Classical glucose transporter type 1 deficiency syndrome (GLUT1-DS) refers to a clinical picture described by de Vivo in 1991 with therapy-resistant epilepsy and epileptic encephalopathy occurring in infancy, severe developmental disability, acquired microcephaly, and a complex movement disorder with muscular hypotonia or spasticity, ataxia, dystonia, or chorea. The phenotypic GLUT1-DS spectrum also includes paroxysmal activity-induced dyskinesia and epilepsy (DYT18) and paroxysmal choreoathetosis with spasticity (DYT9). In 90% of classical GLUT1-DS cases, epilepsy presents within the first two years of life with one of five seizure types: generalized tonic or clonic, myoclonic, atypical absences, atonic, or unclassified epilepsy. Movement disorders are often exacerbated by fasting, fever, or infection. The prevalence is estimated at 1:90,000. In most cases, Glut1-DS is inherited in an autosomal dominant manner, 90% caused by new variants and only 10% of patients having an affected parent.
GLUT1-DS is caused by pathogenic variants in the SLC2A1 gene, which encodes the glucose transporter of the blood-brain barrier (GLUT1). SLC2A1 consists of 10 exons spanning 35 kb of genomic sequence. 81-89% of all pathogenic SLC2A1 variants are point mutations, with genomic deletions present in 11-14% of patients. Pathogenic SLC2A1 variants are loss-of-function variants that include frameshift and missense variants with residual protein activity. In particularly severe cases, a complete SLC2A1 allele is missing. There is a genotype-phenotype correlation. Pathogenic missense variants result in a mild to moderate phenotype while nonsense, splice, and frameshift mutations as well as intragenic deletions have been described in moderate to severe phenotypes. Complete genetic deletions result in particularly severe clinical courses. In addition to the classical GLUT1-DS, alterations in the SLC2A1 gene are also found in about 10% of all patients with early-onset absence epilepsy (EOAE).
GLUT1 (solute carrier family 2, facilitated glucose transporter member 1) is an integral membrane protein consisting of 492 amino acids that provides the only transport pathway of glucose across the blood-brain barrier through a pore region. Pathogenic SLC2A1 variants result in hypoglycorrhachia. Therapeutically, a ketogenic diet can be used to bypass the glucose pathway and offer ketones as an alternative energy source.
Diagnosis can be determined neurologically by hypoglycorrhachia (decreased glucose concentration in CSF (<60 mg/dl in all cases described so far; <40 mg/dl in >90% of cases; 41-52 mg/dl in ~10% of cases) with normal blood glucose concentration after a 4-hour fast. Lactate can be used as an alternative source of energy and can therefore also be measured at a reduced level in the CSF of some patients.
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