GLUT1 Deficiency Research Articles

Atypical Manifestations in Glut1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome is a genetically determined, treatable, neurologic disorder that is caused by an insufficient transport of glucose into the brain. It is caused by a mutation in the SCL2A1 gene, which is so far the only known to be associated with this condition. Glucose transporter type 1 deficiency syndrome consists of a wide clinical spectrum that usually presents with cognitive impairment, epilepsy, paroxysmal exercise-induced dyskinesia, acquired microcephaly, hemolytic anemia, gait disturbance, and dyspraxia in different combinations. However, there are other clinical manifestations that we consider equally peculiar but that have so far been poorly described in literature. In this review, supported by a video contribution, we will accurately describe this type of clinical manifestation such as oculogyric crises, weakness, paroxysmal kinesigenic and nonkinesigenic dyskinesia in order to provide an additional instrument for a correct, rapid diagnosis.

The clinical feature of glucose transporter 1 deficiency syndrome and literature review

Objective To investigate the clinical features of glucose transporter 1 deficiency syndrome(GLUT1-DS) and summarize the characteristics of GLUT1-DS through reviewing related references. Methods The clinical data including manifestation, cerebrospinal fluid(CSF) glucose, electroencephalogram, MRI and gene mutation of a patient with GLUT1-DS was collected and the related literatures were reviewed. Results The patient was a 6 years old boy.The patient, whose seizures occurred at the age of 9 month-old and prolonged to 6 year-old, attacked before breakfast.Physical examination showed microcephaly with head circumference 47.5 cm.Laboratory tests showed that CSF glucose decreased(1.87 mmol/L) and CSF-serum ratio was 0.36.And meantime the MRI was normal and electroencephalogram showed general spike and slow wave complex paroxysm.Mutation of SLC2A1 gene, c.350_385del, was found in the patient.There were 219 cases with GLUT1-DS had been reported and the age of onset was 15.69 months.In 219 patients, 159 cases(72%)suffered seizures, 105 cases(47%) had motor abnormalities, 61 cases(27%) suffered intellectual disability.The CSF glucose values were(1.92±0.31) mmol/L, CSF-serum ratio was 0.36±0.07.SLC2A1 gene mutations were detected in 183 patients(96%)in which missense mutation was the most mutation. Conclusion A wide range of phenotypes of GLUT1-DS include seizures, motor abnormalities, mental retardation.The diagnosis is confirmed when CSF glucose and CSF-serum ratio are continuously decreased which in the absence of meningitis.The SLC2A1 gene should be detected in suspicion of GLUTI-DS patients.Early diagnosis and treatment may improve the prognosis of those GLUTI-DS patients. Key words: Glucose transporter 1 deficiency syndrome; SLC2A1 gene; Seizures; Motor abnormalities

AtSWEET4, a hexose facilitator, mediates sugar transport to axial sinks and affects plant development.

Plants transport photoassimilates from source organs to sink tissues through the phloem translocation pathway. In the transport phloem, sugars that escape from the sieve tubes are released into the apoplasmic space between the sieve element/companion cell complex (SE/CC) and phloem parenchyma cells (PPCs) during the process of long-distance transport. The competition for sugar acquisition between SE/CC and adjoining PPCs is mediated by plasma membrane translocators. YFP-tagged AtSWEET4 protein is localized in the plasma membrane, and PromoterAtSWEET4-GUS analysis showed that AtSWEET4 is expressed in the stele of roots and veins of leaves and flowers. Overexpression of AtSWEET4 in Arabidopsis increases plant size and accumulates more glucose and fructose. By contrast, knock-down of AtSWEET4 by RNA-interference leads to small plant size, reduction in glucose and fructose contents, chlorosis in the leaf vein network, and reduction in chlorophyll content in leaves. Yeast assays demonstrated that AtSWEET4 is able to complement both fructose and glucose transport deficiency. Transgenic plants of AtSWEET4 overexpression exhibit higher freezing tolerance and support more growth of bacterium Pseudomonas syringae pv. phaseolicola NPS3121. We conclude that AtSWEET4 plays an important role in mediating sugar transport in axial tissues during plant growth and development.

Paroxysmal Events in Glut1 Deficiency

Paroxysmal Events in Glut1 Deficiency

Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome.

BackgroundGlucose transporter type 1 deficiency syndrome is due to de novo mutations in the SLC2A1 gene encoding the glucose transporter type 1.Phenomenology ShownParoxysmal motor manifestations induced by exercise or fasting may be the main manifestations of glucose transporter type 1 deficiency syndrome.Educational ValueProper identification of the paroxysmal events and early diagnosis is important since the disease is potentially treatable.

Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome

Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome

Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.

Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood. Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE(-/-) mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE(-/-) hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1α signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common β subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1(+/-), ApoE(-/-), and ApoE(-/-)Glut1(+/-) mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE(-/-) hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE(-/-) mice transplanted with ApoE(-/-) bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE(-/-) mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.

Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey

ObjectivesTo evaluate the outcome of ketogenic diets (KDs) in patients with glucose transport type 1 deficiency syndrome (GLUT1DS) in Japan. MethodsA nationwide survey for GLUT1DS was conducted by sending questionnaires to board-certified pediatric neurologists nationwide to obtain clinical and laboratory data. ResultsAmong 39 patients whose diagnosis was confirmed molecularly or by the 3-O-methylglucose uptake assay, 31 were treated with KDs for longer than 1month. Seventeen patients (55%) were on the modified Atkins diet, 11 (35%) were on the classic KD, and 3 were on the medium-chain triglyceride (MCT) diet. The median values and ranges of serum β-hydroxybutyrate levels in patients on the modified Atkins diet, classic KD and MCT diet were 2.5mM (0.75–4.1), 1.7mM (0.23–3.5) and 2.6mM (1.5–3.0), respectively. The KDs were effective on seizures (80%), aggravation after fasting (80%) and ataxia (79%). Thus, ataxia was as responsive as seizures. Two patients on the classic KD with a ketogenic ratio as low as 1:1 showed improvement in neurological symptoms. The development or intelligence quotient measured using the same psychological scales before and after the KDs in 9 patients did not show a significant improvement; the median quotients before and after the diets were 40 (12–91) and 46 (12–67). ConclusionThe KDs were most effective on seizures, transient aggravation after fasting and ataxia. The efficacy on intellectual development was equivocal. The modified Atkins diet was more commonly used for GLUT1DS in this study, and its ketogenicity was equivalent to the classic KD.

Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery.

Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

Use of dietary therapies amongst patients with GLUT1 deficiency syndrome

PurposeGLUT-1 deficiency syndrome (GLUT1DS) is a neurologic disorder manifesting as epilepsy, abnormal movements, and cognitive delay. The currently accepted treatment of choice is the classic 4:1 ratio ketogenic diet. MethodsA 2-page survey was distributed to all attendees of a family-centered conference for GLUT1DS in July 2015. The surveys were completed by parents, collected anonymously, and information analyzed in a database. ResultsSurveys were received from 92 families, of which 90 (98%) had been treated with dietary therapies. Diets used were extremely varied: 59 were treated with the classic ketogenic diet (KD), 29 with the Modified Atkins Diet (MAD), 4 with the Medium-chain Triglyceride (MCT) Diet and 2 with the low glycemic index treatment. The mean diet duration was 5.5 years (range: 1 month–20 years). Of those with seizures, 95% of the children had >50% seizure reduction and 80% had >90% seizure reduction. Children who were seizure-free were currently younger on average (8.2 vs. 11.6 years, p=0.01) and slightly younger at GLUT1DS diagnosis (3.8 vs. 5.3 years, p=0.05). There was an equal percentage of children seizure-free receiving the KD/MCT Diets compared to the MAD/Low Glycemic Index Treatment (74% vs. 63%, p=0.30). The majority (64%) were not receiving anticonvulsants. ConclusionThis represents the largest series of KD experience in children with GLUT1DS. Nearly all patients surveyed were on dietary therapies for long durations with reported excellent seizure control, often without anticonvulsant drugs. Several different ketogenic diets were utilized with similar efficacy. Early diagnosis and treatment were correlated with success.

GLUT-1 deficiency: From pathophysilogy and genetics to abroad clinical spectrum

The classical GLUT-1 deficiency syndrome (GLUT-1 DS, De Vivo disease) was described over 2 decades ago as a metabolic encephalopathy characterized by developmental delay, secondary microcephaly paroxysmal neurological symptoms (epilepsy) and movement disorders. The biochemical parameters of this disease, used in diagnosis, are low levels of glucose in the cerebrospinal fluid, normal level of glucose in the blood and consequent low ratio of cerebrospinal fluid vs. blood glucose levels (<40-45%). So far, more than 200 cases of the classical GLUT-1 DS have been described in the literature. Genetic research demonstrated that this disease is caused by mutations in SLC2A1 gene coding for GLUT-1, a transporter of glucose across the blood brain barrier. Over the last few years the clinical spectrum of GLUT-1 deficiencywas expanded to include other rare diseases such as paroxysmal exertional dyskinesia and early-onset absence epilepsy, but also some more common diseases such as idiopathic generalised epilepsy (1-2%). GLUT-1 deficiency is an important pathophysiological basis of these diseases as early diagnosis (aided by DNA mutation testing) and treatment (ketogenic diet) could lead to improved disease outcomes.

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.

Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

ObjectiveOn the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with...

Glut1 deficiency syndrome: Absence epilepsy and La Soupe du Jour

For some time, paediatric neurologists have recognised glucose transporter type 1 (GluT1) deficiency syndrome as a cause of intractable infantile seizures, microcephaly, developmental delay and hypoglycorrhachia in the presence of...

