Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 16 peer-reviewed journal articles Updated
Medical Genetics

Ruling Out Look-Alike Conditions

At a Glance

A high C4 result on a newborn screen usually indicates SCADD, a typically harmless biochemical finding. However, doctors must perform follow-up urine and genetic tests to rule out rare but severe look-alike disorders such as IBDD, EE, and MADD.

When a newborn screen shows high levels of C4-acylcarnitine, it is like a smoke alarm going off in a specific room of a house [1]. While the alarm most often indicates SCADD—which, as we have learned, is usually a harmless “biochemical entity”—the alarm sounds the same for a few other, more serious conditions [2][3].

The primary goal of follow-up testing is to ensure your baby doesn’t have a “look-alike” condition that requires immediate treatment. It is important to remember that these severe conditions are exceptionally rare compared to the highly common, benign SCADD variants [4].

The Three Main Look-Alikes

There are three main conditions that can mimic a positive SCADD screen by raising C4 levels or producing similar chemical markers:

1. Isobutyryl-CoA Dehydrogenase Deficiency (IBDD)

This is the most common look-alike. It is caused by a change in the ACAD8 gene [5]. Like SCADD, IBDD is often considered benign, and most babies identified through screening stay healthy [6][2]. Doctors can tell the difference by looking at specific ratios of chemicals in the blood (C4/C2) or checking for a substance called isobutyrylglycine in the urine [7][8].

2. Ethylmalonic Encephalopathy (EE)

This is a very rare but severe condition caused by mutations in the ETHE1 gene [3].

  • The Difference: While SCADD involves a slow enzyme, EE involves a toxic buildup of hydrogen sulfide (H2S) in the body [9].
  • What to Watch For: Babies with EE usually have very clear symptoms that SCADD babies do not, such as chronic diarrhea, blueish hands and feet (acrocyanosis), or small red spots on the skin (petechiae) [3][10].
  • Testing: Doctors check for thiosulfate in the urine or perform genetic testing on the ETHE1 gene to rule this out [9][11].

3. Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

Also known as Glutaric Aciduria Type II, MADD is a disorder that affects several different enzymes at once [12].

  • Genetic Cause: It is caused by variants in the ETFA, ETFB, or ETFDH genes [12].
  • Riboflavin Response: A very important difference is that many forms of MADD respond extremely well to high doses of riboflavin (Vitamin B2), which helps the enzymes work better [13][14].
  • Testing: MADD creates a unique pattern of several different organic acids in the urine, not just the one (EMA) seen in SCADD [12].

How Doctors Get the Answer

To clear up the confusion, your metabolic specialist will likely order a “metabolic workup” that includes:

  • Urine Organic Acids: To see if only EMA is high (pointing to SCADD) or if other acids are present (pointing to MADD or IBDD) [8][12].
  • Genetic Sequencing: This is the “gold standard” [15]. By looking at the DNA instructions for the ACADS, ACAD8, ETHE1, and ETF genes, doctors can confirm exactly which “worker” in the factory is affected.

Finding out that a screen is “positive” is stressful, but these follow-up tests are the best way to move from a place of uncertainty to a clear plan for your baby’s health. In most cases, the tests will confirm that the baby has the harmless biochemical signature of SCADD [4][16].

Common questions in this guide

What causes a high C4 result on my baby's newborn screen?
A high C4-acylcarnitine level is the primary marker for SCADD, which is usually a harmless biochemical finding. However, this same marker can also be elevated in other, more serious metabolic conditions, which is why further testing is required.
What is the difference between SCADD and IBDD?
Isobutyryl-CoA Dehydrogenase Deficiency (IBDD) is the most common condition that looks like SCADD on a newborn screen. Like SCADD, it is generally considered benign, and doctors can distinguish between the two using specific urine and blood tests.
What are the signs of Ethylmalonic Encephalopathy (EE)?
Unlike harmless SCADD variants, babies with EE may develop clear symptoms like chronic diarrhea, blueish hands and feet, or small red spots on the skin. EE is a very rare but severe condition caused by a toxic buildup of hydrogen sulfide.
How do doctors confirm a SCADD diagnosis?
Metabolic specialists typically order a combination of urine organic acid tests and genetic sequencing. Genetic testing is considered the gold standard because it allows doctors to look directly at the DNA instructions to see exactly which gene is affected.
Will my baby need treatment while waiting for genetic test results?
If Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is suspected as a look-alike condition, a doctor might recommend high doses of riboflavin (Vitamin B2). You should ask your metabolic specialist if your baby needs this while waiting for the genetic results to come back.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Were my baby's ratios for C4/C2 or C4/C3 calculated? What do they tell us?
  2. 2.Has ethylmalonic encephalopathy (EE) been ruled out? Did you check for thiosulfate or signs of hydrogen sulfide buildup?
  3. 3.Was my baby tested for glutaric acid or other organic acids that might point toward MADD?
  4. 4.Does my baby need to start taking riboflavin while we wait for the genetic results?
  5. 5.Which specific genes are being tested? Does the panel include ETHE1, ACAD8, and the ETFA/B/D genes?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Butyrylcarnitine Elevation in Newborn Screening: Reducing False Positives and Distinguishing between Two Rare Diseases through the Evaluation of New Ratios.

