhood epilepsy. In GLUT1DS, the KD should be introduced early to meet the energy demands of the developing brain and should be maintained into puberty. Seizures are effectively controlled, but the effects on neurodevelopment and on the movement disorder are less impressive. The KD remains the treatment of choice for GLUT1DS, but recent insights into anticonvulsive diet mechanisms, animal models for GLUT1DS, and the development of alternative KDs provide new opportunities to improve the treatment of this condition.
GLUT1 and Brain Energy Metabolism
Glucose is the essential fuel for brain energy metabolism. In the resting state, adult brain can consume up to 25% of the total body glucose supply; in infants and children, the glucose demand can be up to 80% of whole-body glucose utilization (Cremer, 1982; Clarke & Sokoloff, 1994). The diffusion of this essential fuel across the blood–brain barrier is exclusively facilitated by the glucose transporter type 1 (GLUT1). This membrane-bound protein is encoded by the SLC2A1 gene (1p35-31.3) and contains 12 membrane-spanning domains with intracellularly-located amino- and carboxy-termini (Mueckler et al., 1985). In brain, GLUT1 interacts with a network of other specific GLUT1 isoforms mediating glucose transport into astrocytes and neurons. Glucose is consumed in energy metabolism, mostly for ion transport and the maintenance of ion gradients. Only a small fraction is used for biosynthetic processes (Cremer, 1982; Clarke & Sokoloff, 1994).
In the fasting state, brain glycogen storage is exhausted within minutes. Amino acids and fat cannot be utilized by the brain for energy production. To maintain function, the brain switches to ketones as an alternative fuel. Ketones are generated in the liver from fatty acid degradation and enter the brain via facilitated diffusion mediated by the MCT1 transporter. This mechanism is particularly effective in infants and young children with ketone extraction and utilization being three- to four-fold higher than in adults (Cremer, 1982; Clarke & Sokoloff, 1994).
GLUT1 Deficiency Syndrome (GLUT1DS, OMIM 606777)
GLUT1 deficiency syndrome (GLUT1DS) is a treatable epileptic encephalopathy caused by impaired glucose uptake at the blood–brain barrier and into brain cells. It can be diagnosed by low glucose concentrations in cerebrospinal fluid (CSF)—termed hypoglycorrhachia, impaired glucose uptake into erythrocytes, and mutations in the SLC2A1 gene. The majority of patients present with early-onset seizures, developmental delay, and a complex movement disorder. Several atypical presentations such as episodic choreiform movements, infants with reversible hypoglycorrhachia, adult GLUT1DS, and patients without epilepsy have been described (Klepper, 2007). Routine laboratory analyses and neuroimaging are not informative. Interictal fasting EEGs may improve following meals or the delivery of glucose. Mutational analysis has determined heterozygous, mostly de novo mutations in the promoter or the coding regions of the SLC2A1 gene. About 30% of patients do not carry mutations, suggesting alternative disease mechanisms (Klepper, 2007).
The Ketogenic Diet
The KD is a high-fat, carbohydrate-restricted diet that mimics the metabolic state of fasting. It relies on exogenous rather than body fat for ketone production, thus maintaining ketosis without weight loss. It has been used safely and effectively for decades in intractable childhood epilepsy (Freeman et al., 2007). Novel indications include disorders of brain energy metabolism such as pyruvate dehydrogenase deficiency and GLUT1DS. The classical KD as developed by the Johns Hopkins University uses long-chain triglycerides (LCT fats). It consists of 4 g of fat to every 1 g of carbohydrate and protein combined (4:1 ratio) with supplemental vitamins and minerals. Following hospital admission, ketosis is initiated by a 24- to 48-h fast. The traditional protocol also suggests fluid and caloric restriction. Patients and caretakers are trained how to calculate and apply the diet. Ketosis is monitored via urine dipsticks and patients are discharged within 5–8 days of admission (Vining et al., 1998). Currently, the spectrum of the KD has increased considerably and includes several alternative diets such as the medium-chain triglyceride (MCT) diet, the modified Atkins diet, or the low-glycemic index treatment (LGIT).
The Ketogenic Diet in GLUT1DS
Technically, treating GLUT1DS with a KD does not differ from treating intractable childhood epilepsy. The diet has to be carbohydrate-restricted, individually calculated, and supplemented with multivitamins and minerals. The pathophysiological concept in each disorder, however, is different. In intractable childhood epilepsy, it remains currently unclear how the diet works despite a much better understanding of anticonvulsant mechanisms (Bough & Rho, 2007). In GLUT1DS, the KD primarily provides an alternative fuel, though the anticonvulsant actions might add to KD's effectiveness in this disorder. For that reason, the KD should be started as early as possible whenever GLUT1DS is suspected. To date, in practically all patients with GLUT1DS the classical LCT diet with ratios of 4:1 and 3:1 has been used (Coman et al., 2006). There are two reports from Japan about the use of alternative KDs in GLUT1DS: a MCT diet (2:1 ratio) was successfully introduced in an 11 y/o patient (Yasushi et al., 2005), and Ito et al describe a 7 y/o boy responding to a modified Atkins diet (Ito et al., 2008).
