Short-Chain Acyl-CoA Dehydrogenase Deficiency

⚙

Pathophysiology

4

ACADS molecular function deficiency

Biallelic variants in ACADS reduce short-chain acyl-CoA dehydrogenase (SCAD) activity in the mitochondrial matrix. SCAD is a homotetrameric flavoprotein with a non-covalently bound FAD prosthetic group that catalyzes the first, FAD-dependent dehydrogenation step of beta-oxidation, with its physiologic role specific to butyryl-CoA. Most disease-associated variants are missense changes that impair folding and stability rather than abolishing intrinsic catalytic chemistry.

ACADS hgnc:90

short-chain acyl-CoA dehydrogenase activity GO:0003995 ↓ DECREASED FAD binding GO:0071949

mitochondrial matrix GO:0005759

Downstream

Impaired short-chain fatty acid beta-oxidation Reduced SCAD activity blocks the first dehydrogenation step of short-chain (C4) acyl-CoA beta-oxidation.

Show evidence (2 references)

PMID:18977676 SUPPORT Other

"SCAD is a homotetramer with each monomer containing a non-covalently bound flavin adenine dinucleotide (FAD) molecule as a prosthetic group"

Defines SCAD as an FAD-dependent flavoprotein, the enzyme whose activity is reduced in SCADD.

PMID:18977676 SUPPORT Other

"its physiologic role is specific to butyryl-CoA as none of the other ACADs are active with this substrate in vivo"

Establishes that SCAD is the enzyme physiologically responsible for butyryl-CoA dehydrogenation.

Impaired short-chain fatty acid beta-oxidation

Loss of SCAD activity blocks dehydrogenation of butyryl-CoA, the terminal short-chain step of the mitochondrial beta-oxidation spiral. Because SCAD acts only at the end of the cycle and its substrate specificity partly overlaps with MCAD, fasting ketogenesis and gluconeogenesis are largely preserved, which distinguishes SCADD from medium- and long-chain fatty acid oxidation disorders.

fatty acid beta-oxidation GO:0006635 ↓ DECREASED fatty acid beta-oxidation using acyl-CoA dehydrogenase GO:0033539 ↓ DECREASED

mitochondrial matrix GO:0005759

Downstream

Toxic metabolite accumulation The blocked butyryl-CoA dehydrogenation step causes butyryl-CoA and its byproducts to accumulate.

Absence of hypoketotic hypoglycemia Unlike MCAD/VLCAD deficiency, SCADD usually does not cause hypoketotic hypoglycemia because ketogenesis is largely preserved.

Show evidence (1 reference)

PMID:18977676 SUPPORT Other

"Overlap of substrate specificity of SCAD and MCAD may also partially compensate for the deficiency of the former enzyme."

Explains why the short-chain block is partially compensated, accounting for the absence of classic FAO-disorder decompensation.

Toxic metabolite accumulation

Blocked short-chain beta-oxidation causes accumulation of butyryl-CoA, which is diverted into butyrylcarnitine, butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid. EMA, the biochemical hallmark, is thought to form by carboxylation of excess butyryl-CoA by propionyl-CoA carboxylase. These metabolites appear in blood and urine and are the basis of newborn-screening detection, though levels may be normal when the individual is well and rise during fasting or illness.

mitochondrial matrix GO:0005759

Downstream

Elevated plasma butyrylcarnitine (C4) Accumulated butyryl-CoA is esterified to carnitine and detected as elevated C4 acylcarnitine.

Ethylmalonic aciduria Excess butyryl-CoA diverted through carboxylation produces increased urinary ethylmalonic acid.

Urinary methylsuccinic acid During metabolic stress, methylsuccinate is also excreted in the urine.

Nonspecific neuromuscular and developmental features A direct neurotoxic effect of accumulated metabolites (EMA, butyric acid) has been hypothesized to explain the predominantly neurologic features in symptomatic cases, but causation is unproven and debated.

Show evidence (1 reference)

PMID:18977676 SUPPORT Other

"EMA, the hallmark of SCAD deficiency, is likely formed by the carboxylation of excess butyryl-CoA by propionyl-CoA carboxylase."

Provides the biochemical route by which ethylmalonic acid, the hallmark metabolite, accumulates.

