Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS) [G40.3]

OMIM numbers: 606777138140 (SLC2A1)

Dr. rer. nat. Karin Mayer

Scientific Background

The classic glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a disease which was described by de Vivo in 1991. It is characterized by early onset (during infancy), therapy-resistant epilepsy and epileptic encephalopathy, severe developmental delay, acquired microcephaly as well as complex movement disorder with muscular hypotonia or spasticity, ataxia, dystonia or chorea. The phenotypical GLUT1-DS spectrum also comprises the paroxysmal activity-induced dyskinesia and epilepsy (DYT18) and the paroxysmal choreoathetosis with spasticity (DYT9). In 90% of all classic GLUT1-DS cases, the epilepsy starts within the first two years of life with one of the five seizure types: generalized tonic or clonic, myoclonic, atypical absence, atonic or unclassified epilepsy. The severity of the movement disorders is frequently increased by fasting, fever or infections. The incidence is estimated to be 1 in 90,000. In most cases, Glut1-DS is autosomal dominant; although 90% are caused by new mutations and only 10% of all patients have one affected parent.

GLUT1-DS is caused by mutations in the SLC2A1 gene, which encodes the glucose transporter in the blood-brain barrier, GLUT1. SLC2A1 consists of 10 exons, extending over 35 kb of genomic sequence. About 81-89% of all SLC2A1 mutations are point mutations; 11-14% of all patients have genomic deletions. SLC2A1 mutations are loss of function mutations, which contain both frameshift as well as missense mutations with residual activity of the protein; in severe cases, however, an SLC2A1 allele may be entirely absent. There is a genotype-phenotype correlation. Missense mutations lead to a mild to moderate phenotype; nonsense, splice and frameshift mutations as well as intragenic deletions are described to cause a moderate or severe phenotype. Entire gene deletions result in a particularly severe clinical course. Apart from GLUT1-DS, alterations in SLC2A1 are also detected in 10% of all patients with childhood absence epilepsies (early onset absence epilepsy, EOAE).

GLUT1 (solute carrier family 2, facilitated glucose transporter member 1) is an integral membrane protein of 492 amino acids, which enables the only possibility of transport of glucose through the blood-brain barrier via a pore region. SLC2A1 mutations result in hypoglycorrhachia. A ketogenic diet can avoid the metabolic pathway of glucose and provides ketones as an alternative source of energy.

The diagnosis can be established neurologically by detecting hypoglycorrhachia (decreased glucose concentration in the liquor (< 60 mg/dl in all cases described; < 40 mg/dl in > 90% of all cases; 41-52 mg/dl in ~10% of all cases)) with normal blood glucose levels after four hours of fasting. Since lactate can be used as an alternative source of energy as well, lower lactate concentrations can be detected in the liquor of some patients.