Short-chain Acyl-CoA Dehydrogenase Deficiency

Have you tried fasting or perhaps a ketogenic diet and felt horrible?  If so, one reason could be found in the way that your body uses different types of fats.

Using Fat for Fuel: Short-chain fatty acids

The human body is wonderfully made and resilient enough to get energy from a variety of food sources. Most people can survive and thrive using either carbs or fats. When our ancestors ran out of grain or potatoes they could survive on fish or sheep. 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 in the mitochondria can begin with either glucose (a sugar) or fatty acids.

If you start with glucose, 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 production of ATP in the Krebs’ cycle and then the electron energy transport chain.

Short-Chain Acyl-CoA Dehydrogenase enzyme deficiency

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

Mutations in the ACAD gene can cause short-chain acyl-CoA dehydrogenase deficiency (SCADD). SCADD is classified as an inborn error of metabolism, which means it is an inherited disorder that affects a person’s ability to metabolize a specific nutrient. It is a rare disorder that is usually detected in infancy. Two copies of the mutation are needed in order to have the disorder.

Symptoms in infants with SCADD include hypoglycemia, lack of energy, vomiting, poor feeding, seizures, poor muscle tone, developmental delays, and failure to grow/thrive. This can be deadly if not managed with regular feedings.

Some newborn screenings now look for SCADD. Early detection and treatment can mitigate developmental problems.[ref] Increased screening has led to research showing that not all people who carry the SCADD mutations have symptoms.

Affected individuals may only have symptoms during times of fasting, illness, or other physiologic stress. During fasting or stress, the body can shift from using carbohydrates for energy to burning fatty acids. A recommendation for children with SCADD is to make sure they eat regularly to prevent hypoglycemia.(More info on SCADD)

Carriers of just one mutation in the ACADS gene may also have symptoms when their bodies are stressed, but not to the same extent as children or adults with SCADD. Studies so far have been small and inconclusive.[ref]

Recent research points to the mutations in ACADS causing the protein to misfold. It is theorized that SCADD symptoms may be due both to the decreased cellular energy combine with a toxic accumulation of the enzyme.[ref]


ACADS Genetic variants:

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Mutations in the ACADS gene are the cause of short-chain acyl-CoA dehydrogenase deficiency. The list below is only a partial list – not all genetic mutations are covered by 23andMe or AncestryDNA testing.  Keep in mind also that 23andMe and AncestryDNA do not guarantee the accuracy of their data for clinical use, so there is a chance that a rare mutation could be a false positive.

Check your genetic data for rs1800556 C511T (23andMe v4, v5; AncestryDNA),

  • T/T:  possibly pathogenic for short-chain acyl-CoA dehydrogenase deficiency, some sources say possibly not pathogenic so it may depend on other variables [ref]
  • C/T: carrier (heterozygous) of SCAD deficiency allele
  • C/C: normal

Members: Your genotype for rs1800556 is .

 

Check your genetic data for rs28940874 C575T (23andMe v4, v5; AncestryDNA)

  • T/T:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • C/T: carrier (heterozygous) of SCAD deficiency allele
  • C/C: normal

Members: Your genotype for rs28940874 is .

 

Check your genetic data for rs61732144 C319T (23andMe v4, v5; AncestryDNA)

  • T/T:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • C/T: carrier (heterozygous) of SCAD deficiency allele
  • C/C: normal

Members: Your genotype for rs61732144 is .

 

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

  • T/T:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • C/T: carrier (heterozygous) of SCAD deficiency allele
  • C/C: normal

Members: Your genotype for rs28941773 is .

 

Check your genetic data for rs28940872 (23andMe v4, v5; AncestryDNA):

  • T/T:  pathogenic for short-chain acyl-CoA dehydrogenase deficiency[ref]
  • C/T: carrier (heterozygous) of SCAD deficiency allele
  • C/C: normal

Members: Your genotype for rs28940872 is .

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]

 


Lifehacks

Fasting:

People with one copy of the pathogenic variants listed above may have problems with low blood sugar in extended fasting. This is something to be aware of and plan for in times of fasting or illness. This may be especially true for kids.

Avoid low-carb and ketogenic diets:

Animal studies show that a low-fat diet (or at least avoiding a 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.

 

Riboflavin:

FAD (flavin adenine dinucleotide) is essential for SCAD function as well as other steps in the production of energy in 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.