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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Glucose Transporter Type 1 Deficiency Syndrome

Synonyms: De Vivo Disease, Glucose Transporter Protein Syndrome, Glut-1 Deficiency Syndrome, Glut1-DS

, MD, , MD, PhD, and , MD.

Author Information
, MD
Department of Neurology
Montefiore Medical Center
Albert Einstein College of Medicine
Bronx, New York
, MD, PhD
Rare Brain Disorders Clinic and Laboratory
The University of Texas Southwestern Medical Center
Dallas, Texas
, MD
Department of Pediatric Neurology
Columbia University
Neurological Institute of New York
New York, New York

Initial Posting: ; Last Update: August 9, 2012.

Summary

Disease characteristics. The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1-DS) is now known to be a continuum that includes the classic phenotype as well as dystonia 9, dystonia 18, atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures begin before age two years in approximately 90% and later in approximately 10%. Five seizure types occur: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continuous with fluctuations in severity influenced by environmental factors such as fasting, fever, and intercurrent infection. Symptoms often improve substantially when a ketogenic diet is started.

Diagnosis/testing. The diagnosis is established in neurologically affected individuals who have a low-normal or low CSF lactate concentration, normal blood glucose concentration, and low CSF glucose concentration (<60 mg/dL in all cases reported to date; <40 mg/dL in >90%; 41-52 mg/dL in ~10%). Detection of a heterozygous disease-causing mutation (or rarely, biallelic mutations) in SLC2A1 confirms the diagnosis. If no mutation is identified, 3-O-methyl-D-glucose uptake in erythrocytes can be performed; results between 35%-74% of controls are diagnostic.

Management. Treatment of manifestations: The ketogenic diet is highly effective in mitigating clinical findings (i.e., controlling the seizures and improving the movement disorder and alertness). Ketone bodies use a different transporter to cross the blood-brain barrier and thus provide brain with the only known alternative fuel for metabolism. The ketogenic diet is generally well-tolerated particularly if the family is properly instructed in the basic dietary principles at the beginning. Prognosis is improved if the ketogenic diet is started early in childhood. The ketogenic diet is deficient in L-carnitine and several vitamins necessitating daily supplementation. Patients also develop a mild compensated metabolic acidosis when ketotic.

Prevention of primary manifestations: Early initiation of the ketogenic diet, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.

Agents to avoid: Barbiturates (e.g., phenobarbital, the most commonly used AED in infants), methylxanthines (e.g., caffeine), valproic acid.

Evaluation of relatives at risk: If the disease-causing mutation has been identified in an affected family member, it is appropriate to test at-risk newborns and symptomatic infants so that morbidity can be reduced by early diagnosis and treatment.

Genetic counseling. Most commonly Glut1-DS is inherited in an autosomal dominant (AD) manner. About 90% of individuals with AD Glut1-DS have the disorder as the result of a de novo heterozygous mutation; about 10% have a clinically affected parent. Parents who are heterozygous for the disease-causing mutation may have a mild phenotype or be asymptomatic, findings that can suggest mosaicism in the parent. Offspring of an individual with AD Glut1-DS have a 50% chance of inheriting the mutation and being clinically affected. Rarely, Glut1-DS is inherited in an autosomal recessive (AR) manner. Carriers in families with AR Glut1-DS are asymptomatic. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in families with AD inheritance or both disease-causing mutations have been identified in families with AR inheritance.

GeneReview Scope

Glucose Transporter Type 1 Deficiency Syndrome: Included Disorders
  • Dystonia 9 (DYT9)
  • Dystonia 18 (DYT18)

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Glucose transporter type 1 deficiency syndrome (Glut1-DS) usually presents in one of two ways:

  • Classic Glut1 DS (~90% of affected individuals). Seizures (onset between ages 1 and 6 months in ~70%, before age 2 years in ~90%, and after age 2 years in ~10%); delayed neurologic development, dysarthria , acquired microcephaly and complex movement disorders including ataxia, dystonia and chorea
  • Non-epileptic Glut1 DS (~10% of affected individuals). No clinical seizures and a milder phenotype, often demonstrating paroxysmal dyskinesias including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia

Testing

CSF glucose concentration. The single most important laboratory observation in Glut1-DS is hypoglycorrhachia (reduced cerebrospinal fluid (CSF) glucose concentration). Following a four-hour fast, a blood sample is obtained just before performing the lumbar puncture.

