GLUT1 Deficiency Syndrome, GLUT1DS

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Introduction to GLUT1 Deficiency Syndrome, GLUT1DS

GLUT1 deficiency syndrome-1 (GLUT1DS) is an autosomal dominant disorder where over 90% of cases represent the appearance of a new mutation, i.e. no prior familial involvement. GLUT1DS represents an epileptic encephalopathy whose symptoms manifest due to a lack of glucose transport across the blood-brain-barrier, BBB. Glucose is a critically important fuel for brain energy metabolism. At rest the adult brain can consume up to 25% of the total amount of glucose oxidized by the entire body. In infants and children, this demand for blood glucose can exceed 80% of total body glucose utilization. The vast majority of the glucose consumed by the brain is for the maintenance of ion gradients and ion transport. A very small percentage of brain glucose is needed for biosynthetic pathways. Glucose entry into the brain requires transport across the BBB and then it must be taken up into cells in order to be oxidized. Transport of glucose across the BBB is the responsibility of the GLUT1 transporter present in the membranes of the endothelial cells of the BBB. Like all the members of the GLUT family, GLUT1 is also known by its solute carrier family nomenclature, SLC2A1. Uptake of glucose, by neurons and glial cells, from the cerebral vasculature, is the role of the GLUT3 transporter present in the plasma membranes of these cells. GLUT1 participates in this latter glucose uptake process as well by interacting with GLUT3.

During periods of fasting the supply of glucose in brain glycogen is rapidly consumed. Unlike other tissues of the body, the brain cannot derive energy from the oxidation of amino acids or fatty acids. Under these conditions the brain will switch to the use of ketone oxidation as an alternative fuel. The ketones that the brain utilizes come from the liver via hepatic fatty acid oxidation and ketogenesis. Ketones are transported into the brain via the action of the monocarboxylate transporter 1 (MCT1) protein. MCT1 is a member of the SLC family of transporters and as such is also known as SLC16A1. Infants are very inefficient at carrying out gluconeogenesis and so this mechanism of ketone utilization by the brain is physiologically significant. Indeed, ketone uptake by the infant brain occurs at rates three- to four-fold higher than in the adult brain.

GLUT1 is encoded by the SLC2A1 gene located on chromosome 1p34.2 which spans 35kbp and encompasses 10 exons encoding a 492 amino acid membrane-bound glycoprotein. GLUT1 contains 12 membrane-spanning domains with both the N-terminus and C-terminus located inside the cell. There are two distinct isoforms of GLUT1 both of which are encoded by the SLC2A1 gene. These two isoforms differ only in the extent of their glycosylation. The form found in the endothelial cells of brain capillaries of the BBB is55kDa and the form found in astrocytes is 45kDa. GLUT1 also transports dehydroascorbic acid (the oxidized form of vitamin C) into the brain. Vitamin C concentrations in the brain exceed those in blood by 10-fold. Ascorbic acid is not able to cross the BBB whereas, dehydroascorbate readily enters the brain and is retained in the brain tissue in the form of ascorbic acid. Transport of dehydroascorbic acid into the brain is inhibited by D-glucose.

Clinical Features of GLUT1 Deficiency Syndrome

Inheritance of defects in the GLUT1 gene results in deprivation of brain glucose resulting in an early onset encephalopathy. The classical phenotype of GLUT1DS presents in infancy and includes generalized hypotonia and early-onset seizures that are unresponsive to anticonvulsants. The onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, will usually occur within the first four months of life. A complex movement disorder is also evident that includes elements of ataxia, dystonia, and spasticity. Other paroxysmal findings include confusion, lethargy, and sleep disturbance. Infants will also exhibit a delay in the attainment of developmental milestones, in particular language. In severe cases secondary microcephaly becomes prominent. Varying degrees of cognitive impairment may also be evident in affected infants that ranges from learning disabilities to severe mental retardation. As the number of cases of GLUT1 deficiency syndrome has progressively increased, the phenotypes have also broadened to include individuals with ataxia and mental retardation but without seizures, individuals with dystonia and choreoathetosis, and rare individuals with absence of seizures and no movement disorder.

Hypoglycorrhachia (abnormally low levels of glucose in the cerebrospinal fluid, CSF: <40mg/dL) with low CSF lactate in the presence of normal levels of blood glucose characterizes the impaired glucose transport into the brain causing the associated symptoms. A standardized fasting lumbar puncture, which can assess the different glucose fluxes in blood and CSF, is required to determine hypoglycorrhachia. The differential diagnosis of low CSF glucose concentration includes all causes of hypoglycemia and meningitis, subarachnoid hemorrhage, prolonged status epilepticus, meningeal sarcoidosis, cysticercosis, and trichinosis, lupus myelopathy and Erdheim–Chester disease. Therefore, it is important to measure CSF lactate levels since low to normal concentrations differentiate GLUT1DS from these other disorders of brain energy metabolism. Current correct diagnosis of GLUT1DS involves analysis for the presence of known mutations in the SLC2A1 gene. If the patient is negative for one of these known gene mutations then GLUT1 defects can be diagnosed by impaired glucose uptake into their erythrocytes and/or reduced GLUT1 immunoreactivity in erythrocyte membranes.

The treatment of choice for GLUT1DS is a high fat, low carbohydrate diet that mimics the metabolic state of fasting. This diet is referred to as the ketogenic diet because the high level of fat oxidation results in increased ketone production which then provides the brain with an oxidizable energy source. The contents of the diet have to be individually calculated and supplemented with multivitamins and minerals. The ketogenic diet is also used to treat patients with intractable childhood epilepsy. However, unlike in the cases of GLUT1DS where the diet is necessary to compensate for the lack of brain glucose uptake, it is not fully understood how it works in these other epilepsy patient. Correct diagnosis of GLUT1 deficiency is important because the ketogenic diet often results in marked clinical improvement of the seizure symptoms. Indeed, seizures in these patients are rapidly controlled by the ketogenic diet. The movement abnormalities and the the cognitive impairment improve to a somewhat lesser extent. Patients with GLUT1DS should be started on the ketogenic diet as early as possible and should remain on the diet at least until adolescence. Conversely, inhibitors of GLUT1 function should be avoided at all times and ages in GLUT1DS patients. These substances including green tea catechins, caffeine, tyrosine kinase inhibitors, genistein, GTP analogs, ethanol, androgens, tricyclic antidepressants, general anaesthetics, and anticonvulsants such as phenobarbital, chloralhydrate, diazepam, and valproate.












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