Clinical Diagnosis

Glucose transporter type 1 deficiency syndrome (Glut1-DS) usually presents in early infancy with seizures refractory to anticonvulsants, followed by deceleration of head growth, delays in mental and motor development, spasticity, ataxia, dysarthria, opsoclonus, and other paroxysmal neurologic phenomena, often occurring prior to meals [Klepper et al 1999c].

Testing

Glucose concentration

• Cerebrospinal fluid (CSF). The single most important laboratory observation in Glut1-DS is hypoglycorrhachia (reduced CSF glucose concentration); the absolute CSF glucose concentration seldom exceeds 40 mg/dL.

• Ratio of CSF glucose concentration to blood glucose concentration. CSF glucose concentration is measured following a four-hour fast. Blood glucose concentration is measured shortly before lumbar puncture. Under these conditions, the ratio is consistently about 0.33±0.01 (normal ratio: 0.65±0.01). Mild phenotypes may have higher ratios [De Vivo & Wang 2008].

CSF lactate concentration. This value is low-normal or low, often below 1.3 mmol/L [Wang et al 2005].

Erythrocyte glucose transporter activity. Decreased 3-O-methyl-D-glucose uptake in erythrocytes also supports the diagnosis of Glut1-DS. Individuals with Glut1-DS have a reduction of approximately 50% in glucose uptake relative to normal controls [Klepper et al 1999b]. Testing is available on a clinical basis.

Positron emission tomography (PET). Cerebral fluoro-deoxy-glucose PET findings are quite distinctive with diffuse neocortical hypometabolism and regional hypometabolism involving the cerebellum, mesial temporal lobes, and thalamus. Basal ganglia metabolism is relatively preserved. This disparity in metabolism appears in early infancy and persists into adulthood regardless of disease severity or therapy [Pascual et al 2002]. PET is an additional tool that can aid in the diagnosis of Glut1-DS; however, the sensitivity and specificity of PET in Glut1-DS are not known.

Molecular Genetic Testing

Gene. SLC2A1 is the only gene in which mutation currently known to be associated with Glut1-DS.

Clinical testing

• Sequence analysis detected mutations in 106/116 (91%) of affected individuals tested [Wang et al 2005; Wang et al, unpublished data].

• Deletion/duplication analysis. Four individuals with whole-gene deletions have been reported to date [Seidner et al 1998, Wang et al 2000, Vermeer et al 2007].

Table 1. Summary of Molecular Genetic Testing Used in Glucose Transporter Type 1 Deficiency Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SLC2A1	Sequence analysis 2	Sequence variants 3	91%	Clinical
	Deletion / duplication analysis 4	Exonic, multiexonic, or whole-gene deletions	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

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

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), SNP oligonucleotide microarray analysis (SOMA), fluorescence in situ hybridization (FISH), or array GH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband

• Following a four-hour fast, measure glucose concentration in the CSF and calculate the ratio of CSF glucose concentration to blood glucose concentration obtained just before the lumbar puncture. The blood glucose concentration should be normal, ruling out hypoglycemia as the cause of the hypoglycorrhachia.

• Perform erythrocyte glucose transport assay (when feasible).

• Perform molecular genetic testing of SLC2A1.

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

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than the ones described in this GeneReview are known to be caused by mutations in SLC2A1.

Natural History

Infants with glucose transporter type 1 deficiency syndrome (Glut1-DS) appear normal at birth following an uneventful pregnancy and delivery. Birth weight and Apgar scores are normal. Affected children then experience infantile-onset epileptic encephalopathy associated with delayed neurologic development, deceleration of head growth and acquired microcephaly, ataxia, dystonia and spasticity [De Vivo et al 2002a, De Vivo et al 2002b].

Seizures, usually beginning between age one and four months, are the first clinical indication of brain dysfunction. Apneic episodes and abnormal episodic eye movements simulating opsoclonus may precede the onset of seizures by several months. The infantile seizures are clinically fragmented (i.e., non-generalized), as is typical at this age.

The electroencephalogram (EEG) demonstrates multifocal spike discharges. With further brain maturation, the seizures become more synchronized and present clinically as generalized events associated with an atypical 3- to 4-Hz spike and wave discharge.

Five seizure types occur: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. The frequency of seizures varies among individuals: some experience daily events; others have only occasional seizures separated by days, weeks, or months; two reported individuals never had a clinical seizure [von Moers et al 2002, Leary et al 2003]. About 10% of cases never have clinical seizures [De Vivo et al, unpublished observations].

Paroxysmal exercise-induced dyskinesia and epilepsy. Heterozygous mutations in SLC2A1 have been identified in six families and two simplex cases with paroxysmal exercise-induced dyskinesia and epilepsy (also known as dystonia 18 [DYT18]) These familial cases differ clinically from those with classic glucose transporter type 1 deficiency in that they demonstrate normal interictal neurologic examination (most individuals), normal head circumference, exercise-induced dyskinesias, and later onset of seizures [Suls et al 2008, Weber et al 2008, Zorzi et al 2008]. The CSF glucose concentrations tend to be higher (41-52 mg/dL) in this allelic variant [De Vivo & Wang 2008].

Other paroxysmal events including intermittent ataxia, mental confusion, lethargy or somnolence, hemiparesis, total body paralysis, sleep disturbances, and recurrent headaches have been described [Overweg-Plandsoen et al 2003]. It is unclear whether these events represent epileptic or non-epileptic phenomena. These neurologic symptoms generally fluctuate and may be influenced by factors such as fasting or fatigue.

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 disproportionately affected.

Varying degrees of cognitive impairment, ranging from learning disabilities to severe intellectual disability, are observed.

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.

Pathogenesis. 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 member 1), the protein product of SLC2A1, is the fundamental vehicle by which glucose enters the brain. The cerebral metabolic rate for glucose is low during fetal development and at birth. The rate increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and gradually declines 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 and the newborn period is low, whereas the risk is increased later in infancy and early childhood.

Genotype-Phenotype Correlations

For the moment, the 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. Intermittent symptoms (epilepsy, dyskinesias and ataxia) may be predicted with modest (perhaps 25%) reduction in Glut1 transporter expression; and more continuous and severe brain symptoms (intellectual disability, microcephaly, epilepsy, and dystonia) may be predicted with greater (perhaps 25%-75%) reduction in Glut1 transporter expression. Absence of Glut1 transporter expression is embryonic lethal [De Vivo & Wang 2008].

Several mutation hot spots have been identified:

• Three affected individuals, each from a different family, have a heterozygous p.Arg333Trp missense mutation. The clinical phenotypes are mild in each case [Author, personal observation].

• Six affected individuals have a heterozygous missense mutation at amino acid residue arginine 126.

  • Three family members have a p.Arg126His mutation [Brockmann et al 2001] and two family members have a p.Arg126Cys mutation [Ho et al 2001a]. These five individuals have a mild phenotype as discussed previously.

  • One affected individual has a p.Arg126Leu mutation in trans with a p.Lys256Val mutation [Pascual et al 2008]. The genetic compound (p.Arg126Leu and p.Lys256Val) is associated with a severe phenotype. The father is clinically well and has neither missense mutation. The mother is asymptomatic but is heterozygous for the p.Lys256Val mutation. Mutagenesis studies in Xenopus oocytes showed in an “uptake study” under zero-trans influx conditions that the p.Arg126Leu missense mutation is more pathogenic than the p.Lys256Val missense mutation. We have concluded that the asymptomatic mother has sufficient residual Glut1 activity to allow her to function normally. It remains unclear whether synergy between the two missense mutations is causing a severe phenotype in the compound heterozygous state [Author, unpublished data].

All except three 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, Fuji et al 2007]. Two of these three exceptional individuals shared a similar mild phenotype including monthly seizures beginning in infancy, developmental delay, ataxia, microcephaly, language deficit, hypoglycorrhachia, and low normal CSF lactate concentrations. The erythrocyte zero-trans influx of 3-OMG was normal and both were heterozygous for the p.Thr295Met mutation in GLUT1. Mutagenesis studies suggest that the p.Thr295Met mutation specifically alters Glut1 conformation and asymmetrically affects glucose flux across the cell by perturbing efflux more than influx. These findings explain the seemingly paradoxical findings of Glut1 DS with hypoglycorrhachia and “normal” erythrocyte glucose uptake [Wang et al 2008].