  • The blood glucose concentration should be normal, ruling out hypoglycemia as the cause of the hypoglycorrhachia.
  • The CSF/blood glucose ratio usually is less than 0.4 in persons with Glut1-DS; however, this value is less reliable than the absolute CSF glucose value.
  • All affected individuals reported to date have had CSF glucose values below 60 mg/dL; in more than 90% it is below 40 mg/dL and in approximately 10% it is 41-52 mg/dL [De Vivo & Wang 2008, Yang et al 2011].

CSF lactate concentration is low-normal or low, often below 1.3 mmol/L [De Vivo et al 1991, Wang et al 2005, Yang et al 2011].

Erythrocyte 3-O-methyl-D-glucose uptake assay. The uptake assay is a functional measure of glucose transport across the cell membrane. Individuals with Glut1-DS have abnormal values that range from 35% to 74% of controls, with an average reduction of approximately 50% [Yang et al 2011]. As such, it is abnormally low in almost all suspected cases.

  • Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of Glut1-DS.
  • Molecular genetic testing detects a pathogenic mutation in 95% of persons with abnormally low uptake assay.
  • Of note, 3% of persons with Glut1-DS have a normal uptake assay, a finding that correlates with the presence of an SLC2A1 missense mutation (see Genotype-Phenotype Correlations).

    Note: The 3-O-methyl-D-glucose uptake assay is currently viewed as the diagnostic gold standard for this disease [Yang et al 2011]; however, such testing may not be available on a clinical basis.

Positron emission tomography (PET). Cerebral fluoro-deoxy-glucose PET findings are distinctive with diffuse hypometabolism of the cerebral cortex and regional hypometabolism of the cerebellum and thalamus. Basal ganglia metabolism appears relatively preserved. This distinctive PET signature appears in early infancy and persists into adulthood regardless of disease severity or therapy with a ketogenic diet [Pascual et al 2002]. The sensitivity and specificity of PET in the diagnosis of Glut1-DS have not been established.

Molecular Genetic Testing

Gene. SLC2A1 is the only gene in which mutations are known to cause glucose transporter type I deficiency syndrome (Glut1-DS).

Table 1. Summary of Molecular Genetic Testing Used in Glut1-DS

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SLC2A1Sequence analysis 4, 5Sequence variants48/54 (89%) 6
60/74 (81%) 7
Deletion/duplication analysis 8(Multi)exonic or whole-gene deletions6/54(11%) 6
10/74(14%) 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Including the promoter and exons of SLC2A1 [Wang et al 2005]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. 48/54 (89%) probands with a SCL2A1 mutation, 6/54(11%) with (multi)exonic or whole-gene deletions [Leen et al 2010]

7. 60/74 (81%) probands with a SCL2A1 mutation, 10/74(14%) with (multi)exonic or whole-gene deletions [Yang et al 2011]

8. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To establish the diagnosis in a proband with clinical findings suggestive of Glut1-DS

1.

Measure CSF and blood glucose concentrations following a four hour fast.

2.

In those with normal blood glucose concentration and CSF glucose concentration lower than 60 mg/dL, perform molecular genetic testing of SLC2A1.

a.

Begin with sequence analysis.

b.

If no pathogenic mutation is identified, perform deletion/duplication analysis

3.

If molecular genetic testing fails to detect a pathogenic SLC2A1 mutation, consider performing erythrocyte glucose uptake assay (when feasible).

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Glucose transporter type 1 deficiency syndrome (Glut1-DS) usually presents as either classic Glut1-DS (~90% of affected individuals) or non-epileptic Glut1-DS (~10% of affected individuals).

