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    • br Acknowledgements The authors are grateful

    2022-08-03


    Acknowledgements The authors are grateful for funding provided by the Health Research Council of New Zealand.
    Introduction Glucose is the most important energy carrier of the brain. Glucose transporter type 1 (Glut1) is located at the blood–brain barrier and assures the energy-independent, facilitative transport of glucose into the brain [1]. Twelve transmembrane segments of the protein and an intracellular N- and C-terminus (Fig. 1A) are forming the protein pore (Fig. 1B) [5]. The original name of Glut1 was HepG2/erythrocyte/brain transporter since it also expressed at the surface of red blood cells [6]. The protein is encoded by SLC2A1, a gene on chromosome 1p34.2 which contains 10 exons and spans 35 kb [2].
    The clinical phenotypes associated with Glut1 defects
    Phenotype–genotype correlations The reason for the broad clinical spectrum associated with SLC2A1 mutations is unclear. Special genetic features of mutations and their functional consequences are discussed as the main reasons, but they cannot explain all phenotypic variations.
    Diagnostics
    Therapy The ketogenic diet (KD) as a therapy for patients with epilepsy was proclaimed for the first time in the early twenties [36]. Ketogenic diet is defined as a high-fat and calorie-reduced diet which produces ketone bodies that bypass the Glut1 defect by diffusing across the blood–brain barrier facilitated by a monocarboxylic HAMI3379 transporter. Ketone bodies serve as an alternative energy source for brain metabolism. For the other forms of epilepsies, the anticonvulsant effect of ketone is still unclear but may reduce seizure activity significantly in pharmacoresistant epilepsies in up to 50% of cases [37], [38]. For patients with Glut1 defect, the KD is a precision medicine therapy and should be started early in the disease stage. We know from case reports that children respond very well to KD, which help in the prevention of mental retardation and in the restoration from mental decline [39]. In our own hands, patients with Glut1 deficiency benefit also from late onset KD in adulthood (unpublished observation). In classical KD, the serum ketones should be 3–4 mg/dl, but very often at that level, side effects such as diarrhea or fatigue occur and are intolerable. Especially for adult patients with Glut1, the classical KD is not compatible with daily life. In our hands, modified KD with lower ketone serum levels (e.g., 1–2 mg/dl) such as the Atkins diet can be better tolerated and is similarly effective (unpublished observation). For the future, gene therapy might be an option for patients with Glut1 defect [40].
    Conclusions Glucose transporter type 1 defect syndromes are rare but should be diagnosed early since a precision therapy via the KD is available and should be started as soon as possible. Characterizing history features are episodic seizures induced by fasting state or permanent voluntary movement. Laboratory diagnostics include CSF/serum glucose ratio, EEG, and SLC2A1 sequencing coding for Glut1.
    Introduction The primary source of energy for life is glucose. Glucose is the major energy for all mammalian cells. The human brain consumes approximately 25% of glucose supply however, it represents only about 2% of total body mass of an adult. Neurons need a continuous supply of glucose. Astrocytes produce lactate from anaerobic metabolism of glucose [1] and from glycogenolysis [2]. Lactate is another source of energy utilized by neuronal cells [3], [4]. Ketones can also be the source of energy for brain [5], [6]. In adult brain, the fatty acid transport, the source of ketones, across the blood-brain barrier (BBB) is extremely slow [7]. Therefore, fatty acids do not provide carbon to the Krebs cycle or the precursor for the lactate production [8] and continuous supply of glucose is required for mammalian brain function. In the case of heart, this organ consumes more energy than any other organ. The heart can utilize various metabolic substrates as a source of energy. The primary substrates are free fatty acids (FFAs), especially long-chain fatty acids (LCFA), and glucose. Glucose generates about 25%–30% of total energy [9]; therefore oxidation of FFAs is a major metabolic process for myocardial ATP production. In this way, a minimum of 60% of ATP is derived. During anoxic conditions, glucose is the predominant fuel for the heart to maintain ATP production by anaerobic glycolysis [45]. Considerably, lactate can be used in place of glucose if there is lack of exogenous supply, and during long-term starvation ketone bodies can be used [10]. As mentioned above, the source of energy for cardiac muscle depends on substrate availability.