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 13 peer-reviewed journal articles Updated
Pediatrics · Short-Chain Acyl-CoA Dehydrogenase Deficiency

The Biology of SCADD: ACADS, C4, and EMA

At a Glance

SCADD is a harmless biochemical condition where variations in the ACADS gene cause a slight backup in breaking down short fats. This shows up as high C4 in blood and EMA in urine on a newborn screen, but most babies with SCADD never develop symptoms and remain completely healthy.

To understand SCADD (Short-Chain Acyl-CoA Dehydrogenase Deficiency), it helps to think of your baby’s body as a multi-step factory line that turns fat into energy [1]. When the body runs out of sugar (glucose), it switches to burning fats. These fats are broken down like a long chain being cut into smaller and smaller pieces.

The Role of the ACADS Gene

The ACADS gene provides the instructions for making an enzyme (a specialized protein) called short-chain acyl-CoA dehydrogenase [1]. This enzyme’s specific job is to handle the very last, shortest pieces of the fat chain [2].

  • The Enzyme “Worker”: If the ACADS gene has a mutation, the enzyme “worker” may be missing or not working at full speed.
  • The Backup: When this worker is slow, the “factory line” for short fats gets backed up. This backup is what doctors measure on the newborn screen [3].

SCADD is an autosomal recessive condition [3]. This means both parents are typically healthy “carriers” of the gene variant but don’t show any biochemical changes themselves. When both parents are carriers, there is a 25% chance of passing this biochemical trait to a child [3]. Parents often wonder if older siblings should be tested. Since most cases are harmless, you can discuss with your metabolic specialist whether testing older, healthy siblings is necessary [4].

Understanding the Markers: C4 and EMA

Because the body can’t process the short fats normally, they spill over into the blood and urine in forms that doctors can measure. When the “factory line” backs up, the unprocessed short fats spill over in two different, independent ways [5][3]:

  • Butyrylcarnitine (C4): This byproduct is the primary marker measured in the blood during the initial newborn screen [5]. High levels of C4 suggest that the short-chain fats are backing up in the system [3]. However, C4 is not perfect; it can also be high in other harmless conditions, such as IBDD (Isobutyryl-CoA dehydrogenase deficiency), which involves a different gene called ACAD8 [6][7].
  • Ethylmalonic Acid (EMA): This is another byproduct of the same fat backup, but it is measured in the urine [5]. Testing the urine for EMA is a “second-tier” test that helps confirm if the backup is truly related to the SCAD enzyme [8].

Common Variants vs. Rare Mutations

The severity of the “backup” often depends on exactly what is wrong with the ACADS gene.

  1. Common Variants: Many people carry “common variants” (like c.625G>A or c.511C>T) [9][10]. These are like minor typos in the instruction manual. They make the enzyme work slightly less efficiently, leading to mildly high C4 or EMA levels, but they almost never cause health problems [11][4].
  2. Rare Pathogenic Mutations: These are more significant changes in the gene that can cause the enzyme to stop working almost entirely. Even in these cases, many infants still remain completely asymptomatic (showing no symptoms) and develop normally [12][13].

Why Second-Tier Testing Matters

The initial blood test (C4) is very sensitive, meaning it catches almost everyone with even a tiny enzyme slowdown. This leads to many “referrals” for babies who are perfectly healthy. Second-tier testing—checking the urine for EMA—helps doctors filter out these cases [8]. If the urine EMA is low or normal, it is very likely that the initial high C4 was not a cause for concern [8].

In summary, SCADD is a “biochemical signature” that shows up in lab work (as high C4 or EMA) but rarely translates into a physical illness that affects your baby’s life [4][12].

