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PubMed This is a summary of 19 peer-reviewed journal articles Updated
Medical Genetics

The Biology of Energy: Understanding MADD and Your Labs

At a Glance

Multiple acyl-CoA dehydrogenase deficiency (MADD) often produces a broad pattern of abnormal fat-processing markers in blood and organic acids in urine, but results can look normal when a person is well or taking supplements. Repeat testing and gene testing may be needed.

To understand Multiple acyl-CoA dehydrogenase deficiency (MADD), it helps to think of your cells as a complex power grid. For your body to stay energized, it must break down various fuels—specifically fats and proteins. This process requires a series of “delivery trucks” (enzymes) to carry energy in the form of electrons to the cell’s main power plant, the mitochondria [1].

In MADD, the “electrical wiring” that connects these trucks to the power plant is impaired. This wiring consists of two main parts: electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF-QO) [2].

  • The ETFA and ETFB genes provide instructions for making the two parts of ETF.
  • The ETFDH gene provides instructions for making ETF-QO.

When any of these genes have pathogenic variants (mutations), the energy cannot efficiently reach its destination [3]. Instead, the “fuel” (fats and proteins) backs up in the system, causing byproducts to spill into the blood and urine [4].

Reading the Biochemical Map

When doctors suspect MADD, they look for specific “markers” left behind by the metabolic bottleneck.

Blood Tests: The Acylcarnitine Profile

Newborn screening and follow-up blood tests look at acylcarnitines—compounds that form when fats aren’t processed correctly. In MADD, you typically see elevations across a wide range of these markers, from short-chain to long-chain (specifically C4 through C18 species) [5][6].

Urine Tests: Organic Acids

Urine testing looks for the “spillover” of acids that the body couldn’t use for energy. Common findings in MADD include:

  • Glutaric acid (the namesake of GA2) [7].
  • Ethylmalonic acid and isovaleric acid [8].
  • 2-hydroxyglutaric acid [9].

Why Labs Might Look “Normal”

One of the most confusing aspects of MADD is that biochemical tests can sometimes come back normal, even in a person who definitely has the condition [10]. This “false negative” can happen for several reasons:

  • Stability: If you are feeling well and your body is not under stress, your metabolism may be functioning “well enough” that the markers don’t build up to detectable levels [8][11].
  • Treatment: If you have already started taking riboflavin or carnitine, these supplements can alter the metabolic pathways and make your labs look normal [12][4].
  • Sample Timing: In some cases, a newborn’s initial screen may be abnormal, but a follow-up test days later looks normal because the baby’s metabolism has temporarily stabilized [13].

Because of this, a single normal test result does not rule out MADD if your symptoms or family history suggest the condition [10].

Beware of “Mimics”

Several other conditions can “mimic” the laboratory signature of MADD, especially on a newborn screen. Your doctor must distinguish MADD from:

  • FLAD1 Deficiency: A defect in making FAD (a form of Vitamin B2), which is essential for the ETF “wiring” to work [14].
  • Riboflavin Transporter Disorders: Conditions where the body cannot absorb or move Vitamin B2 correctly [15].
  • Nutritional Deficiency: A mother with low Vitamin B2 levels—sometimes related to maternal diet (like a vegan or restrictive diet that is not adequately supplemented)—can give birth to a baby who temporarily shows MADD-like markers on a newborn screen [16][17]. (Note that vegan and lactose-free diets are not inherently deficient, but maternal deficiency should be assessed.)
  • Medications: Certain drugs, most notably the antidepressant sertraline, have been reported to cause temporary biochemical patterns that look exactly like MADD on newborn screens or labs [18][19]. Never stop or change a prescribed medication without consulting your doctor, as these medication effects are often transient and represent lab interference, not actual disease.

Common questions in this guide

What lab pattern is typical of MADD?
MADD often causes elevations in many acylcarnitines, including short- and long-chain markers from C4 through C18. Urine may show organic acids such as glutaric, ethylmalonic, isovaleric, and 2-hydroxyglutaric acids.
Can normal blood and urine tests rule out MADD?
No. Results may be normal when a person is well, after riboflavin or carnitine supplementation has started, or when a follow-up sample is collected after an abnormal newborn screen has temporarily settled. Your clinician may decide whether repeat testing or genetic testing is appropriate when suspicion remains.
Which genes are associated with MADD?
MADD is linked to pathogenic variants in ETFA, ETFB, or ETFDH. These genes provide instructions for parts of the electron-transfer system that helps cells use fats and proteins for energy.
What can look like MADD on a newborn screen?
MADD-like results can occur with FLAD1 deficiency, riboflavin transporter disorders, maternal vitamin B2 deficiency, or certain medication effects. Sertraline has been reported to cause a temporary pattern that resembles MADD, so prescribed medicines should not be stopped or changed without medical advice.
Why are acylcarnitines and organic acids checked for MADD?
Acylcarnitines can build up when fats are not processed correctly, while organic acids can spill into urine when the body cannot use certain fuels efficiently. Looking at both types of markers helps clinicians recognize the biochemical pattern and consider other explanations.
What should I tell my doctor before MADD testing?
Tell your clinician whether the sample was collected during illness or while you or your child felt well, and mention current medicines, riboflavin or carnitine use, and relevant diet history. These details can affect test results or create a pattern that resembles MADD.

Questions For You

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific gene is affected (ETFA, ETFB, or ETFDH), and were two pathogenic changes found?
  2. 2.Based on the specific acylcarnitines and organic acids found in my/my child's labs, how severe is the metabolic block?
  3. 3.If our biochemical tests were normal but symptoms continue, should we repeat the tests during a time of stress or illness?
  4. 4.Have you ruled out "mimics" like FLAD1 deficiency or riboflavin transporter issues?
  5. 5.Could any current medications or maternal diets be interfering with these newborn screening test results?

References

References (19)
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    Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease.

    Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P

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    An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

    Mosegaard S, Bruun GH, Flyvbjerg KF, et al.

    Molecular genetics and metabolism 2017; (122(4)):182-188 doi:10.1016/j.ymgme.2017.10.014.

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    Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies.

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    The international journal of biochemistry & cell biology 2021; (132()):105899 doi:10.1016/j.biocel.2020.105899.

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    Multiple Acyl-CoA Dehydrogenase Deficiency: A Rare Cause of Hepatomegaly.

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    Case report: A novel c.1842_1845dup mutation of ETFDH in two Chinese siblings with multiple acyl-CoA dehydrogenase deficiency.

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    Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series.

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    Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): A Case Report With a Complex Biochemical Profile.

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    Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report.

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    Hypoketotic hypoglycemia without neuromuscular complications in patients with SLC25A32 deficiency.

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    Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity.

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This page is for informational purposes only and does not constitute medical advice. A metabolic specialist or genetic counselor should interpret your or your child's MADD results and guide next steps.