Clinical characteristics.

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported into the brain exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood.

When first diagnosed in infancy to early childhood, the predominant clinical findings of Glut1DS are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and developmental delay. Subsequently children develop complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome.

When first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings of Glut1DS are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability.

Diagnosis/testing.

The diagnosis of Glut1DS is established in a proband with suggestive clinical findings, hypoglycorrhachia documented by lumbar puncture, and a (usually) heterozygous pathogenic variant in SLC2A1 identified by molecular genetic testing. Rarely, an individual with suggestive clinical findings and hypoglycorrhachia has biallelic SLC2A1 pathogenic variants.

Management.

Targeted therapy: Age-specific KDTs primarily provide a supplemental fuel, namely, ketone bodies, for brain energy metabolism. KDTs create chronic ketosis by largely replacing carbohydrates and proteins with lipids in varying ratios.

Supportive care: In addition to educational programs to address the individual's needs, multidisciplinary care by specialists in neurology familiar with KDTs, physical medicine and rehabilitation, physical therapy, occupational therapy, speech and therapy, and clinical genetics and genetic counseling.

Surveillance: Routinely scheduled evaluations with a neurologist (to determine response to KDTs and identify any new manifestations) as well as follow up per treating physical therapists, occupational therapists, and speech-language therapists.

Agents/circumstances to avoid: In individuals on KDTs: (1) avoidance of treatment of seizures with valproic acid, because it increases the risk of a Reye-like illness and may also inhibit glucose transport; (2) other anti-seizure medications (ASMs) including phenobarbital, acetazolamide, topiramate, and zonisamide may be relatively contraindicated as adjunctive treatment.

Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborns, infants, and other relatives of a proband to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early initiation of KDTs, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.

Genetic counseling.

Glut1DS is most commonly caused by a heterozygous SLC2A1 pathogenic variant and inherited in an autosomal dominant manner. About 90% of individuals with Glut1DS have the disorder as the result of a de novo SLC2A1 pathogenic variant; about 10% of individuals have the disorder as the result of a pathogenic variant inherited from a parent. The degree of impairment in the transmitting parent may be mild or nonexistent; parental somatic mosaicism for the SLC2A1 pathogenic variant may explain this observation. Each child of an individual with autosomal dominant Glut1DS has a 50% chance of inheriting the SLC2A1 pathogenic variant and being clinically affected.

Autosomal recessive inheritance has been reported in two families to date.

Once the SLC2A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for Glut1DS are possible.

Suggestive Findings

Glut1DS should be suspected in probands with the following clinical features by age, laboratory findings, and family history [Klepper et al 2020].

Establishing the Diagnosis

The diagnosis of Glut1DS is established in a proband with suggestive clinical findings, hypoglycorrhachia documented by lumbar puncture (see Table 1), and a (usually) heterozygous pathogenic (or likely pathogenic) variant in SLC2A1 identified by molecular genetic testing [Klepper et al 2020] (full text) (see Table 2). Rarely, an individual with suggestive clinical findings and hypoglycorrhachia has biallelic SLC2A1 pathogenic (or likely pathogenic) variants [Klepper et al 2009, Rotstein et al 2010].

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SLC2A1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include comprehensive genomic testing (exome sequencing, genome sequencing) or gene-targeted testing (multigene panel). Comprehensive genomic testing does not require that the clinician determine which gene(s) are likely involved, whereas use of a multigene panel does.

Note: (1) Single-gene testing (sequence analysis of SLC2A1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Given the broad phenotypic spectrum of Glut1DS, use of a multigene panel may also be too restrictive.

• Comprehensive genomic testing. Exome sequencing is most often used; genome sequencing is also possible. While the majority of SLC2A1 pathogenic variants reported to date are within the coding region and are likely to be identified on exome sequencing, non-coding variants have been reported that would be detectable by genome sequencing [Liu et al 2016].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes SLC2A1 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood [Chugani et al 1987].

The cardinal findings of Glut1DS in children are eye-head movement abnormalities, epilepsy, movement disorders, and developmental delay (DD); however, affected children may not have all these early movement abnormalities and/or they are often not identified as such and thus are overlooked. When Glut1DS is diagnosed in infancy to early childhood, the predominant clinical findings are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and DD. Subsequently these children display complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome [Alter et al 2015, Kramer & Smith 2021].

When Glut1DS is first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability.

To date, several hundred individuals have been reported with Glut1DS [Klepper et al 2020]. This number represents only a fraction of affected individuals predicted by available data (see Prevalence).

