GLUT1 Deficiency Syndrome—Early Treatment Maintains Cognitive Development? (Literature Review and Case Report)

Abstract

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood–brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and various paroxysmal neurological phenomena. In most cases, GLUT1DS is caused by heterozygous single-nucleotide variants (SNVs) in the SLC2A1 gene that provoke complete or severe impairment of the functionality and/or expression of GLUT1 in the brain. Despite the rarity of these diseases, GLUT1DS is of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms, especially if it is started as early as possible. We present a clinical phenotype, biochemical analysis, electroencephalographic and neuropsychological features of an 11-month-old boy with myoclonic seizures, hypogammaglobulinemia, and mildly impaired gross motor development. Using sequence analysis and deletion/duplication testing, deletion of an entire coding sequence in the SLC2A1 gene was detected. Early introduction of a modified Atkins diet maintained a seizure-free period without antiseizure medications and normal cognitive development in the follow-up period. Our report summarizes the clinical features of GLUT1 syndromes and discusses the importance of early identification and molecular confirmation of GLUT1DS as a treatable metabolic disorder.

Diagnostic and Clinical Manifestation Differences of Glucose Transporter Type 1 Deficiency Syndrome in a Family with SLC2A1 Gene Mutation

“…During the process of diagnosis, an EEG examination is usually performed—in most cases, the result is correct. This is because, in GLUT1-DS, the EEG result between the seizures often shows no abnormalities [ 21 ]. On the other hand, the morphology of EEG waveforms recorded in the time of a seizure may show focal slow-wave activity, high voltage spikes, or spike-and-wave patterns [ 22 ].…”

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

“…So far, over 200 types of genetic defects have been described, among which are missense, nonsense, frameshift, and splice-site mutations, and large fragment deletions [ 12 , 32 ]. Of these, missense mutations seem to be associated with a milder phenotype, but no definite genotype–phenotype correlation has been described [ 5 , 45 ]. Pathogenic variants in SLC2A1 are most often identified by sequencing (81–89% of cases), and less often by deletion/duplication analysis (11–14%) [ 29 ].…”

“…Glut1 deficiency selectively impairs thymocyte and T effector functions [ 84 ]. In Glut1DS, the serum levels of antibodies are significantly lower, favoring the development of severe infections [ 45 ]. Furthermore, Glut1-deficient T cells are metabolically stressed, as their pAMPK level increases after activation, and cannot sustain activated mTORC1 signaling, while other signaling pathways such as Akt or ERK (extracellular regulated kinase) are generally unaffected [ 84 , 85 ].…”

Timing of Ketogenic Dietary Therapy (KDT) Introduction and Its Impact on Cognitive Profiles in Children with Glut1-DS—A Preliminary Study

“…Based on the analysis of various indices in the context of intelligence measurements using neuropsychological tests, conclusions can be drawn regarding correlations between the different cognitive components based on performance discrepancies between the individual sub-scores. Single studies have focused on the specific analysis of cognitive profiles, particularly with respect to the selected subdomains of intelligence within the phenotypic spectrum of Glut1DS [ 12 , 14 , 17 , 18 , 19 , 20 ]. Study results indicate the superiority of linguistic cognitive competencies over cognitive subdomains or overall IQ score [ 12 , 14 , 19 , 20 ].…”