A Novel Frameshift Mutation in SLC2A1 Associated with a Mild form of Glucose Transporter Type 1-Related Movement Disorder

The phenotypic spectrum of glucose transporter type 1 (GLUT1) deficiency syndrome is now known to be a continuum that includes the classic phenotype as well as atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal nonepileptic findings such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. We report the case of a mentally normal child with history of infantile seizures, which remitted but later developed nonepileptic movement disorder, responsive to carbohydrate intake, with a novel frameshift mutation (c.1344_1347delCTAC p.Y449fs) in the last exon of the GLUT1 gene. This case further broadens the phenotypic spectrum of GLUT1 deficiency syndrome. We provide evidence from this case and previous reports that mutations affecting the length and composition of the intracellular C-terminal domain of the GLUT1 protein have a variable and somewhat unpredictable range of pathological effects. These range from null phenotypes associated with C-terminal domain absence, to milder presentations associated with C-terminal domains comprising partially and (in this case study) completely abnormal amino acid sequences.

Diagnosis of glucose transporter deficiency syndrome type 1 in a 17-year-old male

Diagnosis of glucose transporter deficiency syndrome type 1 in a 17-year-old male

Neutropenia responsive to ketogenic diet in an infant with GLUT1 deficiency syndrome

Glucose transporter 1 deficiency syndrome (GLUT1-DS1) is a rare and complex congenital metabolic encephalopathy characterized by infantile seizures, movement disorder, delayed development and acquired microcephaly. GLUT1-DS1 is most often caused by a de novo heterozygous mutation of the gene encoding the GLUT1 transporter, SLC2A1. We present an other- wise classical case of GLUT1-DS1 presenting at 6 wk of age with seizures. The infant had unexplained neutropenia during the months preceding molecular diagnosis. Mutational analysis of the SLC2A1 gene identified a de novo novel heterozygous dele- tion of 26 nucleotides between exon 5 and 6. As expected, the treatment with ketogenic diet remedied the seizures, but surpris- ingly it also corrected the neutropenia. We cannot rule out that this might be a phenomenon of neutropenia as an unexplained association in this single patient, but this novel observation has led us to hypothesize that in a subset of susceptible individuals with GLUT1-DS1, disturbed myelopoieses may be an accompanying phenomenon, which may be explained by deficient energy flux in hematological progenitor cells.

Early-onset absence epilepsy associated with GLUT 1 deficiency

We describe a 4.5-year-old girl with an unremarkable personal and family history. At 16 mo of age, she had a single generalized tonic-clonic seizure while awake. At 3 yr of age, she started with daily absence seizures while awake and hyperki- netic and aggressive behavior. The interictal electroencephalography showed bilateral temporo-occipital spike and wave com- plexes. The ictal video-electroencephalography recordings showed symmetric or asymmetric and synchronized spike and wave paroxysms associated with absences. Neurological examination revealed motor clumsiness, ataxia, and receptive and expressive language deficits. Routine laboratory and imaging studies as well as blood and urine neuro-metabolic investigations were normal. The absences were refractory to antiepileptic drugs. Cerebrospinal fluid glucose concentration was 36 mg/dL, lac- tate concentration was 1 mmol/L, and cerebrospinal fluid/plasma glucose ratio was 0.49. Based on the electro-clinical manifes- tations, neurological examination, and the metabolic study results, glucose transporter-1 deficiency was diagnosed and the girl was started on the ketogenic diet with good response.

From splitting GLUT1 deficiency syndromes to overlapping phenotypes

IntroductionGlucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia).The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. Methods265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. Results53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. ConclusionsOur data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations.

Ketogenic diets in patients with inherited metabolic disorders.

Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets have been widely used in patients with seizures/epilepsies, mostly children. This review focuses on the use of KDs in patients with various inherited metabolic disorders (IMD). In glucose transporter type 1 deficiency syndrome (GLUT1-DS) and pyruvate dehydrogenase complex (PDHc) deficiency, KDs are deemed the therapy of choice and directly target the underlying metabolic disorder. Moreover, in other IMD, mainly of intermediary metabolism such as glycogen storage diseases and disorders of mitochondrial energy supply, KDs may ameliorate clinical symptoms and laboratory parameters. KDs have also been used successfully to treat symptoms such as seizures/epilepsy in IMD, e.g. in urea cycle disorders and non-ketotic hyperglycinemia. As a note of caution, catabolism may cause the condition of patients with IMD to deteriorate and should thus be avoided during KDs. For this reason, careful monitoring (clinical, laboratory and apparatus-supported) is warranted. In some IMDs specific macronutrient supply is critical. Therefore, in cases of PDHc deficiency the carbohydrate intake tolerated without lactate increase and in urea cycle disorders the protein tolerance should be determined. Considering this, it is particularly important in patients with IMD that the use of KDs be individualized and well documented.