Center For Human Genetics - July 2024

Pyruvate Dehydrogenase Complex Deficiency Natural History Study.

Suzanne DeBrosse, MD

CWRU has a decades-long history of research into pyruvate dehydrogenase complex deficiency (PDCD). The pyruvate dehydrogenase complex (PDC) is a multiple enzyme complex in the shape of a pentagonal dodecahedron. It is key to carbohydrate metabolism. Glucose is metabolized to pyruvate, which then is metabolized by the PDC into acetyl Co-A for entry into the Krebs cycle and eventually, ATP generation. Individuals who are deficient in PDC activity are unable to use carbohydrates for energy. The neonatal form is often fatal, but there are several other forms and many adults living with PDCD. There is no cure, and only limited treatment options. It is frequently diagnosed late, despite an estimated incidence of 1 in 50,000 to 75,000 births (somewhat common for an inborn error of metabolism, with multiple known cases in Northeast Ohio alone).

Our team at UH/CWRU has led the world’s largest natural history study of PDCD (Suzanne DeBrosse, PI), along with PDCD genetic studies, newborn screening pilot projects, and participation in a multi-site treatment study. Data analysis is currently in progress for the natural history portion of this effort, with a focus on neurological outcomes. This is a collaboration with the North American Mitochondrial Disease Consortium (NAMDC), led by Columbia University.

We hope that these efforts will yield information about course and outcomes in PDCD that will be useful for counseling the families of newly diagnosed children. These data are also essential for the design of randomized controlled treatment trials. Our team has published studies of the neurological and survival outcomes in individuals with PDCD, several review articles intended to aid pediatric neurologists and others in diagnosing and managing this disorder, as well as case reports about rare subtypes. We are also a clinical referral center, seeing children with PDCD from across the country.

1) DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS.  Spectrum of Neurological and Survival Outcomes in Pyruvate Dehydrogenase Complex (PDC) Deficiency: Lack of correlation with genotype.  Molecular Genetics and Metabolism.  2012 Nov;107(3):394-402.  PMID: 23021068

2) Huang X, Bedoyan JK, Demirbas D, Harris DJ, Miron A, Edelheit S, Grahame G, DeBrosse SD, Wong LJ, Hoppel CL, Kerr DS, Anselm I, Berry GT. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab. 2017 Mar;120(3):213- 222. PMID: 27913098

3) Bedoyan JK, Yang SP, Ferdinandusse S, Jack RM, Miron A, Grahame G, DeBrosse SD, Hoppel CL, Kerr DS, Wanders RJ. Lethal neonatal case and review of primary short-chain enoyl- CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency.  Mol Genet Metab. 2017 Apr;120(4):342- 349.  PMID: 28202214

4) Bedoyan JK, Hecht L, Zhang S, Tarrant S, Bergin A, Demirbas D, Yang E, Shin HK, Grahame GJ, DeBrosse SD, Hoppel CL, Kerr DS, Berry GT.  A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 2019;48(1):26–35. PMID: 31392110

5) Bedoyan JK, Hage R, Shin HK, Linard S, Ferren E, Ducich N, Wilson K, Lehman A, Schillaci LA, Manickam K, Mori M, Bartholomew D, DeBrosse S, Cohen B, Parikh S, Kerr D. Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects. JIMD Rep. 2020 Aug 16;56(1):70-81.  PMID: 33204598