Infants with the classic phenotype appear normal at birth following an uneventful pregnancy and delivery. Birth weight and Apgar scores are normal. They commonly experience infantile-onset epileptic encephalopathy refractory to anticonvulsants and associated with delayed neurologic development; later deceleration of head growth and acquired microcephaly; and ataxia, dystonia and spasticity [Klepper et al 1999b, De Vivo et al 2002a, De Vivo et al 2002b; Pons et al 2010, Yang et al 2011].

Non-epileptic Glut1-DS includes a broad phenotypic spectrum that has expanded over the past few years as more affected individuals have been identified. Paroxysmal non-epileptic manifestations that have been reported include intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. Several disorders including dystonia 9, dystonia 18, atypical childhood absence epilepsy, and myoclonic astatic epilepsy are now known to be caused by Glut1 deficiency [Chinnery 2010, Leen et al 2010, Yang et al 2011].

Seizures. Seizures in classic early-onset Glut1-DS, which usually begin between age one and six months, are often the first clinical indication of brain dysfunction. In some infants, apneic episodes and abnormal episodic eye movements indistinguishable from opsoclonus may precede the onset of seizures. Infantile focal seizures are clinically fragmented (i.e., non-generalized; typical at this age) and may include paroxysmal eye movements, cyanotic spells, complex absence, and atonic seizures. The electroencephalogram (EEG) demonstrates multifocal spike discharges in infancy.

With further brain maturation, the seizures become synchronized and manifest clinically as generalized events associated with 3- to 4-Hz spike and wave discharges. Five seizure types have been described: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified [Leary et al 2003].

The frequency of seizures varies among individuals: some experience daily events; others have only occasional seizures separated by days, weeks, or months. Seizure frequency does not correlate with phenotypic severity.

Some individuals with Glut1-DS never have a clinical seizure [von Moers et al 2002, Leary et al 2003]. About 10%-15% of cases, diagnosed thus far, never have had clinical seizures [Leen et al 2010; Author, unpublished observations].

Intellectual disability. Varying degrees of speech and language impairment are observed in all affected individuals.

Dysarthria is common and is accompanied by dysfluency (i.e., excessively interrupted speech).

Both receptive and expressive language skills are affected, with expressive language skills being disproportionately affected.

Varying degrees of cognitive impairment, ranging from learning disabilities to severe intellectual disability, are observed. Minimally affected individuals have estimated IQ scores in the normal range.

Social adaptive behavior is an exceptional strength. Individuals with Glut1-DS tend to be comfortable in group and school settings and interact well with others. Autistic spectrum disorders seem to be under-represented in those with Glut1-DS.

Movement disorders. A complex movement disorder is commonly seen and is characterized by ataxia, dystonia, and chorea which may be continuous, paroxysmal, or continuous with fluctuations determined by environmental stressors [Leen et al 2010, Pons et al 2010]. Often, paroxysmal worsening occurs before meals, during fasting, or with infectious stress.

Pons et al [2010] described the frequency of abnormal movements in 57 persons with Glut1-DS. Clinical findings included the following:

  • Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
  • Action limb dystonia (86%)
  • Mild chorea (75%)
  • Cerebellar action tremor (70%)
  • Non-epileptic paroxysmal events (28%)
  • Dyspraxia (21%)
  • Myoclonus (16%)

The 40 individuals on a ketogenic diet had less severe gait disturbances, but more complex movement disorders than those on a conventional diet [Pons et al 2010], an observation suggesting that the extrapyramidal and cerebellar findings are more apparent in the milder phenotypes.

Paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18] [Suls et al 2008, Weber et al 2008, Zorzi et al 2008, Urbizu et al 2010]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9] [Weber et al 2011]) are now recognized to be part of the phenotypic spectrum of Glut1-DS.

