A novel gross deletion caused by non-homologous recombination of the PDHX gene in a patient with pyruvate dehydrogenase deficiency.

We report here the molecular analysis of a pyruvate dehydrogenase E3-binding protein (PDH-E3BP) deficiency in a new patient, born to first cousin parents. She has initially presented with a non-progressive and unspecific encephalopathy, followed by an acute neurological deterioration at 14 years of age. E3BP subunit was undetectable on Western blot. The sequence of exons 1-9 and exon 11 of the PDHX gene were normal, but exon 10 was impossible to amplify with standard PCR. Long-range PCR including exons 9-11 (11.5 kb) was performed. The patient's sample displayed a unique PCR product of 7.5 kb, whereas the parents' samples displayed two bands (11.5 and 7.5 kb). The deletion breakpoints were determined by restriction analysis followed by direct sequencing. The homozygous deletion covered the end of intron 9, exon 10 and the beginning of intron 10 and was found to be 3913 bp long. The cDNA sequencing confirmed the deletion of exon 10. The most probable mechanism for this gross deletion appears to be a slipped mispairing mediated by an exact direct repeat CCACTG. It is the first time that a non-homologous recombination is reported in the PDHX gene causing pyruvate dehydrogenase complex (PDHc) deficiency.