Common questions in this guide

What is the role of the ACADS gene in SCADD?
The ACADS gene provides instructions for making an enzyme that handles the final step of breaking down short-chain fats for energy. If there is a variant or mutation in this gene, the enzyme works slower, causing a backup in the system.
What do high C4 and EMA levels mean on my baby's test results?
High C4 in the blood and EMA in the urine are byproducts that spill over when short-chain fats back up in the body. Doctors use these markers on newborn screens to identify if the ACADS enzyme is working properly.
Do common ACADS genetic variants cause health problems?
Common variants like c.625G>A or c.511C>T are like minor typos in the genetic instruction manual. While they may lead to slightly high C4 or EMA levels on a lab test, they almost never cause health problems or symptoms.
Why does my baby need a second-tier urine test for EMA?
The initial C4 blood test is highly sensitive and often flags perfectly healthy babies. Checking the urine for EMA is a second-tier test that filters out false alarms and confirms if the backup is truly related to the SCADD enzyme.
Should we test our older children for these genetic variants?
Because most cases of SCADD are harmless and asymptomatic, testing healthy older siblings is rarely medically necessary. You should discuss with your metabolic specialist whether testing your older children makes sense for your family.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my baby have the 'common' genetic variants (c.625G>A or c.511C>T) or 'rare' pathogenic mutations?
  2. 2.How do the levels of C4 in the blood compare to the levels of EMA in the urine for my baby?
  3. 3.Can you explain why a high EMA level might not necessarily mean my baby will have symptoms?
  4. 4.Were the levels of isobutyrylglycine checked to make sure this isn't actually IBDD?
  5. 5.Based on these biochemical markers, how often do we need to re-test or follow up?
  6. 6.Should we test our older children for these genetic variants?

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 (13)
  1. 1

    Crosstalk between butyrate oxidation in colonocyte and butyrate-producing bacteria.

    Park B, Kim JY, Riffey OF, et al.

    iScience 2024; (27(9)):110853 doi:10.1016/j.isci.2024.110853.

    PMID: 39310762
  2. 2

    Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases.

    Han A, Bennett N, Ahmed B, et al.

    Oncotarget 2018; (9(43)):27280-27292 doi:10.18632/oncotarget.25546.

    PMID: 29930765
  3. 3

    [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
  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

    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
  6. 6

    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
  7. 7

    Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function.

    Fahnehjelm KT, Liu Y, Olsson D, et al.

    Acta paediatrica (Oslo, Norway : 1992) 2016; (105(12)):1451-1460 doi:10.1111/apa.13536.

    PMID: 27461099
  8. 8

    Genomic Analysis of Historical Cases with Positive Newborn Screens for Short-Chain Acyl-CoA Dehydrogenase Deficiency Shows That a Validated Second-Tier Biochemical Test Can Replace Future Sequencing.

    Adhikari AN, Currier RJ, Tang H, et al.

    International journal of neonatal screening 2020; (6(2)) doi:10.3390/ijns6020041.

    PMID: 32802992
  9. 9

    Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants.

    Dessein AF, Fontaine M, Joncquel-Chevalier Curt M, et al.

    Clinica chimica acta; international journal of clinical chemistry 2017; (471()):101-106 doi:10.1016/j.cca.2017.05.026.

    PMID: 28532786
  10. 10

    Unexpected elevation in valproic acid concentration and agranulocytosis in a patient with short-chain acyl-CoA dehydrogenase deficiency.

    Suzuki Y, Ito S, Otani Y, et al.

    Brain & development 2021; (43(5)):657-660 doi:10.1016/j.braindev.2021.01.001.

    PMID: 33549404
  11. 11

    Tread carefully: A functional variant in the human NADPH oxidase 4 (NOX4) is not disease causing.

    Nafisinia M, Menezes MJ, Gold WA, et al.

    Molecular genetics and metabolism 2018; (123(3)):382-387 doi:10.1016/j.ymgme.2018.01.007.

    PMID: 29398271
  12. 12

    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
  13. 13

    [Clinical, biochemical and gene mutation characteristics of short chain acyl-coenzyme A dehydrogenase deficiency by neonatal screening].

    Huang XW, Zhang Y, Yang JB, et al.

    Zhonghua er ke za zhi = Chinese journal of pediatrics 2016; (54(12)):927-930 doi:10.3760/cma.j.issn.0578-1310.2016.12.011.

    PMID: 27938594

This page explains the biology and newborn screening markers of SCADD for educational purposes only. Always consult your pediatric metabolic specialist to interpret your baby's specific genetic and biochemical test results.

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.