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

Abstract

Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1 alpha subunit of the complex. Two of these patients illustrate typical presentations of PDH E1 alpha 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 E1 alpha 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 patient, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1 alpha deficiency. The genetic basis of the variable expression of X-linked PDH E1 alpha deficiency in heterozygous females is discussed.

Aberrant Splicing of Exon 6 in the Pyruvate Denydrogenase-Elα mRNA Linked to a Silent Mutation in a Large Family with Leigh's Encephalomyelopathy

“…This nonrandom X inactivation could explain the asymptomatic phenotype of the females in this family. This study therefore is in agreement with previous studies in which it was shown that the degree of clinical penetration of the disease in PDH-Eladeficient females correlates with the proportional inactivation of the mutated X chromosome (17)(18)(19).…”

“…However, previous studies (17) have shown that girls also can be severely affected, with early onset presentations and cerebral developmental abnormalities. A mother with mental retardation and a daughter with severe brain anomalies and the same point mutation in the PDH-Ela gene were described by Dahl et al (18).…”

“…In the literature, fewer than 30 cases of PDH-Ela deficiency with mutations in the E l a gene have been reported (9,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Most cases are due to new or germline mutations.…”

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

“…The majority of patients have a mutation located in the PDHA1 gene encoding the E1a subunit, which is located on the X chromosome (Robinson and Sherwood 1984;McKay et al 1986;Wicking et al 1986;Brown et al 1989b;Lissens et al 2000). The differences in presentation result from variations in mutations and from the degree of X inactivation in females (Brown et al 1989b;Dahl et al 1992).…”

Arginine 302 mutations in the pyruvate dehydrogenase E1α subunit gene: Identification of further patients and in vitro demonstration of pathogenicity

“…Unlike the majority of PDH E1α mutations, the R302C mutation appears to be rela-tively common, as it has been described in six other patients [Dahl et al, 1992b;De Meirleir et al, 1993;Fujii et al, 1996;Lissens et al, 1996]. This mutation is associated with reduced enzyme activity but normal levels of E1α immunoreactive protein.…”