    Messina M, Arena A, Iacobacci R, et al.

    Biomedicines 2023; (11(12)) doi:10.3390/biomedicines11123247.

    PMID: 38137468
  2. 2

    Isobutyryl-coenzyme a dehydrogenase deficiency: disease, or non-disease?

    Santacruz Reyes MD, Sass JO

    Orphanet journal of rare diseases 2026; (21(1)):35 doi:10.1186/s13023-026-04207-7.

    PMID: 41606743
  3. 3

    Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.

    Platt I, Bisgin A, Kilavuz S

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2023; (44(11)):3827-3852 doi:10.1007/s10072-023-06904-8.

    PMID: 37458841
  4. 4

    Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease.

    Breilyn MS, Kenny EE, Abul-Husn NS

    Molecular genetics and metabolism 2023; (138(1)):106971 doi:10.1016/j.ymgme.2022.106971.

    PMID: 36549199
  5. 5

    Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report.

    Eleftheriadou M, Medici-van den Herik E, Stuurman K, et al.

    Molecular genetics & genomic medicine 2021; (9(2)):e1595 doi:10.1002/mgg3.1595.

    PMID: 33432785
  6. 6

    Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8.

    Feng J, Yang C, Zhu L, et al.

    Orphanet journal of rare diseases 2021; (16(1)):392 doi:10.1186/s13023-021-02018-6.

    PMID: 34544473
  7. 7

    Clinical, biochemical and genetic analysis of Chinese patients with isobutyryl-CoA dehydrogenase deficiency.

    Lin Y, Peng W, Jiang M, et al.

    Clinica chimica acta; international journal of clinical chemistry 2018; (487()):133-138 doi:10.1016/j.cca.2018.09.033.

    PMID: 30253142
  8. 8

    Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population.

    Zhou W, Cai H, Li H, et al.

    Frontiers in pediatrics 2021; (9()):757424 doi:10.3389/fped.2021.757424.

    PMID: 34869113
  9. 9

    Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalopathy: Insights from Animal and Human Studies.

    Grings M, Wajner M, Leipnitz G

    Cellular and molecular neurobiology 2022; (42(3)):565-575 doi:10.1007/s10571-020-00976-2.

    PMID: 33034777
  10. 10

    Ethylmalonic encephalopathy caused by biallelic truncating variants in ETHE1: A case report.

    Ruiz-Martinez DA, Vega-Peniche ER, Quiñonez-Pacheco Y, et al.

    SAGE open medical case reports 2026; (14()):2050313X251412221 doi:10.1177/2050313X251412221.

    PMID: 41551113
  11. 11

    Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy.

    Boyer M, Sowa M, Di Meo I, et al.

    Molecular genetics and metabolism 2018; (124(1)):57-63 doi:10.1016/j.ymgme.2018.02.008.

    PMID: 29526615
  12. 12

    FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening.

    Muru K, Reinson K, Künnapas K, et al.

    Molecular genetics & genomic medicine 2019; (7(9)):e915 doi:10.1002/mgg3.915.

    PMID: 31392824
  13. 13

    Pearls & Oy-sters: A curable myopathy manifesting as exercise intolerance and respiratory failure.

    Silva AMS, Mendonça RH, Soares DC, et al.

    Neurology 2018; (91(4)):187-190 doi:10.1212/WNL.0000000000005867.

    PMID: 30037914
  14. 14

    A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene.

    Wen B, Tang R, Tang S, et al.

    Journal of human genetics 2024; (69(3-4)):125-131 doi:10.1038/s10038-023-01216-3.

    PMID: 38228875
  15. 15

    [An analysis of clinical characteristics and gene mutation in two patients with medium- and short-chain acyl-CoA dehydrogenase deficiency].

    Tan JQ, Chen DY, Li ZT, et al.

    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2016; (18(10)):1019-1025.

    PMID: 27751224
  16. 16

    Clinical characteristics and related gene mutations of infants with short-chain acyl-CoA dehydrogenase deficiency by neonatal screening in Beijing.

    Gong L, Yang N, Zhao J, et al.

    Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 2022; (51(3)):278-283 doi:10.3724/zdxbyxb-2022-0214.

    PMID: 36207829

This page provides educational information about SCADD and newborn screening follow-up. It is not medical advice; always consult your pediatrician or metabolic specialist regarding your baby's specific test results and care plan.

Get notified when new evidence is published on Short chain acyl-CoA dehydrogenase deficiency.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.