Genotype-Phenotype Correlations

Milder manifestations (e.g., intermittent epilepsy, dyskinesias, and ataxia) of Glut1DS are associated with 25%-35% reduction in Glut1 transporter function [Rotstein et al 2010]. More severe manifestations in infantile- and childhood-onset Glut1DS are associated with greater reductions (perhaps 40%-75%) in Glut1 transporter function [Yang et al 2011]. The following classes of SLC2A1 pathogenic variants associated with these phenotypes [Klepper et al 2020]:

• Missense variants. Predominantly mild or moderate clinical phenotype
• Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype
• Complete gene deletions. Severe clinical phenotype

Penetrance

Penetrance in Glut1DS inherited in an autosomal dominant manner is complete. If an asymptomatic or minimally symptomatic parent of a fully symptomatic child is identified by genetic testing, one should investigate the possibility that the parent is mosaic for the SLC2A1 pathogenic variant. Mosaicism blunts the clinical severity of the condition.

Nomenclature

The following disorders are now recognized to be part of the Glut1DS phenotypic spectrum [Suls et al 2008, Weber et al 2008, Zorzi et al 2008, Chinnery 2010, Leen et al 2010, Urbizu et al 2010, Flatt et al 2011, Weber et al 2011, Yang et al 2011, Furia et al 2023]:

• Paroxysmal exercise-induced dyskinesia and epilepsy (also referred to as PxMD-SLC2A1 [Marras et al 2016] and previously known as dystonia 18 [DYT18] or DYT-SLC2A1)
• Paroxysmal choreoathetosis with spasticity (DYT9)
• Early-onset childhood absence epilepsy
• Epilepsy with myoclonic-atonic seizures
• Cryohydrocytosis (stomatocytosis that leads to hemolytic anemia induced by cold exposure)

Prevalence

The first attempt to estimate birth incidence and point prevalence that was conducted in Australia suggested a prevalence of 1:90,000 [Coman et al 2006]. A later study from Scandinavia yielded an incidence/prevalence of 1:83,000 [Larsen et al 2015]. The most recent study to date, using epilepsy in early childhood as a clinical marker, suggested an incidence/prevalence of 1:24,000 in Scotland [Symonds et al 2019]. If correct, about 150-200 individuals would be newly diagnosed annually in the United States and 5,000-5,500 annually worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Glut1DS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for Glut1DS.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Barbiturates. Generally, children with infantile-onset seizures are treated with phenobarbital, the most used ASM in this age group. In vitro studies indicate that barbiturates aggravate the glucose transporter type 1 (Glut1) transport defect in erythrocytes of individuals with Glut1DS [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.

Valproic acid. Although studies suggest that valproic acid effects in vitro are mixed and the clinical consequences of valproic acid usage in individuals with Glut1DS cannot be predicted [Wong et al 2005, Kim et al 2013], the authors do not feel that these mixed in vitro data minimize the clinical concerns and recommend avoiding this drug as a treatment of seizures in the setting of KDTs.

Acetazolamide, topiramate, and zonisamide inhibit carbonic anhydrase and may potentiate metabolic acidosis. They can also cause kidney stones.

Methylxanthines (e.g., caffeine), which are known to inhibit transport of glucose by Glut1 [Ho et al 2001], have been reported to worsen the clinical findings in individuals with Glut1DS [Brockmann et al 2001]. Thus, it is advisable for affected individuals to avoid coffee and other caffeinated beverages.

Evaluation of Relatives at Risk

It is appropriate to evaluate at-risk newborns, infants, and other relatives to identify as early as possible those who would benefit from initiation of treatment and preventive measures; early initiation of KDTs, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.

• Molecular genetic testing can be used to clarify the genetic status of at-risk relatives if the SLC2A1 pathogenic variant in the family is known.
• If the SLC2A1 pathogenic variant in the family is not known, lumbar puncture can be performed to measure cerebrospinal fluid (CSF) glucose and lactate concentrations in family members with clinical findings suggestive of Glut1DS (see Diagnosis). (See also Author Notes for information on research assays expected to be available on a clinical basis in the near future.)

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

Pregnancy Management

Experience with KDTs during pregnancy is limited. One mildly affected woman with Glut1DS tolerated KDT well during pregnancy. KDT was continued postnatally in her infant, who inherited the mother's pathogenic variant [Kramer & Smith 2021]. At age ten years, the child is developmentally normal and seizure activity / movement disorders have not been reported [D De Vivo, unpublished data].

Therapies Under Investigation

Triheptanoin. This odd-carbon medium-chain triglyceride consists of three seven-carbon fatty acids on a glycerol backbone. Open-label studies suggested possible benefit of triheptanoin as a treatment for seizures and movement disorders in Glut1DS. However, in a randomized, double-blind trial of triheptanoin for treatment of drug-resistant epilepsy in Glut1DS, triheptanoin did not significantly reduce seizure frequency in individuals with Glut1DS who were not on KDTs [Striano et al 2022]. Similarly, triheptanoin did not show benefit vs placebo for the treatment of paroxysmal movement disorders in Glut1DS [De Giorgis et al 2024]. Both studies used safflower oil as the placebo.

