GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier

Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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“…Clinical features of GLUT1 DS include: seizures, hypotonia, ataxia, language deficits, and microcephaly. 10 …”

Section: Brain Metabolismmentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

294

120

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“…Heterozygous variants in the cerebral glucose transporter GLUT1 (or SLC2A1) also cause ID and epilepsy. 2,12,13 Variants in the GLUT1 transporter appear to be haploinsufficient or hypomorphic in that they decrease glucose uptake in erythrocytes to 37%-72% of that of controls. 14 There is a correlation between the decrease in glucose uptake and clinical severity.…”

mentioning

confidence: 99%

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy

Srour

Shimokawa

Hamdan

et al. 2017

The American Journal of Human Genetics

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Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect wellconserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p ¼ 0.013) and 33% (p ¼ 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.Glucose is the major energy fuel of the central nervous system. However, its availability is restricted given the selective permeability of the blood brain barrier (BBB) and the relative lack of carbohydrate stores in the brain. Thus, glucose transport across the BBB and into neural cells is critical for cerebral physiologic function and energy metabolism (for a review, see Chen et al. 1 ). GLUT1 is the key regulator of glucose across the BBB. 1 The importance of this process is illustrated by the observation that dominant mutations in SLC2A1 (OMIM: 138140), which encodes GLUT1, cause epilepsy with variable degrees of intellectual disability (ID) and/or movement disorder. 2 Once glucose enters the brain's extracellular space, it is taken up by different cerebral cells through various glucose transporters, which are expressed in developmentally and celltype-specific manners. Whether disruption of these neural glucose transporters also causes neurodevelopment disorders remains unknown.We report on four affected children from two unrelated consanguineous families with moderate to severe ID associated with epilepsy and variable neuropsychiatric features. Using whole-exome sequencing, we identified homozygous missense variants in SLC45A1 (OMIM: 605763), which codes for a neuronal glucose transporter that is predominantly expressed in the developing and adult brain. 3 Functional studies indicate that the identified variants reduce the activity of the protein, thus implicating SLC45A1 dysfunction in the etiology of ID a...

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“…The molecular bases of three congenital defects of cellular glucose transport, affecting either facilitative ("passive") or sodium-dependent ("active") transport, have been elucidated in recent years (1)(2)(3). In addition, a defect of the renal lowaffinity sodium/glucose cotransporter SGLT2 gene (also referred to as SLC5A2, [OMIM 182381]) has long been proposed to cause renal glucosuria (OMIM 233100) (4).…”

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confidence: 99%

Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria

Santer

Kinner

Lassen³

et al. 2003

Journal of the American Society of Nephrology

272

262

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Abstract. The role of SGLT2 (the gene for a renal sodiumdependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.

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GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier

Cited by 344 publications

References 15 publications

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy

Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria

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