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JIMD Rep. 2019 Jun 17;48(1):26-35. doi: 10.1002/jmd2.12054. eCollection 2019 Jul.

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

Author information

1
Department of Genetics and Genome Sciences Case Western Reserve University (CWRU) Cleveland Ohio.
2
Pediatrics Case Western Reserve University (CWRU) Cleveland Ohio.
3
Center for Human Genetics University Hospitals Cleveland Medical Center (UHCMC) Cleveland Ohio.
4
Center for Inherited Disorders of Energy Metabolism (CIDEM) University Hospitals Cleveland Medical Center (UHCMC) Cleveland Ohio.
5
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research Boston Children's Hospital, Harvard Medical School Boston Massachusetts.
6
Pathology and Laboratory Medicine University of Kentucky Lexington Kentucky.
7
Department of Neurology Boston Children's Hospital, Harvard Medical School Boston Massachusetts.
8
Radiology Boston Children's Hospital, Harvard Medical School Boston Massachusetts.
9
School of Medicine Case Western Reserve University (CWRU) Cleveland Ohio.
10
Medicine Case Western Reserve University (CWRU) Cleveland Ohio.
11
Pharmacology Case Western Reserve University (CWRU) Cleveland Ohio.

Abstract

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.

KEYWORDS:

PDP1; branched‐chain 2‐ketoacid dehydrogenase; developmental delay; lactic acidosis; pyruvate dehydrogenase complex deficiency; pyruvate dehydrogenase phosphatase deficiency

Conflict of interest statement

The authors declare that they have no conflict of interest.

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