  • DYT18 differs clinically from classic Glut1-DS in that most affected individuals appear to have a normal interictal neurologic examination and a normal head circumference, and experience exercise-induced dyskinesias and later-onset seizures [Suls et al 2008, Weber et al 2008, Zorzi et al 2008, Urbizu et al 2010]. The CSF glucose concentrations tend to be higher (41-52 mg/dL) than those in classic Glut1-DS [De Vivo & Wang 2008].
  • The two families with DYT9 had paroxysmal, mainly exercise-induced dyskinesia with onset between ages one and 15 years [Weber et al 2011] caused by heterozygous SLC2A1 mutations (p.Arg212Cys and p.Arg126Cys). Dyskinesia triggers included prolonged exercise, anxiety, and emotional stress. The frequency of dyskinesias decreased or stopped later in life. Other associated findings included progressive spastic paraparesis with onset in early adulthood, mild gait ataxia, mild-to-moderate cognitive impairment, and epileptic seizures.

Other paroxysmal events have been reported [Overweg-Plandsoen et al 2003, Pérez-Dueñas et al 2009, Pons et al 2010, Urbizu et al 2010]. It is unclear whether these events represent epileptic or non-epileptic phenomena. These neurologic signs, which generally fluctuate and may be influenced by factors such as fasting or fatigue, include the following:

  • Confusion
  • Lethargy
  • Somnolence
  • Recurrent headaches, migraines
  • Sleep disturbances
  • Hemiparesis
  • Total body paralysis
  • Intermittent ataxia
  • Chorea
  • Action limb dystonia
  • Cerebellar action tremor
  • Writer’s cramp
  • Dystonic tremor (DT); described as the only finding in a mother and daughter [Roubergue et al 2011]
  • Parkinsonism
  • Myoclonus
  • Dyspraxia
  • Non-kinesigenic dyskinesias

Microcephaly. Thirty-two of 58 persons with Glut1-DS had microcephaly ranging from mild (<1 SD below the mean in 14 patients), moderate (<2 SD below the mean in 10) to severe (<3 SD below the mean in 8).

Pathophysiology

The disease manifestations can be explained in terms of current understanding of glucose transport in the brain: glucose is the principal fuel source for brain metabolism; the glucose transporter, Glut1 (solute carrier family 2, facilitated glucose transporter 1), the protein product of SLC2A1, is the fundamental vehicle that facilitates glucose entry into the brain. The cerebral metabolic rate for glucose (which is low during fetal development) increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and declines gradually during the second decade of life to the rate of glucose utilization seen in early adulthood. It thus appears that the risk for clinical manifestations during fetal development is low and then rises throughout infancy and early childhood.

Human and animal data suggest that the margin of safety for glucose transport across the blood-brain barrier to meet the needs of brain metabolism and cerebral function is narrow. A milder clinical phenotype with intermittent symptoms (epilepsy, dyskinesias, and ataxia) may be predicted with 25%-35% reduction in Glut1 transporter function [Rotstein et al 2010]; a more severe phenotype results from greater reductions (perhaps 40%-75%) [Yang et al 2011].

The erythrocyte glucose uptake assay is a functional surrogate measure of residual Glut1 transporter function. Individuals displaying the classic phenotype have on average a 50% uptake assay, resulting from loss-of-function mutations that result in 50% reduction in Glut1 activity. Absence of Glut1 transporter expression is embryonic lethal [Wang et al 2006].

Genotype-Phenotype Correlations

A correlation between the specific type of SLC2A1 mutation and the clinical severity has been noted recently [Leen et al 2010, Yang et al 2011]. A clinical scoring system, developed to classify phenotypic severity for mitochondrial diseases and Glut1-DS [Kaufmann et al 2004], has been used to correlate phenotype with other markers including genotype [Levy et al 2010, Rotstein et al 2010, Yang et al 2011].

Fifty-three affected individuals were stratified clinically according to the Columbia Neurological Score (CNS) into four groups [Yang et al 2011]:

  • Minimal (CNS 70-76)
  • Mild (CNS 60-69)
  • Moderate (CNS 50-59)
  • Severe (CNS 40-49)

Comparison of the type of SLC2A1 heterozygous mutations among the four groups revealed the following:

  • Missense mutations occurred predominantly in the mild and moderate clinical categories.
  • Splice site and nonsense mutations and insertions, deletions, and exonic deletions occurred almost exclusively in the moderate and severe clinical categories.
  • Complete gene deletions clustered in the severe clinical category.

