Glucose transporter type 1 deficiency syndrome (MIM 606777, GLUT1 DS) is a rare neurologic disorder with a considerable clinical heterogeneity including early-onset seizures, intellectual disability, neurodevelopmental problems, ataxia and microcephaly, caused by a defective transport of glucose into the brain, due to mutations in the SCL2A1 gene, coding for GLUT1. Most cases are sporadic, with an autosomal dominant mode of inheritance. Several pathogenic mutations have been described but no clear genotype-phenotype correlation has been defined. For patients with GLUT1 defects, a high-fat and calorie-reduced, i.e., the ketogenic diet, is administered to control symptoms of seizures. The ketogenic diet should be started early making an early diagnosis of crucial importance.
The diagnosis is based on neurological examination and neuropsychological testing, and is
confirmed with biochemical (glucose levels in cerebrospinal fluid and serum) and molecular (SLC2A1 sequencing) approaches. However, the clinical diagnosis is challenging because of the lack of distinctive clinical manifestations, and a spectrum of symptoms appearing and changing over the years.
The purpose of our study is to improve the diagnostic yield of genetic test, to bring new insights into the GLUT1 DS molecular pathology and to clarify genotype-phenotype correlations.
We aim at implementing data analysis workflow of genetic test based on SLC2A1 sequencing to analyze variants in regions not routinely screened or classified as neutral in standard analyses. We also aimed at characterizing the functional effects of coding and non-coding mutations using advanced in silico (molecular dynamics simulations) and in vitro (expression/localization/glucose transport) approaches.
Efforts aimed at disclosing molecular functions of GLUT1 and its dysfunctions in pathogenesis are a fundamental prerequisite that will provide information with direct impact on diagnosis, prognosis, counseling, and patient management.
