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A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fl...

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Autores principales: Bedoyan, Jirair K., Hecht, Leah, Zhang, Shulin, Tarrant, Stacey, Bergin, Ann, Demirbas, Didem, Yang, Edward, Shin, Ha Kyung, Grahame, George J., DeBrosse, Suzanne D., Hoppel, Charles L., Kerr, Douglas S., Berry, Gerard T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606986/
https://www.ncbi.nlm.nih.gov/pubmed/31392110
http://dx.doi.org/10.1002/jmd2.12054
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author Bedoyan, Jirair K.
Hecht, Leah
Zhang, Shulin
Tarrant, Stacey
Bergin, Ann
Demirbas, Didem
Yang, Edward
Shin, Ha Kyung
Grahame, George J.
DeBrosse, Suzanne D.
Hoppel, Charles L.
Kerr, Douglas S.
Berry, Gerard T.
author_facet Bedoyan, Jirair K.
Hecht, Leah
Zhang, Shulin
Tarrant, Stacey
Bergin, Ann
Demirbas, Didem
Yang, Edward
Shin, Ha Kyung
Grahame, George J.
DeBrosse, Suzanne D.
Hoppel, Charles L.
Kerr, Douglas S.
Berry, Gerard T.
author_sort Bedoyan, Jirair K.
collection PubMed
description Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched‐chain 2‐ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched‐chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary‐specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. SYNOPSIS: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis.
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spelling pubmed-66069862019-08-07 A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency Bedoyan, Jirair K. Hecht, Leah Zhang, Shulin Tarrant, Stacey Bergin, Ann Demirbas, Didem Yang, Edward Shin, Ha Kyung Grahame, George J. DeBrosse, Suzanne D. Hoppel, Charles L. Kerr, Douglas S. Berry, Gerard T. JIMD Rep Case Reports Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched‐chain 2‐ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched‐chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary‐specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. SYNOPSIS: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis. John Wiley & Sons, Inc. 2019-06-17 /pmc/articles/PMC6606986/ /pubmed/31392110 http://dx.doi.org/10.1002/jmd2.12054 Text en © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Case Reports
Bedoyan, Jirair K.
Hecht, Leah
Zhang, Shulin
Tarrant, Stacey
Bergin, Ann
Demirbas, Didem
Yang, Edward
Shin, Ha Kyung
Grahame, George J.
DeBrosse, Suzanne D.
Hoppel, Charles L.
Kerr, Douglas S.
Berry, Gerard T.
A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title_full A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title_fullStr A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title_full_unstemmed A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title_short A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency
title_sort novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (pdp1) causing pyruvate dehydrogenase complex deficiency
topic Case Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606986/
https://www.ncbi.nlm.nih.gov/pubmed/31392110
http://dx.doi.org/10.1002/jmd2.12054
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