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Glucose transporter type 1 (GLUT1) deficiency is an early-onset neurodevelopmental disorder characterized by hypoglycorrhachia, refractory seizures, acquired microcephaly, and movement disorders linked to impaired cerebral glucose uptake. In a consanguineous case, a male infant presented with infantile spasms, focal and generalized seizures, myoclonus, choreoathetosis, and microcephaly responsive to a 4:1 ketogenic diet (PMID:23604616). Subsequent series identified 15 children with GLUT1 deficiency harboring heterozygous mutations including missense, nonsense, splice-site, insertions, and deletions correlating with reduced CSF glucose and erythrocyte transporter activity (PMID:10980529). Screening in 84 myoclonic-astatic epilepsy probands yielded 4 additional SLC2A1 mutations, and sequencing of 504 idiopathic generalized epilepsy cases revealed 7 functionally validated variants absent in controls (PMID:21555602; PMID:23280796). A multigenerational pedigree demonstrated autosomal dominant inheritance of the R126H variant in five affected members over three generations with segregation of epilepsy and hypoglycorrhachia (PMID:11603379).
Inheritance of GLUT1 deficiency is predominantly autosomal dominant due to haploinsufficiency of SLC2A1, with rare de novo events and occasional mosaicism. Segregation analysis across families identified at least 8 additional affected relatives with segregating variants. Over 30 distinct missense variants cluster in transmembrane domains (e.g., c.376C>G (p.Arg126Gly)), alongside loss-of-function alleles including frameshifts (p.Glu393fs), nonsense (p.Arg330Ter), and splice-site changes. Recurrent mutations such as p.Arg126His and p.Thr295Met exhibit population-specific recurrence, and a Q282_Ser285del in the pore region underlies paroxysmal exertion-induced dyskinesia with hemolytic anemia. Allele frequencies in control databases are negligible, and combined prevalence estimates align with a carrier frequency of <1:1000.
Functional studies across multiple systems confirm reduced glucose transport activity consistent with haploinsufficiency. Site-directed mutagenesis of glycosylation site Asn45 demonstrated a 2–2.5-fold increase in Km and 30–70% reduction in transporter labeling (PMID:1761560). Helix 7 and large-loop mutants showed dramatic decreases in affinity for exofacial ligands and compromised membrane targeting. Xenopus oocyte assays of patient-derived missense alleles (e.g., p.Gly91Asp, p.Thr295Met) uniformly decrease Vmax and alter Km, mirroring hypoglycorrhachia severity. A GLUT1-deficient mouse model revealed embryonic lethality in homozygotes and 50% protein reduction in heterozygotes without overt phenotype, supporting dosage sensitivity.
Despite robust evidence, absence of detectable SLC2A1 coding mutations does not exclude GLUT1 deficiency syndrome, suggesting alternative mechanisms such as regulatory or deep-intronic variants (PMID:23483445). Comprehensive testing including MLPA and transcript analysis may reveal cryptic alleles. Treatment with a ketogenic diet is strongly indicated, with early initiation improving seizure control and developmental outcomes.
Integration of genetic, segregation, and functional data yields a definitive gene–disease association for SLC2A1 and encephalopathy due to GLUT1 deficiency. The combined evidence surpasses ClinGen criteria for a definitive classification, guiding molecular diagnosis, family counseling, and metabolic therapy. Key take-home: Identification of pathogenic SLC2A1 variants enables early ketogenic diet intervention to prevent irreversible neurologic injury.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong
Functional EvidenceStrongExtensive site-directed mutagenesis and Xenopus oocyte assays demonstrate loss of transport activity consistent with human phenotype |