Protein misfolding, aggregation and oxidative stress

Nearly all SCADD-associated ACADS variants are missense changes, and both the common variants and most rare variants impair folding and stability. In vitro studies show these variant proteins misfold and aggregate within mitochondria, especially at elevated temperatures, and this cellular toxicity has been linked to excessive reactive oxygen species production and chronic oxidative stress. This gain-of-toxicity mechanism, together with as-yet-unknown genetic and environmental modifiers, has been proposed to contribute to symptomatic disease in a subset of individuals, but no correlation between the degree of SCAD dysfunction and clinical phenotype has been established.

protein folding GO:0006457 ↓ DECREASED reactive oxygen species metabolic process GO:0072593 ↑ INCREASED response to oxidative stress GO:0006979 ↑ INCREASED

mitochondrial matrix GO:0005759

Downstream

Nonspecific neuromuscular and developmental features Intramitochondrial aggregation of misfolded SCAD has been proposed to contribute to symptoms, analogous to other misfolding-associated neurologic disorders, but the association with clinical disease is unproven.

Show evidence (3 references)

PMID:28516284 SUPPORT In Vitro

"missense variants, impair folding, that may lead to toxic accumulation of the"

In vitro studies demonstrate that SCADD variants impair folding, leading to toxic protein/metabolite accumulation.

PMID:28516284 SUPPORT In Vitro

"encoded protein, and/or metabolites, and initiate excessive production of ROS"

Links the misfolding defect to excessive reactive oxygen species production.

PMID:18977676 SUPPORT In Vitro

"both variant proteins show impaired folding and increased aggregation in mitochondrial import studies, especially at elevated temperatures."

Mitochondrial import studies show the common variant proteins misfold and aggregate, worsened by elevated temperature.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (5):

Target 'Absence of hypoketotic hypoglycemia' (from 'Impaired short-chain fatty acid beta-oxidation') not found in named elements
Target 'Elevated plasma butyrylcarnitine (C4)' (from 'Toxic metabolite accumulation') not found in named elements
Target 'Urinary methylsuccinic acid' (from 'Toxic metabolite accumulation') not found in named elements
Target 'Nonspecific neuromuscular and developmental features' (from 'Toxic metabolite accumulation') not found in named elements
Target 'Nonspecific neuromuscular and developmental features' (from 'Protein misfolding, aggregation and oxidative stress') not found in named elements

●

Phenotypes

10

Digestive 1

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"1) failure to thrive with feeding difficulties and hypotonia (23 patients, 20%);"

Documents feeding difficulties (with failure to thrive and hypotonia) as a reported symptomatic subgroup.

Genitourinary 1

Ethylmalonic aciduria VERY_FREQUENT HP:0003219

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle"

Identifies increased urinary EMA as a defining biochemical marker of SCADD.

Metabolism 2

Hypoglycemia OCCASIONAL HP:0001943

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"A 14 month old with SCADD was reported to have hypoglycemia, but ketonuria was also present, suggesting that ketone body formation is not significantly impacted in SCADD"

Documents that hypoglycemia in SCADD is accompanied by ketonuria, unlike the hypoketotic hypoglycemia of other FAO disorders.

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia."

Lists metabolic acidosis among phenotypes ascribed to primary SCADD.

Musculoskeletal 2

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia."

Lists hypotonia among the neuromuscular phenotypes ascribed to primary SCADD.

Myopathy HP:0003198

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"neuromuscular symptoms such as myopathy and hypotonia."

Lists myopathy among the neuromuscular symptoms ascribed to primary SCADD.

Nervous System 3

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:18977676 SUPPORT Human Clinical

"In the largest series of patients published to date, 69% of 114 patients had developmental delay."

Quantifies developmental delay as the predominant reported feature in a large symptomatic SCADD series.

PMID:16926354 SUPPORT Human Clinical

"Developmental delay, epilepsy, behavioral"

The Dutch cohort lists developmental delay among the most frequently reported nonspecific symptoms.

Seizures HP:0001250

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"2) developmental delay and seizures (25 patients, 25%); and 3) developmental delay and hypotonia without seizures (34 patients, 30%)."

Documents a developmental-delay-plus-seizures subgroup within a large symptomatic SCADD series.

Behavioral abnormality Atypical behavior HP:0000708

Show evidence (1 reference)

PMID:16926354 SUPPORT Human Clinical

"Developmental delay, epilepsy, behavioral"

Lists behavioral disturbance among the most frequently reported SCADD symptoms.

Growth 1

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia."

Lists failure to thrive among phenotypes ascribed to primary SCADD.

🧬

Genetic Associations

1

ACADS gene variants

Gene: ACADS hgnc:90

Autosomal recessive

Show evidence (2 references)

PMID:16926354 SUPPORT Human Clinical

"ACADS genotype showed a statistically significant association with EMA and C4-C"

Documents that ACADS genotype correlates with biochemical (EMA, C4-C) levels.

PMID:16926354 SUPPORT Human Clinical

"were free of symptoms."

Documents that SCADD relatives sharing the proband genotype were largely asymptomatic, underscoring uncertain clinical significance.

Variants (2)

ACADS - rare inactivating missense variants

Most SCADD-associated ACADS variants are rare, largely private missense mutations. For alleles tested, these lead to complete inactivation, impaired biogenesis, or intramitochondrial aggregation of misfolded protein, and the degree of dysfunction correlates with biochemical (EMA) but not clinical phenotype.

Show evidence (1 reference)

PMID:18977676 SUPPORT In Vitro

"no correlation was found between the clinical phenotype and the degree of SCAD dysfunction"

Documents the lack of genotype-clinical-phenotype correlation for ACADS variants.

ACADS - c.511C>T (p.Arg147Trp) and c.625G>A (p.Gly185Ser) common variants

Two common ACADS variants, c.511C>T (R147W) and c.625G>A (G185S), have little effect on catalytic kinetics but impair folding and stability. They are relatively common in the general population (allele frequencies ~22% and ~3% in one U.S. study), are overrepresented among individuals with ethylmalonic aciduria, and are considered susceptibility/variant alleles of uncertain clinical significance rather than fully penetrant pathogenic mutations.

Show evidence (2 references)

PMID:28516284 SUPPORT Human Clinical

"individuals has identified rare gene variants along with two common gene"

Identifies the two common ACADS variants alongside rare variants.

PMID:16926354 SUPPORT Human Clinical

"c.511C>T or c.625G>A susceptibility variants"

The Dutch study explicitly designates c.511C>T and c.625G>A as susceptibility variants.

💊

Medical Actions

4

No specific treatment (biochemical phenotype)

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because SCADD is generally a biochemical phenotype without clinical manifestations, GeneReviews recommends no treatment and gives no dietary or supplement recommendations; surveillance is likewise not recommended.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"without clinical manifestations, no treatment is recommended and there are no"

GeneReviews states that no treatment is recommended for SCADD.

Avoidance of fasting

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

If preventive measures are undertaken, they likely include only avoidance of fasting to reduce catabolic drive; the need for a low-fat diet has not been substantiated.

Mechanism Target:

MODULATES Impaired short-chain fatty acid beta-oxidation — Avoiding fasting reduces reliance on the impaired short-chain fatty acid oxidation pathway during catabolic stress.

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"Preventive measures, if necessary, likely include only avoidance of fasting. The need for a low fat diet has not been substantiated."

Supports avoidance of fasting as the main preventive measure and notes low-fat diet is unsubstantiated.

Riboflavin supplementation (unproven)

Action: Pharmacotherapy NCIT:C15986

Agent: riboflavin CHEBI:17015

Because FAD is an essential cofactor for SCAD, riboflavin has been suggested as a possible chemical-chaperone therapy to stabilize misfolded mutant enzyme. Its need and efficacy in SCADD remain unproven.

Mechanism Target:

MODULATES Protein misfolding, aggregation and oxidative stress — Riboflavin (FAD precursor) is proposed to act as a chemical chaperone to stabilize misfolded SCAD, but evidence is anecdotal.

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"riboflavin supplementation has been suggested as a possible therapy for SCADD due to its potential ability to act as a chemical chaperone and stabilize mutant enzyme."

States the proposed chemical-chaperone rationale for riboflavin in SCADD.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling regarding autosomal recessive inheritance and recurrence risk. Because SCADD is not thought to be clinically significant, prenatal and preimplantation genetic testing are considered medically unnecessary.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"SCADD is inherited in an autosomal recessive manner."

Autosomal recessive inheritance supports the role of genetic counseling for recurrence-risk assessment.

🔬

Biochemical Markers

3

Butyrylcarnitine (C4) (INCREASED)

Context: Increased plasma butyrylcarnitine (C4 acylcarnitine) is the primary tandem-mass-spectrometry marker used to detect SCADD on newborn screening. It is not specific (isobutyryl-CoA dehydrogenase deficiency also elevates C4) and may be normal except during physiologic stress.

Pathograph Readouts

Readout Of Toxic metabolite accumulation Positive Diagnostic

Elevated C4 acylcarnitine reports the accumulation of butyryl-CoA when SCAD activity is deficient.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"in individuals with SCADD include increased butyrylcarnitine (C4 acylcarnitine)"

GeneReviews identifies increased butyrylcarnitine (C4) as a defining biochemical finding of SCADD.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"in individuals with SCADD include increased butyrylcarnitine (C4 acylcarnitine)"

GeneReviews lists increased butyrylcarnitine (C4 acylcarnitine) as a characteristic biochemical finding.

Ethylmalonic acid (urine) (INCREASED)

Context: Increased urinary ethylmalonic acid (EMA) is the hallmark organic-acid finding in SCADD. It is characteristic but not diagnostic, as EMA is also elevated in glutaric acidemia type II, ethylmalonic encephalopathy, and some oxidative phosphorylation defects, and may be normal when the individual is well.

Pathograph Readouts

Readout Of Toxic metabolite accumulation Positive Diagnostic

Increased urinary EMA reports diversion of accumulated butyryl-CoA through carboxylation to ethylmalonic acid.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"concentration in plasma and/or increased ethylmalonic acid concentration in"

GeneReviews identifies increased ethylmalonic acid concentration as a defining biochemical finding of SCADD.

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle"

Identifies increased urinary EMA as a defining biochemical marker of SCADD.

SCAD enzyme activity (DECREASED)

Context: Decreased SCAD activity in skin fibroblasts or muscle supports the diagnosis, although some enzymatic assays lack sufficient sensitivity for reliable measurement, and molecular testing is the preferred confirmatory step.

Pathograph Readouts

Readout Of ACADS molecular function deficiency Negative Diagnostic

Reduced SCAD enzyme activity in fibroblasts or muscle directly reports the ACADS molecular-function defect.

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle"

Lists decreased SCAD activity in fibroblasts or muscle as a biochemical marker of SCADD.

Show evidence (1 reference)

PMID:18977676 SUPPORT Human Clinical

"Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle"

Documents decreased SCAD enzyme activity as a biochemical marker.

🔬

Diagnosis

1

Biochemical and molecular diagnosis of SCADD

Diagnosis rests on characteristic increased plasma butyrylcarnitine (C4 acylcarnitine) and/or increased urinary ethylmalonic acid under non-stressed conditions, confirmed by biallelic ACADS variants on molecular genetic testing.

genetic testing NCIT:C15709

Results: Increased C4 acylcarnitine and/or ethylmalonic acid under non-stressed conditions plus biallelic ACADS variants.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"The diagnosis of SCADD is established in an individual with characteristic increased butyrylcarnitine (C4 acylcarnitine) concentration in plasma and/or increased ethylmalonic acid concentration in urine under non-stressed conditions (on at least two occasions) and biallelic SCADD-related..."

GeneReviews diagnosis/testing criteria for SCADD (biochemical markers under non-stressed conditions plus biallelic ACADS variants).

📈

Progression

1

SCADD is a biochemical phenotype that is not predicted to cause clinical findings; long-term follow-up of individuals identified on newborn screening shows normal growth and development. Where nonspecific symptoms have been reported, they are generally uncomplicated and often transient, with many patients improving or normalizing over time.

Show evidence (1 reference)

PMID:21938826 SUPPORT Human Clinical

"SCADD is not predicted to cause clinical findings based on long-term evaluation of individuals following identification on newborn screening."

GeneReviews clinical-characteristics summary states SCADD is not predicted to cause clinical findings on long-term follow-up after newborn screening.

📊

Prevalence

1

Netherlands (biochemically and molecularly ascertained)

Using strict biochemical and molecular criteria, a birth prevalence of at least 1:50,000 was estimated in a Dutch retrospective study, and the authors concluded SCADD is far more common than previously assumed.

Show evidence (1 reference)

PMID:16926354 SUPPORT Human Clinical

"RESULTS: A birth-prevalence of at least 1:50,000 was calculated. Most patients"

This retrospective Dutch cohort provides a direct biochemically/molecularly ascertained birth-prevalence estimate for SCADD.

📊

Related Datasets

3

H4K16 acylations fine-tune transcriptional response to short-chain acyl-CoA dehydrogenase deficiency (RNA-seq) geo:GSE296978

Bulk RNA-seq of wild-type versus Acads-deficient (SCADD) mouse liver, linking accumulating short-chain acyl-CoAs to histone H4K16 acylation and transcriptional remodeling — an epigenetic consequence of the SCAD metabolic block.

BULK RNA SEQ

PMID:41421336

Organism: mouse (Mus musculus), male liver. NCBI GEO subseries (companion GSE296977 ChIP-seq, GSE296976 ATAC-seq).

Effects of diet and Acads genotype on transcriptional response in brain and liver geo:GSE35180

Microarray transcriptomics of Acads-deficient versus wild-type mouse brain and liver under high- versus low-fat diet, revealing AMPK/energy-sensing transcriptional rewiring under dietary fat challenge.

MICROARRAY

PMID:22936979

Organism: mouse (Mus musculus). ABI Mouse Genome Survey microarray.

Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies massive:MSV000094418

Targeted metabolomics, organic acids, and lipidomics (LC-MS/MS) of serum and urine from SCAD-deficient patients (n=11), ATP-synthase-deficient, combined, and control groups, showing glycerophospholipid/sphingolipid depletion alongside butyrylcarnitine elevations — membrane and complex-lipid remodeling beyond the diagnostic acylcarnitine signature.

METABOLOMICS

PMID:41477503

Organism: human (serum and urine). MassIVE MSV000094418 (DOI 10.25345/C5D50G81T).

{ }

Source YAML

click to show

name: Short-Chain Acyl-CoA Dehydrogenase Deficiency
category: Mendelian
creation_date: '2026-07-02T00:00:00Z'
synonyms:
- SCAD deficiency
- SCADD
- ACADS deficiency
- Deficiency of butyryl-CoA dehydrogenase
- Short-chain acyl-coenzyme A dehydrogenase deficiency
description: >
  Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an autosomal recessive
  disorder of mitochondrial fatty acid beta-oxidation caused by biallelic variants
  in ACADS, which encodes the FAD-dependent flavoprotein that catalyzes the first,
  dehydrogenation step of the beta-oxidation spiral for short-chain (C4-C6)
  acyl-CoA substrates, principally butyryl-CoA. Loss of SCAD activity blocks
  butyryl-CoA dehydrogenation, causing accumulation of butyryl-CoA and its
  byproducts: elevated butyrylcarnitine (C4 acylcarnitine) in blood and increased
  ethylmalonic acid, methylsuccinic acid, and butyrylglycine in urine, the
  biochemical hallmarks used for detection on tandem mass spectrometry newborn
  screening. In marked contrast to medium-chain (MCAD) and long-chain fatty acid
  oxidation disorders, SCADD does not typically produce hypoketotic hypoglycemia,
  rhabdomyolysis, or cardiomyopathy, and its clinical significance is debated:
  most individuals identified by newborn screening remain asymptomatic, and
  reported features in symptomatic cases (developmental delay, hypotonia, seizures,
  feeding difficulties, failure to thrive, behavioral disturbance) are nonspecific,
  often transient, and not correlated with genotype. Two common ACADS variants,
  c.511C>T (p.Arg147Trp) and c.625G>A (p.Gly185Ser), impair folding and stability
  and are regarded as susceptibility/variant alleles of uncertain clinical
  significance rather than fully penetrant pathogenic mutations.
disease_term:
  preferred_term: short chain acyl-CoA dehydrogenase deficiency
  term:
    id: MONDO:0008722
    label: short chain acyl-CoA dehydrogenase deficiency
parents:
- Fatty Acid Oxidation Disorder
- Inborn Error of Metabolism
prevalence:
- population: Netherlands (biochemically and molecularly ascertained)
  notes: >-
    Using strict biochemical and molecular criteria, a birth prevalence of at
    least 1:50,000 was estimated in a Dutch retrospective study, and the authors
    concluded SCADD is far more common than previously assumed.
  evidence:
  - reference: PMID:16926354
    reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RESULTS: A birth-prevalence of at least 1:50,000 was calculated. Most patients
    explanation: >-
      This retrospective Dutch cohort provides a direct biochemically/molecularly
      ascertained birth-prevalence estimate for SCADD.
progression:
- notes: >-
    SCADD is a biochemical phenotype that is not predicted to cause clinical
    findings; long-term follow-up of individuals identified on newborn screening
    shows normal growth and development. Where nonspecific symptoms have been
    reported, they are generally uncomplicated and often transient, with many
    patients improving or normalizing over time.
  evidence:
  - reference: PMID:21938826
    reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCADD is not predicted to cause clinical findings based on long-term
      evaluation of individuals following identification on newborn screening.
    explanation: >-
      GeneReviews clinical-characteristics summary states SCADD is not predicted
      to cause clinical findings on long-term follow-up after newborn screening.
pathophysiology:
- name: ACADS molecular function deficiency
  description: >
    Biallelic variants in ACADS reduce short-chain acyl-CoA dehydrogenase (SCAD)
    activity in the mitochondrial matrix. SCAD is a homotetrameric flavoprotein
    with a non-covalently bound FAD prosthetic group that catalyzes the first,
    FAD-dependent dehydrogenation step of beta-oxidation, with its physiologic
    role specific to butyryl-CoA. Most disease-associated variants are missense
    changes that impair folding and stability rather than abolishing intrinsic
    catalytic chemistry.
  genes:
  - preferred_term: ACADS
    term:
      id: hgnc:90
      label: ACADS
  molecular_functions:
  - preferred_term: short-chain acyl-CoA dehydrogenase activity
    term:
      id: GO:0003995
      label: acyl-CoA dehydrogenase activity
    modifier: DECREASED
  - preferred_term: FAD binding
    term:
      id: GO:0071949
      label: FAD binding
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  chemical_entities:
  - preferred_term: FAD
    term:
      id: CHEBI:16238
      label: FAD
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SCAD is a homotetramer with each monomer containing a non-covalently bound flavin adenine dinucleotide (FAD) molecule as a prosthetic group
    explanation: >-
      Defines SCAD as an FAD-dependent flavoprotein, the enzyme whose activity is
      reduced in SCADD.
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      its physiologic role is specific to butyryl-CoA as none of the other ACADs are active with this substrate in vivo
    explanation: >-
      Establishes that SCAD is the enzyme physiologically responsible for
      butyryl-CoA dehydrogenation.
  downstream:
  - target: Impaired short-chain fatty acid beta-oxidation
    description: Reduced SCAD activity blocks the first dehydrogenation step of short-chain (C4) acyl-CoA beta-oxidation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28516284
      reference_title: "Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        of mitochondrial fatty acid oxidation that is characterized by the presence of
      explanation: >-
        Identifies SCADD as a disorder of mitochondrial fatty acid oxidation
        downstream of the enzyme defect.
- name: Impaired short-chain fatty acid beta-oxidation
  description: >
    Loss of SCAD activity blocks dehydrogenation of butyryl-CoA, the terminal
    short-chain step of the mitochondrial beta-oxidation spiral. Because SCAD acts
    only at the end of the cycle and its substrate specificity partly overlaps
    with MCAD, fasting ketogenesis and gluconeogenesis are largely preserved,
    which distinguishes SCADD from medium- and long-chain fatty acid oxidation
    disorders.
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation using acyl-CoA dehydrogenase
    term:
      id: GO:0033539
      label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
    modifier: DECREASED
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Overlap of substrate specificity of SCAD and MCAD may also partially compensate for the deficiency of the former enzyme.
    explanation: >-
      Explains why the short-chain block is partially compensated, accounting for
      the absence of classic FAO-disorder decompensation.
  downstream:
  - target: Toxic metabolite accumulation
    description: The blocked butyryl-CoA dehydrogenation step causes butyryl-CoA and its byproducts to accumulate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the absence of SCAD, the byproducts of butyryl-CoA accumulation, including butyrylcarnitine, butyrylglycine, ethylmalonic (EMA) acid, and methylsuccinic acid, accumulate in blood, urine, and cells
      explanation: >-
        Directly states which metabolites accumulate when SCAD activity is lost.
  - target: Absence of hypoketotic hypoglycemia
    description: >
      Unlike MCAD/VLCAD deficiency, SCADD usually does not cause hypoketotic
      hypoglycemia because ketogenesis is largely preserved.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most individuals have not presented with the classic picture of hypoketotic hypoglycemia, recurrent rhabdomyolysis, or cardiomyopathy that characterize many other fatty acid oxidation disorders.
      explanation: >-
        Documents that the classic FAO-disorder decompensation phenotype is
        typically absent in SCADD.
- name: Toxic metabolite accumulation
  description: >
    Blocked short-chain beta-oxidation causes accumulation of butyryl-CoA, which
    is diverted into butyrylcarnitine, butyrylglycine, ethylmalonic acid (EMA),
    and methylsuccinic acid. EMA, the biochemical hallmark, is thought to form by
    carboxylation of excess butyryl-CoA by propionyl-CoA carboxylase. These
    metabolites appear in blood and urine and are the basis of newborn-screening
    detection, though levels may be normal when the individual is well and rise
    during fasting or illness.
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  chemical_entities:
  - preferred_term: butyryl-CoA
    term:
      id: CHEBI:15517
      label: butyryl-CoA
    modifier: INCREASED
  - preferred_term: O-butanoylcarnitine (butyrylcarnitine, C4)
    term:
      id: CHEBI:7676
      label: O-butanoylcarnitine
    modifier: INCREASED
  - preferred_term: ethylmalonic acid
    term:
      id: CHEBI:741548
      label: ethylmalonic acid
    modifier: INCREASED
  - preferred_term: methylsuccinic acid
    term:
      id: CHEBI:89843
      label: methylsuccinic acid
    modifier: INCREASED
  - preferred_term: butyrylglycine
    term:
      id: CHEBI:89963
      label: butyrylglycine
    modifier: INCREASED
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      EMA, the hallmark of SCAD deficiency, is likely formed by the carboxylation of excess butyryl-CoA by propionyl-CoA carboxylase.
    explanation: >-
      Provides the biochemical route by which ethylmalonic acid, the hallmark
      metabolite, accumulates.
  downstream:
  - target: Elevated plasma butyrylcarnitine (C4)
    description: Accumulated butyryl-CoA is esterified to carnitine and detected as elevated C4 acylcarnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
      explanation: >-
        Lists increased plasma butyrylcarnitine as a defining biochemical marker
        of SCADD.
  - target: Ethylmalonic aciduria
    description: Excess butyryl-CoA diverted through carboxylation produces increased urinary ethylmalonic acid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
      explanation: >-
        Increased urinary EMA is the hallmark biochemical readout of SCADD.
  - target: Urinary methylsuccinic acid
    description: During metabolic stress, methylsuccinate is also excreted in the urine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Isomerization of ethylmalonyl-CoA by methylmalonyl-CoA isomerase yields methylsuccinate.
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        During times of metabolic stress, methylsuccinate (the hydrolyzed product of isomerization of ethylmalonyl-CoA by methylmalonyl-CoA isomerase) may also be excreted in the urine
      explanation: >-
        Directly supports urinary methylsuccinate excretion during metabolic
        stress.
  - target: Nonspecific neuromuscular and developmental features
    description: >
      A direct neurotoxic effect of accumulated metabolites (EMA, butyric acid)
      has been hypothesized to explain the predominantly neurologic features in
      symptomatic cases, but causation is unproven and debated.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        EMA has been postulated to play a role in the pathogenesis of SCADD since it has been shown to significantly inhibit creatine kinase activity in the cerebral cortex of Wistar rats
      explanation: >-
        Provides the model-organism basis for a hypothesized neurotoxic role of
        ethylmalonic acid; the human relevance remains uncertain.
- name: Protein misfolding, aggregation and oxidative stress
  description: >
    Nearly all SCADD-associated ACADS variants are missense changes, and both the
    common variants and most rare variants impair folding and stability. In vitro
    studies show these variant proteins misfold and aggregate within mitochondria,