A significant inverse correlation (R² = 0.94) was observed between the median values of the erythrocyte 3-O-methyl-D- glucose uptake and the clinical severity as determined by the Columbia Neurological Score. Thus, the erythrocyte glucose uptake is an indication of the functional effect of the mutation.

Many mutations have been identified [Wang et al 2005, Pascual et al 2008, Wang et al 2008, Leen et al 2010, Yang et al 2011]; several mutation hot spots and gene regions have been detected:

  • Three individuals (each from a different family) have a mild clinical phenotype (as determined by the CNS) and a heterozygous p.Arg333Trp missense mutation.
  • Twelve individuals have a heterozygous missense mutation at amino acid residue arginine 126.
  • A significant fraction (5/21) of mutations is located in a vulnerable region of the Glut 1 protein that involves the fourth transmembrane domain encoded by exon 4, suggesting a critical functional disturbance associated with structural alterations in this region of the protein [Pascual et al 2008].
  • One individual had a p.Arg126Leu mutation in trans configuration with a p.Lys256Val mutation associated with a severe phenotype [Pascual et al 2008]. The father, who was clinically well, had neither missense mutation. The asymptomatic mother was heterozygous for the p.Lys256Val mutation. Mutagenesis studies in Xenopus oocytes showed that in an uptake study under zero-trans influx conditions the p.Arg126Leu missense mutation is more pathogenic than the p.Lys256Val missense mutation. Therefore, the asymptomatic mother may have sufficient residual Glut1 activity to allow her to function normally. (Her glucose uptake assay revealed 83% residual activity; values of >74% residual activity correlate with a clinically normal state.) It is unclear whether synergy between the two missense mutations is causing a severe phenotype in the child who is a compound heterozygote [Rotstein et al 2010].
  • Three individuals heterozygous for the p.Thr295Met mutation had:
    • A similar early-onset classic phenotype including monthly seizures beginning in infancy, developmental delay, ataxia, microcephaly, and language deficit;
    • Hypoglycorrhachia and low normal CSF lactate concentrations;
    • Normal erythrocyte zero-trans influx of 3-OMG.

      Mutagenesis studies suggest that p.Thr295Met specifically affects glucose flux by perturbing efflux rather than influx. These findings explain the seemingly paradoxic findings of Glut1-DS with hypoglycorrhachia and “normal” erythrocyte glucose uptake [Wang et al 2008, Fujii et al 2011].
  • A fourth individual heterozygous for the p.Thr295Met mutation with a similar mild classic phenotype was reported [Leen et al 2010].

Penetrance

Penetrance in Glut1-DS inherited in an autosomal dominant manner is complete.

An asymptomatic parent harboring the disease-causing mutation implies a mosaic state.

Fewer pathogenic mutations may be transmitted as an autosomal recessive trait; carriers are asymptomatic [Rotstein et al 2010].

Nomenclature

Paroxysmal exercise-induced dyskinesia and epilepsy (also known as dystonia 18 [DYT18]) [Suls et al 2008, Weber et al 2008, Zorzi et al 2008, Urbizu et al 2010] and paroxysmal choreoathetosis with spasticity (DYT9) [Weber et al 2011] are now recognized to be part of the Glut1-DS phenotypic spectrum.

Prevalence

No firm estimates of incidence and prevalence can be made, as cases have been reported worldwide and are biased by physician awareness of the disorder. Authors estimate the incidence/prevalence in Queensland, Australia at approximately 1:90,000, which is likely a conservative estimate under the conditions of ascertainment [Coman et al 2006].

