Glucose transporter type 1 deficiency syndrome

Glucose transporter type 1 (GLUT1) deficiency syndrome is a rare inborn error of metabolism. GLUT1 is a protein responsible for the transportation of glucose through the blood-brain barrier. As glucose is required for brain metabolism, a shortage leads to the impairment of brain function and causes a variety of symptoms, including seizures, movement conditions and intellectual disability.

From infancy or early childhood, clinical features include:

• seizures (at all ages, even from the very first months of life): these can be of any type, but are usually absences, myoclonic (‘jerk’), atonic (‘drop’) and/or tonic-clonic (90% of cases);
• acquired microcephaly;
• developmental delay;
• dysarthria;
• intermittent ataxia;
• movement conditions (spasticity, dystonia, chorea, athetosis); and
• atypical paroxysmal eye movements.

Symptoms may be exacerbated by fasting or fatigue. Around 10% of individuals have a milder ‘non-classic’ presentation without clinical seizures, which may include intermittent ataxia, alternating hemiplegia, dystonia and choreoathetosis.

Clinical diagnosis is secured by comparing blood to cerebrospinal fluid (CSF) glucose following a four- to six-hour period of fasting. If the ratio is less than 0.4, GLUT1 deficiency would be the most likely diagnosis.

The GLUT1 protein is encoded by the SLC2A1 gene located on chromosome 1. Genomic testing in those with a clinical diagnosis of GLUT1 deficiency reveals a pathogenic variant in the SLC2A1 gene in approximately 80% of cases.

Around 90% of diagnosed cases are due to heterozygous de novo pathogenic variants of the SLC2A1 gene. In cases in which the variants are inherited, the parent may be less affected than the child.

Rarely, individuals may have pathogenic variants on both copies of the SLC2A1 gene; in these circumstances, carriers are unaffected.

For information about testing, see Presentation: Infant with early onset epilepsy or epileptic encephalopathy.

GLUT1 deficiency syndrome is mainly inherited in an autosomal dominant pattern. An individual with the condition usually has a 50% chance of passing along the SLC2A1 pathogenic variant to his or her offspring.

Where neither parent is shown to have the variant, the chance of recurrence in a future pregnancy is low (less than 1%), though not quite back to population level due to the possibility of the variant being present in a few egg or sperm cells (this is called constitutional (germline) mosaicism).

In those rare cases in which an individual has an autosomal recessive form of the condition with homozygous or compound heterozygous pathogenic variants, parents are typically unaffected carriers. In these cases, there is a 25% chance of each subsequent pregnancy being affected.

If requested, and if the pathogenic variants in SLC2A1 have been identified within the family, prenatal testing or preimplantation genetic diagnosis may be considered.

Management of patients with GLUT1 deficiency syndrome is complex and should be delivered via a multidisciplinary team, with detailed suggested approaches published by several authors (see resources list below). Once diagnosed, a medically supervised ketogenic diet is usually recommended as it can help to control seizures and additional symptoms. Seizures are usually resistant to the majority of anti-seizure medications, and phenobarbitol, caffeine and valproic acid should be avoided.

For clinicians

• GeneReviews: Glucose transporter type 1 deficiency syndrome.
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• US National Library of Medicine: ClinicalTrials.gov database

For patients

• Matthew’s Friends: Ketogenic dietary therapies