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 ATP.

So, it is pretty much 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]

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.”

PDHA1 Gene (on the X chromosome)

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 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.

  • 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 Nutrient Notes:

  • Thiamine and magnesium are cofactors of pyruvate dehydrogenase.  [ref]
  • In a recent case study, 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.


Medium chain acyl-CoA dehydrogenase deficiency

Medium Chain Acyl-CoA Dehydrogenase Deficiency

Medium-chain acyl-COA dehydrogenase (MCAD) deficiency is an “inborn error of metabolism” in which there is an impaired ability to break down medium-chain fatty acids.  In a nutshell, the body can use either glucose (through glycolysis) or fatty acids (through beta-oxidation) to begin producing energy in the mitochondria.  MCAD deficiency affects the body’s ability to efficiently use fatty acids for energy.

MCAD in infants and children:

MCAD deficiency is a fairly rare genetic disorder, and it is usually only diagnosed in children who are homozygous or compound heterozygous for mutations in the ACADM gene.  Symptoms generally occur when an infant or child hasn’t eaten, often due to being sick with a cold, ear infection, or the flu.  Because the body can’t utilize fatty acids efficiently for energy, children with MCAD deficiency can have problems with hypoglycemia, which can progress to a metabolic crisis. [ref]

Note that not every child that has genetic mutations for MCAD deficiency ends up having problems with MCAD deficiency.  Newborn screenings are now being done to identify infants with MCAD deficiency.  [ref]

Heterozygous mutations:

It is now being recognized that people who are heterozygous for ACADM gene mutations may also have problems with (mild) hypoglycemia during times of intense exercise, fasting, surgery, or illness — basically, times when your body may rely on fatty acids instead of glucose for energy.  Those who are heterozygous may have no problems at all under normal conditions since fatty acid oxidation should still work, just at a less than optimal level.  [ref] [ref] [ref] [ref]

One study sums up with this: “As in other metabolic disorders, the distinction between “normal” and “disease” in MCAD deficiency is blurring into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing.” [ref]

Check your 23andMe data for the following mutations in the ACADM gene:

Nutrition and lifestyle considerations:

If you are a carrier (heterozygous) for one of the MCAD deficiency mutations, you may find that a higher carb/ lower fat diet may work better for you.  In this era of carbs being demonized, MCAD carriers may need to buck the low carb trend — or at least be alert for signs of hypoglycemia if eating a low carb diet.

For infants and children with MCAD deficiency, carnitine supplementation is sometimes recommended.  Carnitine is an amino acid that is involved in the transport of long-chain fatty acids into the mitochondria for beta-oxidation.  While carnitine is readily available as a supplement (bodybuilders use it), it is also synthesized by the liver and easily found in food sources such as red meat, nuts, and legumes.  Studies of carnitine supplementation for MCADD patients have had mixed results. [ref]

Illegal drugs with synthetic cathinones (sometimes called “bath salts” or “designer drugs”) may prove deadly to someone with MCAD deficiency.  [ref]  So if you need yet another reason not to do drugs, MCADD is one.

More to read:

My Personal Thoughts:  On anything that is a serious genetic disease, please don’t rely on 23andMe data as the only source of testing.  While it is generally accurate, 23andMe data isn’t guaranteed to be totally free of errors.

Short-chain Acyl-CoA Dehydrogenase Deficiency – Inborn Errors of Metabolism

Inborn errors of metabolism - SCADD


Fatty Acid Molecules (Creative Commons Wikimedia)
Fatty Acid Molecules (Creative Commons Wikimedia)

If you have tried fasting or a ketogenic diet and felt really horrible, this article may apply to you.

The human body is wonderfully made and resilient enough to get energy from either carbs or fats — for most people.  But there are certain genetic mutations that can cause people not to burn fat for energy as efficiently.

Short Chain Acyl-CoA Dehydrogenase Deficiency (SCADD) is a disorder of fatty acid oxidation and mitochondrial energy production.  Think back to high school biology class when you learned that the mitochondria are the cellular “powerhouse”, making ATP or energy for our body.  That process of ATP production can begin with either glucose (a sugar) or fatty acids.  Glycolysis breaks down the glucose into two pyruvate molecules, which are then transformed into acetyl-CoA.  Fatty acids also can be used to create acetyl-CoA, which begins the Kreb’s cycle and the rest of mitochondrial energy production.

