J Korean Med Sci.  2006 Oct;21(5):800-804. 10.3346/jkms.2006.21.5.800.

A Korean Female Patient with Thiamine-responsive Pyruvate Dehydrogenase Complex Deficiency Due to a Novel Point Mutation (Y161C)in the PDHA1 Gene

• Lee EH
• Ahn MS
• Hwang JS
• Ryu KH
• Kim SJ
• Kim SH

• KMID: 1781895
• DOI: http://doi.org/10.3346/jkms.2006.21.5.800

Abstract

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1alpha subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1 x 10(-3) mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP.

Keyword

Pyruvate Dehydrogenase Complex Deficiency Disease; Pyruvate Dehydrogenase (Lipoamide); E1alpha Subunit; Thiamine Pyrophosphate

MeSH Terms

Thiamine Pyrophosphate/metabolism
Thiamine/*therapeutic use
Pyruvate Dehydrogenase Complex Deficiency Disease/drug therapy/*genetics
Pyruvate Dehydrogenase (Lipoamide)/*genetics
*Point Mutation
Infant, Newborn
Humans
Female
Cells, Cultured

Figure

• 

  Fig. 1 Effect of TPP on the activity of DCA-activated PDHC in cultured fibroblasts from normal subject and two patients with PDHC deficiency (Y161C; a patient with thiamine-responsive PDHC deficiency, AAGT insertion at nt.1162; positive control which has non-responsive PDHC deficiency).

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  Fig. 2 Electropherograms of DNA sequencing for Y161C mutation. (A) Normal sequence of exon 5. (B) Patient sequence has both a A (normal) and G (mutant) at nucleotide 482, resulting in the presence of a tyrosine (codon TAC) and cysteine (codon TGC) at position 161.

• 

  Fig. 3 Detection of the 482 A-to-G substitution in the E1α gene. PCR-amplified products (206 bp) of exon 5 were digested by Fau I, which creates two fragments of 108 bp and 98 bp in the case of the mutated sequence (Lane 1, Marker; Lane 2, Normal subject; Lane 3, Patient (heterozygous); and Lane 4, Patient's mother).

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