Pyruvate Dehydrogenase Deficiency – Mitochondrial dysfunction

The Citric Acid Cycle -
The Citric Acid Cycle –

What is Pyruvate dehydrogenase?

Pyruvate dehydrogenase is involved in the production of cellular energy in the mitochondria.  It acts as a catalyst in the conversion of pyruvate into acetyl-CoA, which is used in the citric acid cycle (Kreb’s cycle) in cellular respiration and production of A/TP.

Thus, it’s essential, and deficiencies of pyruvate dehydrogenase can be devastating.  Genetics Home Reference describes it: “Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. ….  Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood” [read more]

Link to CFS/ME:

A December 2016 report looking at the metabolites in Chronic Fatigue Syndrome patients found indicators showing impairment of pyruvate dehydrogenase.  It concludes: “These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.”

Rare mutations linked to pyruvate dehydrogenase deficiency:

PDHA1 Gene (mainly 23andMe v4)

The PDHA1 gene codes for a protein (E1 alpha) that combines with another to form pyruvate dehydrogenase.  This enzyme converts pyruvate into acetyl-CoA, the first step in the citric acid cycle (Kreb’s cycle).  The gene is located on the X chromosome, so males will only see one allele when they look at their DNA data.  Females will see results for two alleles, but one may be inactive due to X chromosome inactivation.  The mutations listed below are fairly rare; 23andme does not cover all of the mutations for pyruvate dehydrogenase deficiency.

A word of caution here: 23andMe does not guarantee clinical accuracy, so it is possible that any mutation could be a false positive.

  • i5002955 (C is risk allele, rs137853257)  pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]
  • i5002957 (A is risk allele, rs137853255) pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]
  • i5002960 (C is risk allele, rs137853253) pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]
  • i5002953 (G is risk allele, rs137853259) pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]
  • i5002956 (A is the risk allele, rs137853256) pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]
  • i5002954 (A is the risk allele, rs137853258) pathogenic for Pyruvate Dehydrogenase E1-Alpha deficiency [ref]


  • rs28933391 (A is the risk allele) pathogenic for Pyruvate Dehydrogenase E1-Beta deficiency
  • rs28935769 (C is the risk allele) pathogenic for Pyruvate Dehydrogenase E1-Beta deficiency


Diet and Nutrients:

Thiamine and magnesium are cofactors of pyruvate dehydrogenase. Thus, getting enough thiamine (vitamin B1) as well as magnesium is important. [ref]

In a recent case study, supplemental thiamine along with dietary restrictions reversed muscle weakness in a boy with pyruvate dehydrogenase deficiency.

A mouse study found that a ketogenic diet may be helpful in the prenatal development of a pyruvate dehydrogenase deficient mouse.

An interesting study recently looked at the mitochondrial cannabinoid receptors and their role in skeletal muscle metabolism including the gene expression of PDHA1.  The full study is available here for free.