GLUCOSE TRANSPORTER TYPE I DEFICIENCY SYNDROME (GLUT 1 DS)

Objectives: to review the diagnostic criteria, emphasize the importance of early treatment and speculate on the neurodevelopmental consequences of diminished glucose transport across the blood-brain barrier (BBB). Glut 1 DS was first recognized in 1991 as a potentially treatable cause of delayed neurological development and infantile-onset epilepsy. Mutations in the responsible GLUT1 gene on chromosome 1 were reported in 1998. Fifteen years after the original description of the clinical syndrome several different phenotypes have emerged, an animal model has been developed, and the efficacy of the ketogenic diet as treatment has been established. Glut 1 DS can serve as a model for brain energy failure during early development.

Methods: Investigations of children with Glut 1 DS and inbred mice with Homologous recombination knock-out (KO) of one GLUT 1 allele.

Results: Three different phenotypes have been recognized. The classical phenotype is an infantile-onset epileptic encephalopathy with acquired microcephaly, mental retardation and spastic ataxia. Two additional phenotypes, focusing on cognitive abnormalities and abnormal movements in the absence of seizures, have been described recently. These more recent observations now show that infantile seizures were an initial ascertainment bias and contributed to delayed recognition of phenotypic variants. The KO mice recapitulate the human phenotypes. Hypoglycorrhachia is a constant finding underscoring the diagnostic essentiality of the lumbar puncture. The distinctive PET scan signature and the dietary influence on clinical symptomatology represent important indicators of diminished glucose transport across the BBB.

Conclusion: Glut 1 DS is more common than initially realized and frequently misdiagnosed. Hypoglycorrhachia is a constant finding and facilitates early diagnosis in every case. Early treatment seems to improve long-term outcome. This clinical syndrome represents proof of concept that glucose transport across the BBB is rate-limiting and a factor determining neurodevelopmental potential.