Differential Diagnosis

The differential diagnosis of glucose transporter type 1 deficiency syndrome (Glut1-DS) includes the following:

  • Other causes of neuroglycopenia, such as conditions causing chronic or intermittent hypoglycemia (e.g., familial hyperinsulinism)
  • All causes of neonatal seizures and of acquired microcephaly; in particular, early presentations of Rett syndrome, Angelman syndrome, and infantile forms of neuronal ceroid-lipofuscinosis
  • Opsoclonus-myoclonus syndrome
  • Cryptogenic epileptic encephalopathies with developmental delays
  • Familial epilepsies with autosomal dominant transmission
  • Episodes of paroxysmal neurologic dysfunction responsive to or preventable by carbohydrate intake, especially when manifesting as alternating hemiparesis, ataxia, cognitive dysfunction, or seizures
  • Movement disorders including dystonia (see Dystonia Overview)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with glucose transporter type 1 deficiency syndrome (Glut1-DS), the following evaluations are recommended:

  • EEG (pre-prandial and post-prandial tracings)
  • Brain imaging, including FDG-PET in selected individuals
  • Neuropsychological assessment

Treatment of Manifestations

Ketogenic diet. Diffusion of ketone bodies across the blood-brain barrier is facilitated by the monocarboxylic transporter 1(MCT1). The ketogenic diet, introduced as a treatment for Glut1-DS in 1991, primarily provides an alternative fuel for brain metabolism. The ketogenic diet creates chronic ketosis by largely replacing carbohydrates and proteins with lipids in varying ratios.

Experience over the past two decades indicates that the ketogenic diet is well tolerated in most cases and is highly effective in controlling the seizures and improving gait disturbance. Of note, seizures may recur even with good dietary compliance [Klepper et al 2005]. Even when seizures are controlled, affected individuals may continue to have neurobehavioral deficits involving cognition and social adaptive behavior [Klepper et al 2002].

In the authors’ experience, the neurologic outcome is influenced by the age at which treatment is initiated: younger patients have a better outcome.

Note: Because the ketogenic diet is deficient in L-carnitine, a co-factor that is essential for the metabolism of fats, dietary supplementation with 50 mg/kg/day of L-carnitine is recommended [De Vivo et al 1998].

Patients develop a mild compensated metabolic acidosis when ketotic.

Antiepileptic drugs (AEDs) are generally ineffective or afford only limited improvement in the absence of a ketogenic diet. Certain AEDs may be relatively contraindicated as adjunctive treatment in children on the ketogenic diet (see Agents/Circumstances to Avoid).

  • Phenobarbital and valproic acid can inhibit Glut1 transport.
  • Valproic acid may partially inhibit beta-oxidation of fatty acids.
  • Acetazolamide, topiramate, and zonisamide inhibit carbonic anhydrase and may potentiate the metabolic acidosis. These agents also can cause kidney stones.

Alpha-lipoic acid (thioctic acid) also has been shown to facilitate glucose transport in Glut4-dependent cultured skeletal muscle cells. Preliminary in vitro studies with Glut1 transport systems have shown similar results. Thus, alpha-lipoic acid supplements have been recommended, without supportive clinical evidence, as a treatment for Glut1-DS. Response has been modest at best; however, the dose taken by mouth may be insufficient to approximate experimental conditions [Kulikova-Schupak et al 2001].

Prevention of Primary Manifestations

Anecdotal observations suggest that early diagnosis and treatment with a ketogenic diet is associated with improved neurologic outcome by nourishing the immature brain during this critical period of growth and development [Authors, personal observation].

