Glucose transporter 1 (GLUT1) deficiency syndrome

Abstract The hereditary stomatocytoses are a series of dominantly inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glucose transporter 1 (glut1) deficiency syndromes (glut1DSs) result from mutations in SLC2A1, encoding glut1. Glut1 is the main glucose transporter in the mammalian blood-brain barrier, and glut1DSs are manifested by an array of neurologic symptoms. We have previously reported 2 cases of stomatin-deficient cryohydrocytosis (sdCHC), a rare form of stomatocytosis associated with a cold-induced cation leak, hemolytic anemia, and hepatosplenomegaly but also with cataracts, seizures, mental retardation, and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. On the basis of a 3-dimensional model of glut1, we propose potential mechanisms underlying the phenotypes of the 2 mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia, and sdCHC phenotypes are compared and discussed.

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Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

Nature Communications ◽

10.1038/ncomms14152 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 41

Author(s):

Maoxue Tang ◽

Guangping Gao ◽

Carlos B. Rueda ◽

Hang Yu ◽

David N. Thibodeaux ◽

...

Keyword(s):

Glucose Transporter ◽

Deficiency Syndrome ◽

Glucose Transporter 1 ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

Brain Microvasculature

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Classic Ketogenic Diet and Modified Atkins Diet in SLC2A1 Positive and Negative Patients with Suspected GLUT1 Deficiency Syndrome: A Single Center Analysis of 18 Cases

Nutrients ◽

10.3390/nu13030840 ◽

2021 ◽

Vol 13 (3) ◽

pp. 840

Author(s):

Jana Ruiz Herrero ◽

Elvira Cañedo Villarroya ◽

Luis González Gutiérrez-Solana ◽

Beatriz García Alcolea ◽

Begoña Gómez Fernández ◽

...

Keyword(s):

Movement Disorder ◽

Glucose Transporter ◽

Deficiency Syndrome ◽

Laboratory Assessment ◽

Modified Atkins Diet ◽

Atkins Diet ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Impact

Background: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by mutations in the SLC2A1 gene and produces seizures, neurodevelopmental impairment, and movement disorders. Ketogenic dietary therapies (KDT) are the gold standard treatment. Similar symptoms may appear in SLC2A1 negative patients. The purpose is to evaluate the effectiveness of KDT in children with GLUT1DS suspected SLC2A1 (+) and (-), side effects (SE), and the impact on patients nutritional status. Methods: An observational descriptive study was conducted to describe 18 children (January 2009–August 2020). SLC2A1 analysis, seizures, movement disorder, anti-epileptic drugs (AEDS), anthropometry, SE, and laboratory assessment were monitored baseline and at 3, 6, 12, and 24 months after the onset of KDT. Results: 6/18 were SLC2A1(+) and 13/18 had seizures. In these groups, the age for debut of symptoms was higher. The mean time from debut to KDT onset was higher in SLC2A1(+). The modified Atkins diet (MAD) was used in 12 (5 SLC2A1(+)). Movement disorder improved (4/5), and a reduction in seizures >50% compared to baseline was achieved in more than half of the epileptic children throughout the follow-up. No differences in effectiveness were found according to the type of KDT. Early SE occurred in 33%. Long-term SE occurred in 10, 5, 7, and 5 children throughout the follow-up. The most frequent SE were constipation, hypercalciuria, and hyperlipidaemia. No differences in growth were found according to the SLC2A1 mutation or type of KDT. Conclusions: CKD and MAD were effective for SLC2A1 positive and negative patients in our cohort. SE were frequent, but mild. Permanent monitoring should be made to identify SE and nutritional deficits.

