Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome

Abstract

The ketogenic diet (KD), established to treat intractable childhood epilepsy, has emerged as the principal treatment of GLUT1 deficiency syndrome (OMIM 606777). This defect of glucose transport into the brain results in hypoglycorrhachia causing epilepsy, developmental delay, and a complex motor disorder in early childhood. Ketones provided by a high-fat, low-carbohydrate diet serve as an alternative fuel to the brain. Glucose, lactate, lipids, and ketones in blood and cerebrospinal fluid were investigated in five GLUT1-deficient patients before and on the KD. Hypoglycorrhachia was detected in the non-ketotic and ketotic state. In ketosis, lactate concentrations in the cerebrospinal fluid increased moderately. The CSF/blood ratio for acetoacetate was higher compared to β-hydroxybutyrate. Free fatty acids did not enter the brain in significant amounts. Blood concentrations of essential fatty acids determined in 18 GLUT1-deficient patients on the KD were sufficient in all age groups. The effects of the KD in GLUT1 deficiency syndrome, particularly the course of blood lipids, are discussed in an illustrative case. In this syndrome, the KD effectively restores brain energy metabolism. Ketosis does not influence impaired GLUT1-mediated glucose transport into brain: hypoglycorrhachia, the biochemical hallmark of the disease, can be identified in GLUT1-deficient patients on a KD. The effects of ketosis on the concentrations of glucose, lactate, ketones, and fatty acids in blood and cerebrospinal fluid in this entity are discussed in view of previous data on ketosis in man.

Introduction

The ketogenic diet (KD) has been used for decades to treat intractable childhood epilepsy [1]. It is a high-fat, low-carbohydrate, adequate-protein diet that mimicks the physiological state of fasting. During fasts, body fat stores are mobilized and ketones, namely β-hydroxybutyrate (OHB) and acetoacetate (AcAC), are generated almost exclusively in the liver. In most tissues ketones replace glucose to meet energy demands, particularly in brain. The KD provides dietary instead of body fat for ketone production, thus maintaining an anabolic nutritional state in a metabolic situation of fasting.

In intractable childhood epilepsy, the diet's effectiveness for seizure control in children with difficult-to-treat epilepsy has been confirmed in several independent studies [1], [2], [3]. Hypotheses on the anticonvulsive mechanisms of the KD include changes in (a) cerebral energy metabolism, (b) cell properties decreasing excitability, (c) neurotransmitter function and transmission, (d) circulating factors acting as neuromodulators, and (e) brain extracellular milieu (for review see [4]). In addition, ketones appear to have direct anticonvulsant effects in vivo [5], and polyunsaturated fatty acids have recently been discussed as potential mechanisms of seizure protection achieved with the KD [6].

The KD has now emerged as the treatment of choice for the only currently known transport defect at the blood–brain barrier, the glucose transporter 1 deficiency syndrome (GLUT1-DS, OMIM 606777). In this entity, glucose transport across the blood–brain barrier and into brain cells is significantly impaired. Consequently, low glucose concentration in CSF termed hypoglycorrhachia is indicative of this disease. As a result of brain energy failure, the patients usually present in early childhood with seizures unresponsive to anticonvulsants, followed by developmental delay and a complex motor disorder with spastic, ataxic, and dystonic elements (for reviews, see [7], [8]). Severe cases develop secondary microcephaly without structural brain abnormalities, but recently characteristic local changes of brain metabolism in the mesial temporal regions, thalami, and basal ganglia have been reported in this entity [9]. Heterozygous autosomal dominant and de novo mutations in the GLUT1 gene have been identified as the cause of the disease in the majority of patients [10], [11], [12]. The anticonvulsive mechanism of the KD in GLUT1 DS is compelling: in hypoglycorrhachia the KD maintains an anabolic state providing ketones that serve as an alternative fuel to the brain (Fig. 1) [13]. The vast majority of patients become seizure-free within days on the KD and show general clinical improvement.

Since the first description of GLUT1 DS in 1991 [14], a lot of insights into underlying disease mechanisms have been gained [7], [15], [16], [17], [18], [19], [20]. However, the effect of cerebral ketone utilization on the impaired GLUT1-mediated glucose transport remained unclear, in particular, one of the remaining questions was if a diagnostic lumbar puncture could confirm hypoglycorrhachia in suspected patients already started on a KD. We therefore investigated blood and CSF parameters in the non-ketotic and ketotic state in five patients with confirmed GLUT1 DS. As essential fatty acids are crucial for brain development, we determined the unsaturated plasma fatty acid profile in 18 patients on the KD. Finally, as a high-fat diet is considered a risk factor for atherosclerosis, we analysed the lipid profile of the illustrative case on the KD over 41 months.