Short Chain Acyl-CoA Dehydrogenase is an enzyme that converts short-chain fatty acids for use in the Kreb’s cycle, and a deficiency of the enzyme makes it harder for an individual to use certain fatty acids for fuel.

SCADD is a type of inborn error of metabolism (inherited disorders that affect a person’s ability to metabolize various foods or substances).  Most of these disorders are inherited in an “autosomal recessive” manner, meaning that a person needs to have two recessive alleles to have the disease.

ACADS Genetic variants:

Mutations in the ACADS gene are the cause of short-chain acyl-CoA dehydrogenase deficiency.  Those listed below are available in 23andMe data.

Check your 23andMe data for rs1800556 (v4, v5),  c.511C>T

  • TT:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency [ref]
  • CT: carrier (heterozygous) of SCAD deficiency allele
  • CC: normal


Check your 23andMe data for rs28940874 (v4, v5)  c.575C>T

  • TT:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • CT: carrier (heterozygous) of SCAD deficiency allele
  • CC: normal


Check your 23andMe data for rs61732144 (v4, v5) c.319C>T

  • TT:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • CT: carrier (heterozygous) of SCAD deficiency allele
  • CC: normal


Check your 23andMe data for rs28941773 (v4,v5) c.1058C>T

  • TT:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • CT: carrier (heterozygous) of SCAD deficiency allele
  • CC: normal


Check your 23andMe data for rs28940872 (v4, v5) c.1147C>T

  • TT:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • CT: carrier (heterozygous) of SCAD deficiency allele
  • CC: normal

i5007491 (v4 only)  rs121908005 -The A allele is listed as pathogenic for SCADD[ref]

i5007492 (v4 only) rs121908006 -The T allele is listed as pathogenic for SCADD[ref]

i5007490 (v4 only)  rs1799958 – This one is a more common variant; it is thought that the A allele adds to susceptibility to SCADD when combined with other ACADS polymorphisms.  [ref]

SCAD deficiency – more information and studies

Infants diagnosed with SCADD have symptoms that can include hypoglycemia, lack of energy, vomiting, poor feeding, seizures, poor muscle tone, developmental delays and failure to grow/thrive.

Some newborn screenings now look for SCADD.  Increased screening has led to now understanding that a lot of infants who carry the pathogenic alleles do not have major SCADD symptoms and no treatment is needed.

Affected individuals may only have symptoms during times of fasting, illness, or other physiologic stress.  This makes sense when you look at how glycolysis and fatty acid oxidation works within our body.  Those who are carriers (heterozygous) for a pathogenic allele along with other polymorphisms in ACADS may also have symptoms when their bodies are stressed.  Studies so far have been small and inconclusive. [ref]  Recommendation for children with SCADD is to make sure they eat regularly to prevent hypoglycemia.


Fasting: For those who are heterozygous (one copy) for one of the pathogenic variants listed above,  be aware that in times of fasting or illness, you may not be able to function as well as others can.  This may be especially true for kids.

No ketogenic or low carb diet:
I know for myself (heterozygous for one of the variants), I felt really terrible and fatigued when trying a low carb diet.

Mouse studies show that a low-fat diet (or a ‘not high-fat diet’) may be helpful.  One study found a decrease in mitochondrial energy with a high-fat diet.  Another mouse study from 2012 found that ACADS deficient mice on a high-fat diet had a state of energy deficiency in the brain. A proteomics (protein) study found that 13 mitochondrial proteins had altered levels in individuals with ACADS mutations.

FAD (flavin adenine dinucleotide) is essential for SCAD function as well as other steps in the production of energy is the mitochondria.  FAD is produced in the body from riboflavin (vitamin B2), thus riboflavin is sometimes supplemented in those who have SCADD. [ref] [ref]

Riboflavin supplements may be worth trying if you don’t think you get enough via your diet. The active form of riboflavin is called riboflavin 5′ phosphate. You can also get powdered riboflavin from Bulk Supplements if you don’t want any added excipients in your supplement.

More to Read:

Medium Chain Acyl-CoA Dehydrogenase Deficiency