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Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex
Etsuo Naito1, Michinori Ito, Ichiro Yokota
1Department of Pediatrics, School of Medicine, University of Tokushima, Kuramoto Cho 3, 770-8503, Tokushima, Japan. enaito@clin.med.tokushima-u.ac.jp
Insights
Pyruvate dehydrogenase complex (PDHC) deficiency in children can be detected by measuring enzyme activity with low thiamine pyrophosphate (TPP). This identifies thiamine-responsive cases, enabling prompt treatment.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Pyruvate dehydrogenase complex (PDHC) deficiency is a significant cause of congenital lactic acidemia.
- PDHC is crucial for thiamine-dependent pyruvate decarboxylation.
- Thiamine treatment has shown efficacy in some PDHC deficiency cases.
Observation:
- Thirty patients with congenital lactic acidemia and normal PDHC activity (high TPP) were re-evaluated.
- PDHC activity was measured using a low thiamine pyrophosphate (TPP) concentration.
- Genetic analysis of the E1alpha subunit gene was performed.
Findings:
- Three male patients exhibited low PDHC activity with low TPP.
- Mutations in the E1alpha subunit gene (V71A, C101F, R263G) were identified in these patients.
- Thiamine treatment proved effective for these three individuals.
Implications:
- Low TPP concentration assays are vital for diagnosing thiamine-responsive PDHC deficiency.
- Early detection allows for timely initiation of thiamine therapy.
- This research refines diagnostic strategies for congenital lactic acidemia.
Abstract:
Pyruvate dehydrogenase complex (PDHC) deficiency is a major cause of congenital lactic acidemia in children. PDHC catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment was effective for some patients with PDHC deficiency. We reexamined 30 patients with congenital lactic acidemia of unknown origin who had normal PDHC activity in their cultured fibroblasts using a routine assay with a high (0.4 mM) thiamine pyrophosphate (TPP) concentration. We measured the activity of PDHC in the presence of a low (1x10(-4) mM) TPP concentration, and analyzed for mutations in the E1alpha subunit gene. Three males had low PDHC activity in the presence of 1x10(-4) mM TPP. The DNA sequence of these three patients' X-linked E1alpha subunit revealed a substitution of alanine for valine at position 71 (V71A) in exon 3, phenylalanine for cysteine at position 101 (C101F) in exon 4, and glycine for arginine at position 263 (R263G) in exon 8, respectively. Thiamine treatment was effective in these three patients. Therefore, they had a thiamine-responsive PDHC deficiency due to a point mutation in the E1alpha subunit gene. PDHC activity should be measured at a low TPP concentration to detect thiamine-responsive PDHC deficiency so that thiamine treatment can be initiated as soon as possible.