Understanding Glut1 DS mechanism of disease

Glucose transporter type-1 deficiency syndrome (Glut1 DS) is caused by mutations in the SLC2A1 gene, which cause a defect in glucose transport to the brain. A mutation of the SLC2A1 gene occurs in 80-90% of people with Glut1 DS. Glucose is inhibited from crossing the blood-brain barrier because of defects in the glucose transporter.1

Efficient transport of glucose across the blood-brain barrier is essential for supplying fuel to the brain. Symptoms of chronic brain energy deficiency include1:

  • Seizures
  • Movement disorders
  • Developmental delays

Mechanism of Disease

Normal glucose transport2
Normal glucose uptake vs Glut1 DS3
Comparison of F-fluorodeoxyglucose (FDG) uptake in normal and Glut1 DS: Red = maximum uptake, blue/black = minimal uptake.

Prevalence and Inheritance1,2,4

First identified in 1991, Glut1 DS is a rare disease that affects from 3000 to 7000 people in the United States. About 90% of cases are caused by spontaneous mutations with no family history.

When Glut1 DS is inherited, it follows an autosomal dominant pattern. Each child of an individual with Glut1 DS has a 50% chance of inheriting the mutation. Genetic testing can determine if other family members carry the mutated gene, even if they are asymptomatic. Learn about genetic testing for Glut1 DS.

Spectrum of Disease1

CLASSIC

NONCLASSIC

SEIZURES
ONLY

SEIZURES
MOVEMENT DISORDERS
DEVELOPMENTAL DELAYS

MOVEMENT DISORDERS

POSSIBLY WITH
DEVELOPMENTAL DELAYS

CLASSIC
SEIZURES
ONLY
• SEIZURES
• MOVEMENT DISORDERS
• DEVELOPMENTAL
DELAYS
NONCLASSIC
• MOVEMENT DISORDERS
• POSSIBLY WITH
DEVELOPMENTAL DELAYS

Classic Glut1 DS1

The classic form of Glut1 DS, with seizures only or with seizures plus movement disorders and developmental delays, occurs in 90% of people with Glut1 DS. Their Glut1 activity is 50% on average compared to that in normal red blood cells (RBCs), with less reduction in milder mutations.4

Seizure onset usually begins in infancy—90% before 2 years of age. Most have more than one seizure type, and the seizures are often difficult to control with antiepileptic drugs (AEDs). Unlike seizures—which may become less frequent with age—movement disorders and developmental delay become more common as patients age.1,4,5

Nonclassic Glut1 DS1

A milder phenotype with less reduction in Glut1 activity in RBCs occurs in 15% of people with Glut1 DS. These patients may have movement disorders and/or developmental delays—symptoms that usually aren’t apparent in infancy.

LEARN ABOUT DIAGNOSING PATIENTS WITH GLUT1 DS >

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References: 1. Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013;13(4):342-350. doi:10.1007/s11910-013-0342-7. 2. De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med. 1991;325(10):703-709. 3. Pascual JM, Liu P, Mao D, et al. Triheptanoin for glucose transporter type 1 deficiency (G1D) modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. JAMA Neurol. 2014;71(10):1255-1265. doi:10.1001/jamaneurol.2014.1584. 4. Wang D, Pascual JM, De Vivo D. Glucose transporter type 1 deficiency syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1430/. Published July 30, 2002. Updated January 22, 2015. 5. Alter AS, Engelstad K, Hinton VJ, et al. Long-term clinical course of Glut1 deficiency syndrome [published online ahead of print April 30, 2014].  J Child Neurol. 2015;30(2):160-169. doi:10.1177/0883073814531822.