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Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain – a review

European Journal of Pediatrics ◽

10.1007/s00431-002-0939-3 ◽

2002 ◽

Vol 161 (6) ◽

pp. 295-304 ◽

Cited By ~ 118

Author(s):

Jörg Klepper ◽

Thomas Voit

Keyword(s):

Glucose Transport ◽

Glucose Transporter ◽

Deficiency Syndrome ◽

Transporter Protein ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

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Alternating Hemiplegia of Childhood in an Infant with Symptoms Resembling Glucose Transporter 1 Deficiency

Journal of Pediatric Neurology ◽

10.1055/s-0037-1598026 ◽

2017 ◽

Vol 15 (04) ◽

pp. 180-182

Author(s):

Mini Sreedharan ◽

Shiji Chalipat ◽

Kunju Mohammed ◽

Kalpana Devadathan

Keyword(s):

Developmental Delay ◽

Glucose Transporter ◽

Gene Mutations ◽

Deficiency Syndrome ◽

Global Developmental Delay ◽

Glucose Transporter 1 ◽

Alternating Hemiplegia Of Childhood ◽

Slc2a1 Gene ◽

Glut1 Deficiency ◽

Atp1a3 Gene

AbstractGlucose transporter type 1 (glut1) deficiency syndrome presents with developmental delay, microcephaly, and recurrent seizures during infancy, as well as cerebrospinal fluid (CSF) hypoglycorrhachia and mutations in the SLC2A1 gene. We describe a baby with microcephaly, global developmental delay, seizures from 3 months of age, and CSF glucose in the lower limit of normal range, with heterozygous p.Glu815Lys mutation of the ATP1A3 gene and no mutation in the SLC2A1 gene. Mutations in ATP1A3 gene are associated with alternating hemiplegia of childhood (AHC). Interestingly the baby developed episodes of recurrent bouts of alternating hemiplegia from 13 months of age. The case is reported to highlight ATP1A3 mutation as a probable etiology for glut1 deficiency like syndrome and AHC. A brief review of literature emphasizing the overlapping paroxysmal and nonparoxysmal symptoms of the two conditions is also included.

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GLUT1 deficiency syndrome: A case report with a novel SLC2A1 mutation

Vojnosanitetski pregled ◽

10.2298/vsp170406120i ◽

2019 ◽

Vol 76 (5) ◽

pp. 543-546 ◽

Cited By ~ 1

Author(s):

Nikola Ivancevic ◽

Natasa Cerovac ◽

Blazo Nikolic ◽

Goran Cuturilo ◽

Ana Marjanovic ◽

...

Keyword(s):

Case Report ◽

Developmental Delay ◽

Ketogenic Diet ◽

Glucose Transporter ◽

Deficiency Syndrome ◽

Chromosome 1 ◽

Brain Membrane ◽

Slc2a1 Gene ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

Introduction. GLUT1 deficiency syndrome (GLUT1 DS, OMIM 606777) is a metabolic brain disorder caused by mutations in SLC2A1 gene (chromosome 1) encoding glucose transporter type 1 located on blood-brain membrane. The ?classic? phenotype in children includes early onset generalized farmacoresistant epilepsy, developmental delay, complex movement disorders and acquired microcephaly. However, there are milder phenotypes without epilepsy which could be seen in older children. The ketogenic diet is a treatment of choice. Case report. We present a four-yearold female patient with farmacoresistant generalized epilepsy, paroxysmal dystonic posturing, ataxia, hypotonia, developmental delay (motor, attention and speech disturbances), and microcephaly. The genetic testing revealed a novel point mutation at c.156T > A (p.Y52X) in exon 3 of SLC2A1 gene. The patient responded excellent on ketogenic diet. Conclusion. GLUT1 DS is treatable, and likely to be under-diagnosed neurological disorder. The ketogenic diet is resulting in good control of seizures in the patients, and it has certain benefit for the neurodevelopmental disability.

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GLUT1 Deficiency Syndrome—Early Treatment Maintains Cognitive Development? (Literature Review and Case Report)

Genes ◽

10.3390/genes12091379 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1379

Author(s):

Ivana Kolic ◽

Jelena Radic Nisevic ◽

Inge Vlasic Cicvaric ◽

Ivona Butorac Ahel ◽

Kristina Lah Tomulic ◽

...

