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Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation

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Abstract

The pyruvate dehydrogenase complex (PDHc) is an intramitochondrial multienzyme system, which plays a key role in aerobic glucose metabolism by catalysing the oxidative decarboxylation of pyruvate to acetyl-CoA. Genetic defects in the PDHc lead to lactic acidemia and neurological abnormalities. In the majority of the cases, the defect appears to reside in the E1α subunit, the first catalytic component of the complex. The report is on a 6-year-old Portuguese boy with mild neurological involvement and low PDHc activity with absence of E1α on immunoblotting analysis. Molecular studies showed a novel and “de novo” mutation in the PDHA1 gene, R253G. Treatment with arginine aspartate showed complete clinical and biochemical recovery. We hypothesise that arginine aspartate acts as a chemical or pharmacological chaperone, and suggest amino acid supplementation as a possible therapy in PDHA1 mutations with mild phenotypes. Conclusion: our results encourage the use of amino acid supplementation to overcome the metabolic/biochemical changes induced by PDHA1 gene specific mutations associated with mild PDHc phenotypes.

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Abbreviations

PDHc:

pyruvate dehydrogenase complex

TPP:

thiamine pyrophosphate

E1:

pyruvate dehydrogenase

PDHA:

subunit α of E1

PDHB:

subunit β of E1

DLAT:

dihydrolipoamide acetyltransferase or E2

DLD:

dihydrolipoamide dehydrogenase or E3

PDHX:

E3 binding protein

PDP:

pyruvate dehydrogenase phosphatase

PDK:

pyruvate dehydrogenase kinase

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Authors and Affiliations

  1. Unidade de Biologia Molecular e Biopatologia Experimental, Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649–003, Lisboa, Portugal

    Maria João Silva, Ana Pinheiro, Isabel Tavares de Almeida & Isabel Rivera

  2. Unidade de Doenças Metabólicas, Hospital de Santa Maria, Lisboa, Portugal

    Filomena Eusébio & Ana Gaspar

Authors
  1. Maria João Silva
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  2. Ana Pinheiro
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  3. Filomena Eusébio
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  4. Ana Gaspar
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  5. Isabel Tavares de Almeida
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  6. Isabel Rivera
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Correspondence to Isabel Rivera.

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João Silva, M., Pinheiro, A., Eusébio, F. et al. Pyruvate dehydrogenase deficiency: identification of a novel mutation in the PDHA1 gene which responds to amino acid supplementation. Eur J Pediatr 168, 17–22 (2009). https://doi.org/10.1007/s00431-008-0700-7

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  • DOI: https://doi.org/10.1007/s00431-008-0700-7

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