Assuntos
Complexo I de Transporte de Elétrons/deficiência , Doença de Leigh/genética , Doenças Mitocondriais/genética , NADH Desidrogenase/genética , Deleção de Sequência/genética , Compostos Azo , Encéfalo/patologia , Criança , Complexo I de Transporte de Elétrons/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Doença de Leigh/patologia , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologiaRESUMO
OBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE. METHODS: The affected individuals were examined clinically by EEG and brain imaging. The coding regions of SLC2A1 were sequenced in the index cases of all families. Wild-type and mutant transporters were expressed and functionally characterized in Xenopus laevis oocytes. RESULTS: We detected a novel nonsynonymous SLC2A1 mutation (c.694C>T, p.R232C) in one IGE family. Nine family members were affected mainly by absence epilepsies with a variable age at onset, from early childhood to adulthood. Childhood absence epilepsy in one individual evolved into juvenile myoclonic epilepsy. Eight affected and 4 unaffected individuals carried the mutation, revealing a reduced penetrance of 67%. The detected mutation was not found in 846 normal control subjects. Functional analysis revealed a reduced maximum uptake velocity for glucose, whereas the affinity to glucose and the protein expression were not different in wild-type and mutant transporters. CONCLUSION: Our study shows that GLUT1 defects are a rare cause of classic IGE. SLC2A1 screening should be considered in IGE featuring absence epilepsies with onset from early childhood to adult life, because this diagnosis may have important implications for treatment and genetic counseling.
Assuntos
Epilepsia Generalizada/genética , Transportador de Glucose Tipo 1/genética , Mutação , Alelos , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Neuroimagem , Linhagem , Fenótipo , Adulto JovemRESUMO
We report the clinical and genetic study of a primary hyperoxaluria type I (PH1) family with two sisters homozygous for p.Gly170Arg who are still asymptomatic at age 29 and 35, and two brothers, also homozygous for the same mutation, who are affected since age 27 and 30. The clear sex difference observed in this family and in others reported in the literature fits well with the prevalence of males over females in the Italian registry. In the KO model of PH1, only male mice develop renal stones, suggesting that the sex difference may affect both oxalate production and stone formation. A likely mechanism is the sex-related expression of glycolate oxidase shown in experimental animals. The stable isotope method recently developed by Huidekoper and van Woerden for in vivo assessment of the endogenous oxalate production could help to clarify the issue in humans.