Keyword(s):

Cognitive Development ◽

Motor Development ◽

Glucose Transporter ◽

Genetic Defect ◽

Deficiency Syndrome ◽

Single Nucleotide Variants ◽

Slc2a1 Gene ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Brain

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood–brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and various paroxysmal neurological phenomena. In most cases, GLUT1DS is caused by heterozygous single-nucleotide variants (SNVs) in the SLC2A1 gene that provoke complete or severe impairment of the functionality and/or expression of GLUT1 in the brain. Despite the rarity of these diseases, GLUT1DS is of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms, especially if it is started as early as possible. We present a clinical phenotype, biochemical analysis, electroencephalographic and neuropsychological features of an 11-month-old boy with myoclonic seizures, hypogammaglobulinemia, and mildly impaired gross motor development. Using sequence analysis and deletion/duplication testing, deletion of an entire coding sequence in the SLC2A1 gene was detected. Early introduction of a modified Atkins diet maintained a seizure-free period without antiseizure medications and normal cognitive development in the follow-up period. Our report summarizes the clinical features of GLUT1 syndromes and discusses the importance of early identification and molecular confirmation of GLUT1DS as a treatable metabolic disorder.

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GLUT1 deficiency and other glucose transporter diseases

Acta Endocrinologica ◽

10.1530/eje.0.1500627 ◽

2004 ◽

pp. 627-633 ◽

Cited By ~ 80

Author(s):

JM Pascual ◽

D Wang ◽

B Lecumberri ◽

H Yang ◽

X Mao ◽

...

Keyword(s):

Glucose Transporter ◽

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

Metabolic Screening ◽

Genetically Determined ◽

Encoding Genes ◽

Rate Limiting ◽

Carrier Systems ◽

Energy Failure

We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transporters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification.

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Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report

BMC Medical Genomics ◽

10.1186/s12920-021-01045-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tugce Bozkurt ◽

Yasemin Alanay ◽

Ugur Isik ◽

Ugur Sezerman

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glucose Transporter ◽

De Novo ◽

Deficiency Syndrome ◽

Splicing Variant ◽

Whole Exome ◽

Wide Range ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

Abstract Background GLUT1 Deficiency Syndrome 1 (GLUT1DS1) is a neurological disorder caused by either heterozygous or homozygous mutations in the Solute Carrier Family 2, Member 1 (SLC2A1) gene. SLC2A1 encodes Glucose transporter type 1 (GLUT1) protein, which is the primary glucose transporter at the blood–brain barrier. A ketogenic diet (KD) provides an alternative fuel for brain metabolism to treat impaired glucose transport. By reanalyzing exome data, we identified a de novo heterozygous SLC2A1 variant in a girl with epilepsy. After reversed phenotyping with neurometabolic tests, she was diagnosed with GLUT1DS1 and started on a KD. The patient's symptoms responded to the diet. Here, we report a patient with GLUT1DS1 with a novel SLC2A1 mutation. She also has a hemangioma which has not been reported in association with this syndrome before. Case presentation A 5-year 8-month girl with global developmental delay, spasticity, intellectual disability, dysarthric speech, abnormal eye movements, and hemangioma. The electroencephalography (EEG) result revealed that she had epilepsy. Magnetic resonance imaging (MRI) showed that non-specific white matter abnormalities. Whole Exome Sequencing (WES) was previously performed, but the case remained unsolved. The re-analysis of WES data revealed a heterozygous splicing variant in the SLC2A1 gene. Segregation analysis with parental DNA samples indicated that the variant occurred de novo. Lumbar puncture (LP) confirmed the diagnosis, and the patient started on a KD. Her seizures responded to the KD. She has been seizure-free since shortly after the initiation of the diet. She also had decreased involuntary movements, her speech became more understandable, and her vocabulary increased after the diet. Conclusions We identified a novel de novo variant in the SLC2A1 gene in a patient who previously had a negative WES result. The patient has been diagnosed with GLUT1DS1. The syndrome is a treatable condition, but the differential diagnosis is not an easy process due to showing a wide range of phenotypic spectrum and the overlapping symptoms with other neurological diseases. The diagnosis necessitates a genomic testing approach. Our findings also highlight the importance of re-analysis to undiagnosed cases after initial WES to reveal disease-causing variants.

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