X‐linked pyruvate dehydrogenase E1α subunit deficiency in heterozygous females: Variable manifestation of the same mutation

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Abstract
Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1α subunit of the complex. Two of these patients illustrate typical presentations of PDH E1α deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1α gene. This mutation, a C-to-T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patients, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1α deficiency. The genetic basis of the variable expression of X-linked PDH E1α deficiency in heterozygous females is discussed.