Agents/Circumstances to Avoid

  • Barbiturates. Generally, children with infantile-onset seizures are treated with phenobarbital, the most commonly used antiepileptic drug in this age group. In vitro studies indicate that barbiturates aggravate the Glut1 transport defect in erythrocytes of individuals with Glut1-DS [Klepper et al 1999a]. On occasion, parents have reported that phenobarbital did not improve their child’s seizure control or may have worsened their child's clinical condition.
  • Methylxanthines (e.g., caffeine), which are known to inhibit transport of glucose by Glut1 [Ho et al 2001b], also have been reported to worsen the clinical state of individuals with Glut1-DS [Brockmann et al 2001]. Thus, it is advisable for affected individuals to avoid coffee and other caffeinated beverages.
  • Valproic acid. The following studies suggest that valproic acid effects in vitro are mixed and the clinical consequences of valproic acid usage in patients with Glut1-DS cannot be predicted.
    • Valproic acid inhibited Glut1 transport activity in normal and Glut1-deficient erythrocytes by 20%-30%. In primary astrocytes as well as in normal and Glut1-deficient fibroblasts, sodium valproate inhibited glucose transport by 20% - 40%, accompanied by an up to 60% down-regulation of GLUT1 mRNA expression [Wong et al 2005].
    • A study using cultured astrocytes from the Glut1-DS mouse model showed an upregulation of Glut1 activity at lower valproic acid concentrations presumably from the valproic acid associated inhibition of histone deacetylase activity [Kim et al 2013].

Evaluation of Relatives at Risk

If the disease-causing mutation has been identified in an affected family member, it is appropriate to test at-risk newborns and symptomatic infants so that morbidity can be reduced by early diagnosis and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is most commonly inherited in an autosomal dominant manner [Brockmann et al 1999, Brockmann et al 2001, Ho et al 2001a, Klepper et al 2001, Wang et al 2001a, Wang et al 2005] and affected individuals are heterogygous for the disease-causing mutation.

Two families have demonstrated autosomal recessive inheritance [Klepper et al 2009, Rotstein et al 2010]; one of the families was consanguineous.

Risk to Family Members – Autosomal Dominant inheritance

Parents of a proband

Sibs of a proband

Offspring of a proband. Each child of an individual with Glut1-DS has a 50% chance of inheriting the mutation and being clinically affected.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, other family members also are at risk.

Risk to Family Members – Autosomal Recessive inheritance

Parents of a proband

  • The parents of an individual with an autosomal recessive Glut1-DS are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with an autosomal recessive form of Glut1-DS are obligate heterozygotes (carriers) for a disease-causing mutation in SLC2A1.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Glut1 Deficiency Foundation
    PO Box 943
    Westfield IN 46074
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Colleen Giblin Foundation
    690 Kindermack Road
    Suite 104
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  • Epilepsy Foundation
    8301 Professional Place
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  • The Child Brain Foundation
    5930 Royal Lane
    Suite E PMB #231
    Dallas TX 75230
    Phone: 214-234-0742
    Fax: 253-648-3112
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  • Dystonia International Patient Registry (DIPR)
    Email: contact@dipregistry.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Glucose Transporter Type 1 Deficiency Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Glucose Transporter Type 1 Deficiency Syndrome (View All in OMIM)

138140SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 1; SLC2A1
606777GLUT1 DEFICIENCY SYNDROME 1; GLUT1DS1
612126GLUT1 DEFICIENCY SYNDROME 2; GLUT1DS2

Gene structure. The genomic sequence is approximately 35 kb, with ten exons and nine introns. The promoter region contains sequence elements for transcription factors, including a TATA box and a phorbol ester-responsive element. Two enhancer elements within SLC2A1 have been identified: the first is located between 3.3 and 2.7 kb upstream from the transcription initiation site; the second is located within the second intron, between 16.7 kb and 18.0 kb downstream from the transcription initiation site. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. No benign variants have been identified.

Pathogenic allelic variants. See Table 2 for summary.

Exonic, multiexonic, or whole-gene deletions have been reported [Seidner et al 1998, Wang et al 2000, Vermeer et al 2007, Leen et al 2010, Levy et al 2010, Yang et al 2011].

