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Review
. 2022 May 19:79:10382.
doi: 10.3389/bjbs.2022.10382. eCollection 2022.

Comparison Between Dichloroacetate and Phenylbutyrate Treatment for Pyruvate Dehydrogenase Deficiency

Patricia Karissa  1 , Timothy Simpson  2 , Simon P Dawson  2 , Teck Yew Low  3 , Sook Hui Tay  1 , Fatimah Diana Amin Nordin  4 , Shamsul Mohd Zain  5 , Pey Yee Lee  3 , Yuh-Fen Pung  1
Affiliations
Review

Comparison Between Dichloroacetate and Phenylbutyrate Treatment for Pyruvate Dehydrogenase Deficiency

Patricia Karissa et al. Br J Biomed Sci. .

Abstract

Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the PDHA1 gene. The PDHA1 gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of PDHA1 gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by PDHA1 pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency.

Keywords: E1a; PDHA1; inborn error of metabolism; lactic acidosis; mitochondrial disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Carbohydrate metabolism. (A) Carbohydrate is broken down to glucose. Glucose undergoes the process of glycolysis where it goes through several enzymatic reactions to produce two molecules of pyruvate and two molecules of NADH (1). Glycolysis is followed by link reaction where each pyruvate will be converted to acetyl CoA and NADH (2). The link reaction was mediated by a group of enzymes called the PDH complex. Acetyl CoA produced in the link reaction enters the Krebs cycle generating 3 NADH and 1 FADH (3). All the NADH and FADH produced were transported to the electron transport chain located at the mitochondrial matrix to produce ATP (4). Pathogenic variants in the PDH complex may result in PDH deficiency and reduce the activity of the complex. Due to these pathogenic variants, pyruvate will be converted to acetyl CoA at a slower rate, affecting the subsequent reaction. The excessive pyruvate will build up and be converted to lactate instead (5). (B) The process of link reaction starts with the removal of one carbon from pyruvate by PDH (E1) resulting in hydroxyethyl which joins together with thiamine pyrophosphate (TPP) to produce hydroxyethyl TPP and release carbon dioxide. Dihydrolipoyl transacetylase (E2) transfers the hydroxyethyl group to oxidized lipoamide. This causes the acetyl group to be transferred to coenzyme A (CoA) forming acetyl CoA. FAD bound to dihydrolipoyl dehydrogenase (E3) oxidizes the reduced lipoamide by accepting an electron to produce FADH2. The electron is donated again to NAD+ resulting in the production of NADH and H+.
FIGURE 2
FIGURE 2
Comparison between a normal link reaction, link reaction in patients with PDH deficiency and in the presence of dichloroacetate or phenylbutyrate. (A) In a normal patient, pyruvate is mostly converted to acetyl CoA with the aid of the PDH complex. This reaction is inhibited by PDH kinase once ATP is produced in the subsequent reaction. (B) In PDH deficiency patients, a pathogenic variant in the PDH complex causes a slower conversion of pyruvate to acetyl CoA. As a result, pyruvate will build up and it will be converted to lactate. (C) The addition of dichloroacetate or phenylbutyrate will inhibit the PDH kinase and this will prolong the activity of the PDH complex; more acetyl CoA will be produced.
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