Diazoxide blocks the release of insulin from the beta cells in the pancreas and has been used for decades as a treatment for genetic hyperinsulinism. Anecdotal experience with diazoxide in Glut1DS suggests that this drug may be helpful in the management of some patients [Logel et al 2021]. The concept behind use of diazoxide as treatment of Glut1DS is the increased transport of glucose from blood to brain associated with mild hyperglycemia.

Levodopa. Movement disorders are difficult to treat in Glut1DS patients. Anecdotal experience suggests that levodopa treatment may benefit patients with dystonia and associated movement disorders [Baschieri et al 2014].

Gene therapy. Mice treated with murine Glut1 packaged into adeno-associated virus 9 (AAV9) and relevant controls were assessed during adult life. In AAV9-Glut1-treated mice, Glut1 RNA and protein levels rose, CSF glucose levels were restored when the mice were treated early in development (but not if treated later), brain size was normalized, seizure frequency was reduced, brain glucose uptake was enhanced, and motor defects were corrected [Monani et al 2014, Tang et al 2017]. Glut1DS caused an arrest in cerebral angiogenesis and triggered significant brain neuroinflammation that could be avoided if gene therapy was performed before age two weeks. Importantly, these studies demonstrated that the benefits of gene therapy persisted for over 12 months without causing off-target effects.

Genetic elements within or outside the SLC2A1 gene locus that have been shown to modulate Glut1 expression could also be delivered in viral vectors as therapies for Glut1DS [Obaid et al 2021, Li et al 2022].

To further develop Glut1 gene therapy for clinical use, AAV9-Glut1 was delivered through the cisterna magna to a porcine model. High levels of virally delivered Glut1 in brain endothelia and, to a lesser extent, in the neuropil were reported [Nakamura et al 2021]. Tropism of AAV9 for the human brain endothelia, a critical cell type to target for Glut1DS [Tang et al 2021], remains to be determined. Such determination, which routinely involves non-human primates, is important before gene therapy for Glut1DS is implemented in the clinic.

Notwithstanding the caveat identified above, gene therapy studies for Glut1DS provide important proof-of-concept data of the therapeutic effects of restoring Glut1 protein function early in the life of individuals with Glut1DS and represent an important step toward finding a disease-modifying treatment for the human disease. These findings also indicate the need for newborn screening to facilitate identification and treatment of individuals with genetically confirmed Glut1DS presymptomatically in early infancy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Glucose transporter type 1 deficiency syndrome (Glut1DS) is most commonly caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner.

Autosomal recessive inheritance has been reported in two families to date:

• A consanguineous family [Klepper et al 2009]
• A family in which a severely affected child had an SLC2A1 missense variant (NM_006516.2:c.766_767delAAinsGT [p.Lys256Val]) inherited from her heterozygous, asymptomatic mother with a de novo missense variant (NM_006516.2:c.377G>T [p.Arg126Leu]) on the opposite homologous allele [Rotstein et al 2010]. (Note: Based on the results of mutagenesis studies in Xenopus oocytes and assay of 3-O-methyl-D-glucose uptake [see Author Notes], it was suggested that synergy between the two missense variants caused the severe phenotype in the child, a compound heterozygote.)

In families with autosomal recessive Glut1DS, heterozygous individuals are asymptomatic [Rotstein et al 2010].

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• About 10% of individuals diagnosed with Glut1DS have the disorder as the result of an SLC2A1 pathogenic variant inherited from a parent [Wang et al 2005, Yang et al 2011]. The degree of impairment in the transmitting parent may be mild or nonexistent; parental somatic mosaicism for the SLC2A1 pathogenic variant may explain this observation [Wang et al 2001; Takahashi et al 2017; D De Vivo, unpublished data].
• About 90% of individuals with Glut1DS have the disorder as the result of a de novo SCL2A1 pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
  • Molecular genetic testing if a molecular diagnosis has been established in the proband;
  • Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
  Note: The family history of some individuals diagnosed with Glut1DS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, de novo occurrence of a SLC2A1 pathogenic variant in the proband cannot be confirmed without appropriate evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an SLC2A1 pathogenic variant may be mildly/minimally affected [Wang et al 2001, Takahashi et al 2017].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have an SLC2A1 pathogenic variant, the risk to sibs is 50%.
• If a molecular diagnosis has been established in the proband and the SLC2A1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental somatic or gonadal mosaicism; somatic and gonadal mosaicism have been reported [Wang et al 2001, Takahashi et al 2017].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent [Striano et al 2012, Çolak et al 2017] or parental somatic/gonadal mosaicism.

