Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

[pyruvate dehydrogenase deficiency]

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC ) deficiency in a patient with an X-linked form of Leigh syndrome . PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP ) concentration (0 .4 mmol /L ). However , in the presence of a low concentration (1 x 10 (-4 ) mmol /L ) of TPP , the activity was significantly decreased , indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP . The patient 's older brother also was diagnosed as PDHC deficiency with Leigh syndrome , suggesting that PDHC deficiency in these two brothers was not a de novo mutation . Sequencing of the X-linked PDHC E 1 alpha subunit revealed a C-->G point mutation at nucleotide 787 , resulting in a substitution of glycine for arginine 263 . Restriction enzyme analysis of the E 1 alpha gene revealed that the mother was a heterozygote , indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance .