Article

Journal of Inherited Metabolic Disease

, Volume 18, Issue 5, pp 534-546

First online:

DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia

  • J. MatsudaAffiliated withDepartment of Pediatrics, School of Medicine, University of Tokushima
  • , M. ItoAffiliated withDepartment of Pediatrics, School of Medicine, University of Tokushima
  • , E. NaitoAffiliated withDepartment of Pediatrics, School of Medicine, University of Tokushima
  • , I. YokotaAffiliated withDepartment of Pediatrics, School of Medicine, University of Tokushima
  • , Y. KurodaAffiliated withDepartment of Pediatrics, School of Medicine, University of Tokushima

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Summary

The diagnosis of pyruvate dehydrogenase (PDH) E1α deficiency, which is an X-linked inborn error of metabolism, is usually established by the measurement of PDH complex activity in cultured cells. However, heterozygous female patients with PDH E1α deficiency may be misdiagnosed when the normal X chromosome is predominantly expressed in the cultured cells. Therefore, in female patients with convincing clinical presentations of PDH E1α deficiency and the normal enzyme activity, the X-inactivation pattern should be analysed and the PDH E1α gene screened for mutations. For this screening, we applied the method of single-strand conformational polymorphism (SSCP) and DNA sequencing and examined 11 female patients with congenital lactic acidaemia whose PDH complex activity was normal in cultured cells. In 2 of the 11 female patients, we found distinct pathogenic missense mutations in the PDH E1α gene (G89S and G291R). Both affected patients showed a similar clinical presentation and had been diagnosed as West syndrome. In 3 of the 11 patients, we found a polymorphic base-pair substitution in exon 9 of the PDH E1α gene which resulted in a changed amino acid residue (M282L). We conclude that PCR-SSCP analysis of the PDH E1α gene, followed by DNA sequencing, is a useful method to screen for mutations of the PDH E1α gene in female patients with congenital lactic acidaemia who have normal enzyme activities in available samples, normal ratio of lactate to pyruvate, and predominantly raised lactate concentration in cerebrospinal fluid.