In the vast majority of GLUT1DS patients, seizure control by the KD is imminent and efficient and anticonvulsant medication can be withdrawn (Klepper, 2007). Compliance is much better than in any other indication of the KD. In a small number of patients, however, add-on anticonvulsants are needed. In a recent report, seizure control was rapid and impressive in eight patients, but only four could be weaned off anticonvulsants completely (Coman et al., 2006). In another study, seizures persisted in 1/15 patients despite anticonvulsants and adequate ketosis (Klepper et al., 2005). GLUT1DS without epilepsy has been reported in seven patients (Klepper, 2007), highlighting the complexity of underlying disease mechanisms.
In GLUT1DS, there is a marked increase in alertness and activity in patients on the KD. Improvement of psychomotor impairment is reported throughout the literature, but is hard to verify as yet no follow-up studies of patients on the KD applying standardized psychological testing have been published, except for a single abstract reporting high phenotypic variability in cognition and behavior and improved socialization skills (Wang et al., 2001). It remains currently unclear if a 4:1 KD will provide a better cognitive outcome in GLUT1DS.
The different qualities of the complex movement disorder, for example, hypotonia, ataxia, and dystonia are also positively affected by the KD (Klepper, 2007). In line with these observations, a 10 y/o boy with atypical GLUT1DS and a prominent movement disorder also responded to a KD as demonstrated in a split-screen video (Friedman et al., 2005). Side effects of the KD in GLUT1DS are similar to those seen in children treated for intractable epilepsy (Ballaban-Gil et al., 1998). Renal stones can effectively be avoided by adequate fluid intake and alkalization of the urine. Abdominal discomfort and constipation often are temporary and easy to treat. Carnitine levels may be reduced responding to supplementation (Klepper et al., 2005). Growth impairment, dyslipidemia, and thus the atherogenic potential of the KD may represent long-term adverse effects and remain a concern. Rare complications of the KD such as bruising, cardiac complications, impaired neutrophil function, basal ganglia injury, or optic neuropathy (Klepper & Voit, 2002) have not been reported in GLUT1DS. The only death reported to date for GLUT1DS was a 9 y/o girl that developed a fulminant hemorrhagic pancreatitis while on a KD (Stewart et al., 2001).
In contrast to intractable childhood epilepsy, patients with GLUT1DS should continue the diet into adolescence to meet the increased energy demands of the developing brain. It remains unclear whether adults with GLUT1DS will benefit from a life-long KD—in the few adults identified within families carrying autosomal-dominant missense mutations, the disease appeared to be stable and epilepsy was not the predominant problem.
The KD has been used effectively in GLUT1DS since the very first description in 1991. It currently remains the treatment of choice for this entity. However, this success story is far from over. It is now understood that changes in ketone bodies, fatty acids, and limited glucose work in concert to stabilize synaptic function and increase the resistance to seizures (Bough & Rho, 2007). More important, the KD might exert neuroprotective effects. Chronic ketosis limits reactive oxygen species generation and boosts energy production. Polyunsaturated fatty acids induce the expression of neuronal uncoupling proteins and upregulate mitochondrial biogenesis. In vitro data in mitochondrial DNA-depleted human cells showed that ketones can distinguish between normal and respiratorily compromised cells causing an heteroplasmatic shift and increasing cell survival (Santra et al., 2004). In neurodegenerative diseases (Parkinson's disease, Alzheimer's disease) or disorders of brain energy metabolism (mitochondrial encephalopathies, GLUT1DS), neuroprotection by a KD might reduce disease severity. Ketones are also important for specific brain cells. Astrocytes, the major class of glial cells in the brain, play a vital role in cerebral glucose uptake. They are strategically located surrounding intraparenchymal blood capillaries and might provide neurons with ketone bodies (Guzman & Blazquez, 2001). As such, astrocyte ketogenesis might serve as a cytoprotective pathway, particularly in disorders of brain energy metabolism such as GLUT1DS.
It remains unclear if a rigorous KD is essential in GLUT1DS. Certainly, seizure control can be achieved by a 2:1 or 3:1 ketogenic ratio but the relationship between ketosis and neurodevelopmental outcome remains undetermined. Alternative KDs might also prove useful in GLUT1DS. A modified Atkins diet is well tolerated and provides effective seizure control in children with intractable epilepsy and in a Japanese patient with GLUT1DS (Ito et al., 2008). As the KD in GLUT1DS needs to be maintained well into adolescence, the modified Atkins diet might be particularly useful in older children to optimize compliance. Finally, four animal models of GLUT1DS have currently been described that might provide new insights in treating GLUT1DS with the KD (Klepper, 2007).
In summary, the KD currently remains the only and first-line treatment in GLUT1DS. Seizure control is immediate and complete in most patients; an effect on cognition and motor development is less prominent. Differences in KD treatment for intractable epilepsy include the mechanism of disease, the early use even in infancy, and the duration of the diet into adolescence. Future challenges will include the determination of the most efficient ratio and composition of the diet and treatment strategies in adult and atypical GLUT1DS. Of note, a very recent paper describes four families with paroxysmal exercise-induced dyskinesia (PED). The authors describe heterozygous mutations in the SCLNA1-gene and a favorable response to the KD (Weber et al., 2008). Defects in GLUT1-mediated glucose transport could thus represent a group of disorders incorporating several distinct clinical entities, expanding the use of the KD and offering novel challenges regarding disease mechanisms.
I am grateful for helpful discussions with numerous colleagues regarding GLUT1DS and the ketogenic diet. In particular, I thank Baerbel Leiendecker, dietician at Essen University Children's Hospital, Germany, for her dedication to our patients and her continuous support.
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Disclosure: The author declares no conflicts of interest.