NEUROGLYCOPENIA: GENOTYPE-PHENOTYPE CORRELATION

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DESCRIPTION (provided by applicant): Glucose transporter protein Type I (Glut1), when deficient (GlutlDS, OMIM 606777), causes chronic neuroglycopenia and developmental encephalopathy. The deficiency results from GLUT1 haploinsufficiency, genetically transmitted as an autosomal dominant trait. The long-term objectives of this research project are improved understanding of the pathogenesis, increased awareness of the phenotypic presentations, and better treatment of the neurodevelopmental syndrome. Four specific aims are proposed to achieve these long-term objectives: (1) To expand our understanding of the GlutlDS phenotypes associated with GLUT1 gene mutations; (2) To correlate genotypic pathogenicity with phenotypic severity; (3) To replicate the human disease in an animal model; (4) To explore alternative treatment options for patients with GlutlDS. The research design and methods have been developed to increase recruitment of patients; to assess phenotypic variability by multi-disciplinary methods; and to serially evaluate patients over time to assess the phenotypic durability during development and the influences of gender on clinical expression. The phenotype will be correlated with the genotype by assessing the nature of the mutation and the kinetic and structure-function perturbations that result from these mutations. The Xenopus oocyte expression system is used to evaluate functional disturbances related to missense mutations. GLUT1 polymorphisms will be determined in the GlutlDS population and compared to the presence/absence of similar polymorphisms in a control population. A transgenic antisense mouse model and gene targeted homologous recombination knock-out mouse model will be examined clinically and neuropathologically for evidence of regional brain injury and neuronal apoptosis. Emphasis will be placed on establishing the cellular types most affected by the disease. Cellular dysfunction and apoptosis will be assessed by the in vitro study of neuronal and glial cultures derived from the mutant mouse models. Treatment opportunities will be explored in the mouse models and applied to the patient population assessing the relative benefits of a ketogenic diet and a carbohydrate diet, and the advantages of sustained hyperglycemia using uncooked cornstarch supplements and diazoxide. A 5-hour oral glucose tolerance test will be evaluated as a possible diagnostic tool measuring clinical, neuropsychological and electrographic changes associated with transient hyperglycemia.