Offspring of a proband. Each child of an individual with Glut1DS has a 50% chance of inheriting the SLC2A1 pathogenic variant and being clinically affected.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have an SLC2A1 pathogenic variant, the parent's family members are also at risk.

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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC2A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for Glut1DS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Glucose is the essential metabolic fuel for the brain. Glucose transport across the endothelial cells forming the blood-brain barrier (BBB) and astrocyte plasma membrane is exclusively facilitated by the protein glucose transporter type 1 (Glut1; also called solute carrier family 2, facilitated glucose transporter member 1) encoded by SLC2A1 [Klepper et al 2020].

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 BBB to meet the needs of brain metabolism and cerebral function is narrow.

A milder clinical phenotype with intermittent manifestations (epilepsy, dyskinesias, and ataxia) may be predicted with 25%-35% reduction in Glut1 transporter function [Rotstein et al 2010]; a more severe phenotype (infantile- or childhood-onset glucose transporter type 1 deficiency syndrome [Glut1DS]) 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 with classic Glut1DS have on average a 50% uptake assay, resulting from pathogenic loss-of-function variants that result in 50% reduction in Glut1 activity. (See Author Notes.)

A significant fraction (5/21) of known pathogenic variants is in a vulnerable region of the Glut1 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].

Mechanism of disease causation. Loss of function

Author Notes

Assay of 3-O-methyl-D-glucose uptake in erythrocytes is available on a research basis only to date (at the Colleen Giblin Laboratory, Columbia University Irving Medical Center, attention Dr Umrao Monani). The uptake assay is a functional measure of glucose transport across the cell membrane. Individuals with glucose transporter type 1 deficiency syndrome (Glut1DS) 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 should be abnormally low in all proven cases, with only one documented exception.

• Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of SLC2A1-related Glut1DS.
• Molecular genetic testing detects a pathogenic variant in more than 95% of people with abnormally low uptake assay.

Of note, approximately 3% of persons with Glut1DS have a normal uptake assay that is performed at 4 °C, a finding that correlates with the presence of an SLC2A1 pathogenic missense variant (NM_006516.2:c.884C>T [p.Thr295Met]) that retains normal function at low temperature [Cunningham & Naftalin 2013].

In one of the two families reported to date with autosomal recessive inheritance of Glut1DS, the 3-O-methyl-D-glucose uptake assay was useful in determining the molecular pathogenesis and the mode of inheritance. A severely affected child in whom the erythrocyte glucose uptake assay was markedly abnormal (only 37% uptake) had one SLC2A1 pathogenic variant (NM_006516.2:c.377G>T [p.Arg126Leu]) and a second SLC2A1 pathogenic variant (NM_006516.2: c.766_767delAAinsGT [p.Lys256Val]) on the opposite homologous allele. The father, who was clinically well, had neither missense variant. The asymptomatic mother was heterozygous for the p.Lys256Val pathogenic variant. Mutagenesis uptake studies in Xenopus oocytes showed that the p.Arg126Leu missense variant is more pathogenic than the p.Lys256Val missense variant (12.7% vs 3.2%). Therefore, the asymptomatic mother may have sufficient residual Glut1 activity to allow her to function normally. (Her erythrocyte glucose uptake assay revealed 87% residual activity; values of >74% residual activity correlate with a clinically normal state.) It was suggested that synergy between the two pathogenic missense variants caused the severe phenotype in the child, a compound heterozygote [Rotstein et al 2010].

Communication with authors. The authors are actively involved in clinical research regarding individuals with Glut1DS and related disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of these disorders or other considerations.

The authors are also interested in hearing from clinicians treating patients affected by a neurologic syndrome associated with hypoglycorrhachia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Drs Umrao Monani and Maoxue Tang to inquire about review of SLC2A1 variants of uncertain significance.

Acknowledgments

The authors thank all who have been involved in this work since the original description of Glut1DS in 1991 including the patients and their families, philanthropic donors, clinical and laboratory colleagues, and administrative assistants. We also acknowledge the Glut1 Deficiency Foundation, Hope for Children Research Foundation, and individual donors for their generous and continuous support and encouragement.

Author History

Darryl De Vivo, MD (2002-present)
Umrao Monani, PhD (2025-present)
Juan M Pascual, MD, PhD; University of Texas Southwestern Medical Center (2002-2025)
Tristan Sands, MD, PhD (2025-present)
Maoxue Tang, PhD (2025-present)
Dong Wang, MD (2002-present)

Revision History

• 6 March 2025 (bp) Comprehensive update posted live
• 1 March 2018 (ha) Comprehensive update posted live
• 22 January 2015 (me) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 7 July 2009 (me) Comprehensive update posted live
• 6 December 2006 (me) Comprehensive update posted live
• 16 July 2004 (me) Comprehensive update posted live
• 30 July 2002 (me) Review posted live
• 21 February 2002 (jp) Original submission

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