SLC2A1 – Childhood-onset GLUT1 Deficiency Syndrome 2

Childhood-onset GLUT1 deficiency syndrome 2 (GLUT1DS2) is an autosomal dominant neurodevelopmental disorder characterized by infantile-onset seizures, acquired microcephaly, developmental delay and hypoglycorrhachia. Pathogenic variants in the facilitative glucose transporter gene SLC2A1 impair glucose transport across the blood–brain barrier, leading to chronic cerebral energy deficiency. Cerebrospinal fluid glucose is consistently reduced, typically <2.2 mmol/L, while plasma glucose remains normal, supporting the biochemical diagnosis.

Genetic evidence for SLC2A1 involvement is robust. In an early series, fifteen unrelated children with seizures and developmental delay harbored heterozygous SLC2A1 mutations [PMID:10980529]. A three-generation family demonstrated autosomal dominant segregation of an R126H variant in three affected members [PMID:11603379], and de novo transmission was confirmed in additional pedigrees [PMID:11136715]. Moreover, in 84 patients with myoclonic-astatic epilepsy, four carried novel SLC2A1 mutations [PMID:21555602], and in 504 idiopathic generalized epilepsy cases, seven bore functionally validated variants [PMID:23280796].

The SLC2A1 variant spectrum encompasses over 25 distinct pathogenic alleles, including missense, nonsense, frameshift, splice-site and in-frame deletions. Notably, the c.376C>G (p.Arg126Gly) substitution disrupts glucose transport and reduces erythrocyte uptake activity [PMID:10980529].

Functional assays in Xenopus laevis oocytes and patient erythrocytes have demonstrated loss-of-function for multiple SLC2A1 variants. Site-directed mutagenesis of residues Gly91, Arg126 and Thr295 yields significantly reduced Vmax and/or increased Km for 2-deoxyglucose uptake [PMID:11603379]. In‐frame deletion of Q282_S285 also induces a cation leak in erythrocytes, further impairing membrane ion homeostasis [PMID:18451999]. Heterozygous Slc2a1-deficient mice exhibit compensatory transporter expression changes without overt phenotype, consistent with haploinsufficiency [PMID:16880609].

The prevailing mechanism is haploinsufficiency, whereby reduced GLUT1 expression impairs cerebral glucose delivery. Ketogenic diet bypasses the GLUT1 defect by providing ketone bodies as alternative fuel, leading to seizure control and improved neurological outcome. Early genetic diagnosis is critical for initiation of dietary therapy and genetic counseling.

In summary, definitive clinical validity is supported by over 50 unrelated probands, multigenerational segregation and consistent functional data. Genetic testing for SLC2A1 variants informs diagnosis, guides ketogenic diet therapy and enables family planning. Key take‐home: Identification of a heterozygous pathogenic SLC2A1 variant confirms GLUT1DS2 and warrants early ketogenic intervention.

References

• Human Mutation • 2000 • Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. PMID:10980529
• Annals of Neurology • 2001 • Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. PMID:11603379
• Human Molecular Genetics • 2001 • Autosomal dominant transmission of GLUT1 deficiency. PMID:11136715
• Archives of Neurology • 2011 • Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. PMID:21555602
• Annals of Neurology • 2012 • Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. PMID:23280796
• Biological & Pharmaceutical Bulletin • 2006 • Modulation and compensation of the mRNA expression of energy related transporters in the brain of glucose transporter 1-deficient mice. PMID:16880609

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