Publications by authors named "George J Grahame"

2 Publications

  • Page 1 of 1

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

JIMD Rep 2019 Jul 17;48(1):26-35. Epub 2019 Jun 17.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research Boston Children's Hospital, Harvard Medical School Boston Massachusetts.

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 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 .

Synopsis: Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to mutations leads to PDC deficiency and congenital lactic acidosis.
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July 2019

Somatic mosaicism for a novel mutation in a male with severe pyruvate dehydrogenase complex deficiency.

Mol Genet Metab Rep 2014 28;1:362-367. Epub 2014 Aug 28.

Center for Human Genetics Laboratory University Hospitals Case Medical Center, Cleveland, OH, USA.

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked gene. Males with hemizygous mutations are clinically more severely affected, while those with mosaic mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of mosaicism.
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August 2014