Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome
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.
Section snippets
Illustrative case (patient #1)
This 8 year old girl is the second child of consanguineous Turkish parents. The first child was stillborn, a younger brother is unaffected. She was born at term following an uncomplicated pregnancy, delivery, and neonatal period. At the age of 3 months she presented with peculiar eye-movements, staring spells occasionally accompanied by cyanosis, and brief generalized cloni of arms and legs. She was started on phenobarbital and later valproate without sufficient seizure control. Within the
The lipid profile
In the illustrative case (patient #1) the lipid profile was maintained over a period of 41 months on the KD (Fig. 2). In summary, lipid parameters showed a sharp increase after the initiation of the KD to be followed by a notable decrease and a tendency to decline. The pre-diet total serum cholesterol of 150 mg/dl increased to 163 mg/dl with the introduction of the KD, then decreased and remained stable around 118–138 mg/dl during follow-up. Likewise, pre-diet triglycerides of 125 mg/dl increased
Discussion
Recent years have seen an increasing interest in the KD [13], [21]. Antiepileptic mechanisms of the diet are being studied in prospective trials [2] and in animal models of epilepsy [22]. In this regard, it is of particular interest that GLUT1 DS, a metabolic epilepsy syndrome caused by impaired glucose transport into brain, responds to the very mechanism of fasting: providing ketones as an alternative fuel to maintain brain energy metabolism (Fig. 1). In fact the benefit of the KD in patients
Acknowledgements
The authors thank the patients, families, and physicians (A. Renneberg, Bremerhaven; F. Heinen and D. Reinhardt, Munich) for their continued participation in ongoing clinical studies of the GLUT1 deficiency syndrome. We also appreciate the input and GLUT1 diagnostic workup by our collegues in the laboratory. Finally, we are grateful to B. Leiendecker for her skillful assistance with the manuscript.
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2020, Journal of the Neurological SciencesCitation Excerpt :The treatment currently recommended for this syndrome is KET [4], although gene therapy, in the near future, might be an option for SLC2A1-positive patients [39]. KET are a high-fat and low-carbohydrate diet which produces ketone bodies that can cross the blood–brain barrier via monocarboxylate transporter 1 and serve as an alternative energy source for brain metabolism [17,18]. Thus, to prevent a chronic glucose deficiency in the brain, KET should be started as soon as Glut1DS is diagnosed [16,18,40].