Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex.

Human PDH complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. In an investigation at the level of the gene into ten cases of PDH complex (E1) deficiency, we found that all had mutations in the coding sequence of the X-linked E1 alpha gene while the E1 beta coding sequence was normal. Six of these patients (three males, three females) had missense mutations resulting in a changed amino acid residue in the E1 alpha subunit at positions amino acid 148 (in two siblings), 170, 202, 234 and 263 of the mature protein. Two of the females had one normal E1 alpha gene and one with a deletion at the sites of tandem repeats of AGTAAGA and TAT respectively. The two remaining females also had one normal E1 alpha gene and one with an insertion. Both insertions, one of 2 bp and one of 4 bp, occurred in DNA hotspots normally associated with deletions. Only two of these ten mutations have been reported in other patients previously. In the five cases (including the two siblings) where parent DNA was available, only in one case could the same mutation be found in the patient as well as the maternal genomic DNA.