Tuesday, January 31, 2023
Mitochondrial Health

Jirair K. Bedoyan MD, PhD, Pyruvate Dehydrogenase Complex Deficiency



Jirair K. Bedoyan MD, PhD is Associate Professor of
Pediatrics in the Division of Genetic and Genomic
Medicine at UPMC Children’s Hospital of Pittsburgh
and the Department of Pediatrics at University of
Pittsburgh School of Medicine.

Pyruvate Dehydrogenase Complex Deficiency: Pilot newborn screening and
prospects of novel target-based small molecule therapeutics
Author: Jirair K. Bedoyan, MD, PhD
Pyruvate dehydrogenase complex (PDC) deficiency is a mitochondrial neurometabolic
disorder of energy deficit, the second most common genetically-resolved mitochondrial
disorder in the NAMDC Registry, and a major cause of primary lactic acidemia resulting
in high morbidity and mortality. The clinical presentation of PDC deficiency (PDCD) is
highly variable ranging from fatal congenital lactic acidosis and congenital brain
abnormalities to relatively mild ataxia or neuropathy with normal cognitive function
and long survival. Greater than 38 genes are associated with functional PDCD, but Xlinked
PDHA1mutations constitute 82-88% of cases.From a pilot newborn screening
study in Ohio, the incidence of PDCD is at least 1 in 41,138 live births (~90 newborns
annually in USA). The combination of alanine/leucine and proline/leucine ratios is
sensitive but not specific for identifying newborns with PDCD. Ketogenic diet (KD) is the
main untargeted intervention for PDCD due to primary-specific genes such as PDHA1,
but KD still leaves patients with significant systemic disease and developmental
disability. There is significant unmet need for novel untargeted and target-based
therapeutics for PDCD.The E1 component of the multi-enzyme PDCis a symmetric
dimer of heterodimers (αβ/α’β’) encoded by PDHA1and PDHB, with two symmetric
active sites. Greater than 85% of E1α residues with disease-causing missense mutations
(DMMs) are solvent inaccessible, with about one-third of them involved in
subunit−subunit interface contact (SSIC). Certain DMMs 15 Å or more from the active
site trigger SSIC changes, leading to reduced PDC activity and disease. Neighboring pair
of DMMs on different subunits perturbing the same SSIC can result in patients with
similar clinical phenotype. Replacements of E1α R349 form “pockets” in E1 favorable to
small-molecule docking and potentially restoring E1 molecular dynamics and PDC
function. Understanding how DMMs perturb E1 structure and function is crucial for
advancing target therapeutics for PDCD, which could lead to its recommendation to the
RUSP.

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