About 50% of the novel mutations we have identified are located in a vulnerable region in the Glut 1 protein that involves the fourth transmembrane domain encoded by exon 4, suggesting a critical disturbance in function associated with structural alterations in this region of the protein [Pascual et al 2008].

Penetrance

Penetrance is complete.

Anticipation

For unknown reasons, familial cases may manifest more severe disease in subsequent generations.

Nomenclature

Paroxysmal exercise-induced dyskinesia and epilepsy (also known as dystonia 18 [DYT18]) is now recognized to be part of the phenotypic spectrum of Glut1-DS.

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. The authors estimate the incidence/prevalence in Queensland, Australia at approximately 1:90,000 – a conservative estimate under the conditions of ascertainment [Coman et al 2006].

Evaluations Following Initial Diagnosis

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

• General physical examination

• Neurologic examination

• Lumbar puncture (glucose, lactate)

• EEG

• Brain imaging

• Neuropsychological assessment

Treatment of Manifestations

Ketogenic diet. Because ketone bodies are easily transported across tissue membranes, they are readily available for uptake and metabolism by brain cells. The ketogenic diet was introduced as a treatment for Glut1-DS in 1991. In the diet, most carbohydrates are replaced by lipids and proteins in varying ratios. Experience over the past decade indicates that the ketogenic diet is highly effective in controlling the seizures and is well tolerated in most cases; however, despite control of seizures, affected individuals continue to have varying neurobehavioral deficits involving cognition and social adaptive behavior [Klepper et al 2002]. Seizures may recur even with good dietary compliance [Klepper et al 2005].

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 initiation of a ketogenic diet results in better seizure control and improved neurologic prognosis by mitigating neuroglycopenia during this critical period. Brain glucose consumption increases rapidly after birth and peaks between ages three and eight years.

Agents/Circumstances to Avoid

Barbiturates are known to inhibit transport of glucose. Generally, individuals with infantile-onset seizures are treated with phenobarbital, the most commonly used antiepileptic drug in this age group. On occasion, parents have reported that phenobarbital did not improve their child’s seizure control or may have worsened their child's clinical condition. In vitro studies indicate that barbiturates aggravate the Glut1 transport defect in erythrocytes of individuals with Glut1-DS [Klepper et al 1999a].

Methylxanthines (e.g., caffeine) also have been reported to worsen the clinical state of individuals with Glut1-DS [Brockmann et al 2001]. Methylxanthines are known to inhibit transport of glucose by Glut1 [Ho et al 2001b]. It is advisable for affected individuals to avoid coffee and other caffeinated beverages.

Testing of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk newborns and symptomatic infants if the disease-causing mutation has been identified in an affected family member 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.

Other

Antiepileptic drugs (AEDs) are generally ineffective or afford only limited improvement.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is 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].

Risk to Family Members

Parents of a proband

• Few individuals diagnosed with Glut1-DS have an affected parent.

• When one parent is affected by the disease, the degree of impairment may be mild or even subclinical. Mosiacism may explain this observation.

• A proband with Glut1-DS often has the disorder as the result of a de novo gene mutation.

• Recommendations for the evaluation of parents of an individual with Glut1-DS and no known family history of Glut1-DS include comparison of erythrocyte glucose uptake with control and molecular genetic testing of both parents if the mutation in the proband has been identified.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.

• If a parent is affected or has a disease-causing mutation, the risk is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. The clinically unaffected parent may be mosaic for the pathogenic mutation.

• If the disease-causing mutation cannot be detected in the DNA extracted from leukocytes of either parent, the risk to sibs is low but greater than that of the general population. Although no instances of germline mosaicism have been reported, it remains a possibility, especially because somatic mosaicism has been reported [Wang et al 2001b].

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, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing 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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

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 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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. Disorders of Glucose Transport, The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 4 ed. Chap 59. Philadelphia, PA: Butterworth-Heinemann; 2008:653-62.

Revision History

• 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