Table 2. SLC2A1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.376C>Tp.Arg126CysNM_006516​.2
NP_006507​.2
c.377G>Ap.Arg126His
c.377G>Tp.Arg126Leu
c.766_767delAAinsGTp.Lys256Val
c.997C>Tp.Arg333Trp
c.884C>Tp.Thr295Met

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Glut1 (solute carrier family 2, facilitated glucose transporter member 1) is a 492-amino acid, 45- or 55-kd (depending on the state of glycosylation) integral membrane protein with intracellular amino and carboxyl termini and 12 transmembrane domains, which probably span the plasma membrane as alpha-helices and line a pore through which glucose and other substrates are translocated. Glut1 is expressed at the blood-brain barrier facilitating transport of glucose across the luminal and abluminal endothelial membranes of the cerebral microvessel and facilitating transport of glucose across the astroglial plasma membrane, thus representing the fundamental vehicle by which glucose enters the brain. Additionally, the transporter recognizes other substrates such as galactose, glycopeptides, water, and dihydroascorbic acid (DHA), some or all of which may also be translocated in significant amounts, although the pathophysiologic role of these processes in Glut1-DS is not known [Klepper et al 1998].

Abnormal gene product. Abnormal Glut1 protein results from frameshift mutations that predict a truncated protein, missense mutations, or, in the most severe cases, absent protein production from a deleted allele [Seidner et al 1998, Wang et al 2000, Levy et al 2010]. Loss of function with missense mutations and deletions ranges from minimal kinetic abnormalities to loss of protein synthesis from the mutant allele.

Almost all individuals with the diagnosis of Glut1-DS have shown decreased erythrocyte 3-OMG uptake (zero-trans influx) values that are about 50% of control values [Wang et al 2005, Fujii et al 2007, Fujii et al 2011, Yang et al 2011]. Values in affected individuals have ranged from 36-74%. In all cases, the normal allele contributes approximately 50% of functional Glut1 protein to the plasma membrane [Wang et al 2005].

Two families with Glut1-DS inherited in an autosomal recessive manner have been described [Rotstein et al 2010].

  • In one family, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother. A de novo mutation developed in the paternal allele, producing compound heterozygosity.
  • In another family, two mildly affected sisters were homozygous for the Arg468Trp missense mutation which they inherited from their asymptomatic heterozygous consanguineous parents. 3-OMG RBC uptake studies in the older and younger sisters were 66% and 63%, and in the mother and father were 84% and 83%, compared with an intra-assay control. The pattern of inheritance is determined by the relative pathogenicity of the mutation and the associated residual Glut1 activity.

References

Literature Cited

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Suggested Reading

  1. De Vivo DC, Wang D, Pascual JM. Disorders of glucose transport. In: Rosenberg R, DiMauro S, Paulson HL, Ptáček L, Nestler E, eds. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 4 ed. Chap 59. Philadelphia, PA: Butterworth-Heinemann; 2008:653-62.
  2. Gaspard N, Suls A, Vilain C, De Jonghe P, Van Bogaert P. "Benign" myoclonic epilepsy of infancy as the initial presentation of glucose transporter-1 deficiency. Epileptic Disord. 2011;13:300–3. [PubMed: 21865127]
  3. Mullen SA, Marini C, Suls A, Mei D, Della Giustina E, Buti D, Arsov T, Damiano J, Lawrence K, De Jonghe P, Berkovic SF, Scheffer IE, Guerrini R. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol. 2011;68:1152–5. [PubMed: 21555602]
  4. Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology. 2010;75:432–40. [PubMed: 20574033]

Chapter Notes

Revision History

  • 9 August 2012 (me) Comprehensive update posted live
  • 7 July 2009 (me) Comprehensive update posted live
  • 9 September 2008 (cd) Revision: mutations in SLC2A1 identified in some families/individuals with paroxysmal exercise-induced dyskinesia and epilepsy; edits to Genetically Related Disorders
  • 4 April 2007 (jp) Revision: deletion/duplication analysis clinically available
  • 6 December 2006 (me) Comprehensive update posted to live Web site
  • 4 April 2005 (jp) Revision: sequence analysis clinically available
  • 16 July 2004 (me) Comprehensive update posted to live Web site
  • 9 August 2002 (jp) Author revisions
  • 30 July 2002 (me) Review posted to live Web site
  • 21 February 2002 (jp) Original submission
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