RESUMO
Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a devastating neurometabolic disorder, usually lethal in the first years of life. Autosomal recessive mutations in the SLC25A1 gene, which encodes the mitochondrial citrate carrier (CIC), were previously detected in patients affected with combined D/L-2-HGA. We showed that transfection of deficient fibroblasts with wild-type SLC25A1 restored citrate efflux and decreased intracellular 2-hydroxyglutarate levels, confirming that deficient CIC is the cause of D/L-2-HGA. We developed and implemented a functional assay and applied it to all 17 missense variants detected in a total of 26 CIC-deficient patients, including eight novel cases, showing reduced activities of varying degrees. In addition, we analyzed the importance of residues affected by these missense variants using our existing scoring system. This allowed not only a clinical and biochemical overview of the D/L-2-HGA patients but also phenotype-genotype correlation studies.
Assuntos
Proteínas de Transporte de Ânions/metabolismo , Encefalopatias Metabólicas Congênitas/metabolismo , Ácido Cítrico/metabolismo , Glutaratos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Transporte de Ânions/química , Proteínas de Transporte de Ânions/genética , Bioensaio/métodos , Encefalopatias Metabólicas Congênitas/genética , Células Cultivadas , Pré-Escolar , Análise Mutacional de DNA , Feminino , Fibroblastos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Modelos Moleculares , Mutação de Sentido Incorreto , Transportadores de Ânions Orgânicos , Fenótipo , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
We report an unusual case of delayed bilateral, right greater than left hemiballismus in a 15-year-old female patient with a history of a craniopharyngioma 2years following the insertion of a right intratumoral chemotherapy catheter. Following cyst decompression, the catheter was found to have changed position, traversing the basal ganglia structures, namely the right subthalamic nucleus. Her movement disorder near-completely resolved immediately following removal of the catheter. A review of the current literature and proposed pathophysiological mechanisms are discussed.