    especially at elevated temperatures, and this cellular toxicity has been linked
    to excessive reactive oxygen species production and chronic oxidative stress.
    This gain-of-toxicity mechanism, together with as-yet-unknown genetic and
    environmental modifiers, has been proposed to contribute to symptomatic disease
    in a subset of individuals, but no correlation between the degree of SCAD
    dysfunction and clinical phenotype has been established.
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:28516284
    reference_title: "Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      missense variants, impair folding, that may lead to toxic accumulation of the
    explanation: >-
      In vitro studies demonstrate that SCADD variants impair folding, leading to
      toxic protein/metabolite accumulation.
  - reference: PMID:28516284
    reference_title: "Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      encoded protein, and/or metabolites, and initiate excessive production of ROS
    explanation: >-
      Links the misfolding defect to excessive reactive oxygen species production.
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      both variant proteins show impaired folding and increased aggregation in mitochondrial import studies, especially at elevated temperatures.
    explanation: >-
      Mitochondrial import studies show the common variant proteins misfold and
      aggregate, worsened by elevated temperature.
  downstream:
  - target: Nonspecific neuromuscular and developmental features
    description: >
      Intramitochondrial aggregation of misfolded SCAD has been proposed to
      contribute to symptoms, analogous to other misfolding-associated neurologic
      disorders, but the association with clinical disease is unproven.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the protein aggregation itself may play a role in the development of symptoms in SCADD
      explanation: >-
        States the hypothesized (unproven) contribution of protein aggregation to
        symptom development.
phenotypes:
- name: Ethylmalonic aciduria
  frequency: VERY_FREQUENT
  description: >
    Increased urinary ethylmalonic acid is the biochemical hallmark of SCADD,
    though it is characteristic rather than diagnostic and may be normal when the
    individual is well.
  phenotype_term:
    preferred_term: Ethylmalonic aciduria
    term:
      id: HP:0003219
      label: Ethylmalonic aciduria
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
    explanation: >-
      Identifies increased urinary EMA as a defining biochemical marker of SCADD.
- name: Global developmental delay
  description: >
    Developmental delay is the most frequently reported feature in symptomatic
    SCADD case series (69% of 114 patients in the largest series), but its causal
    relationship to SCADD is debated and it is not correlated with genotype.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the largest series of patients published to date, 69% of 114 patients had developmental delay.
    explanation: >-
      Quantifies developmental delay as the predominant reported feature in a
      large symptomatic SCADD series.
  - reference: PMID:16926354
    reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay, epilepsy, behavioral
    explanation: >-
      The Dutch cohort lists developmental delay among the most frequently
      reported nonspecific symptoms.
- name: Hypotonia
  description: >
    Hypotonia is reported among the neuromuscular features in symptomatic SCADD
    case series, often together with failure to thrive and feeding difficulties.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia.
    explanation: >-
      Lists hypotonia among the neuromuscular phenotypes ascribed to primary SCADD.
- name: Seizures
  description: >
    Seizures/epilepsy are reported in symptomatic SCADD cohorts; one subgroup was
    characterized by developmental delay with seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2) developmental delay and seizures (25 patients, 25%); and 3) developmental delay and hypotonia without seizures (34 patients, 30%).
    explanation: >-
      Documents a developmental-delay-plus-seizures subgroup within a large
      symptomatic SCADD series.
- name: Feeding difficulties
  description: >
    Feeding difficulties, with failure to thrive and hypotonia, defined one of the
    reported symptomatic SCADD subgroups.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      1) failure to thrive with feeding difficulties and hypotonia (23 patients, 20%);
    explanation: >-
      Documents feeding difficulties (with failure to thrive and hypotonia) as a
      reported symptomatic subgroup.
- name: Failure to thrive
  description: >
    Failure to thrive is among the phenotypes ascribed to symptomatic primary
    SCADD.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia.
    explanation: >-
      Lists failure to thrive among phenotypes ascribed to primary SCADD.
- name: Myopathy
  description: >
    Myopathy (including biopsy-proven multicore disease in some Ashkenazi Jewish
    cases) is reported among the neuromuscular manifestations of symptomatic SCADD.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neuromuscular symptoms such as myopathy and hypotonia.
    explanation: >-
      Lists myopathy among the neuromuscular symptoms ascribed to primary SCADD.
- name: Behavioral abnormality
  description: >
    Behavioral disturbances were among the most frequently reported symptoms in
    the Dutch SCADD cohort.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:16926354
    reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay, epilepsy, behavioral
    explanation: >-
      Lists behavioral disturbance among the most frequently reported SCADD
      symptoms.
- name: Hypoglycemia
  frequency: OCCASIONAL
  description: >
    Hypoglycemia is reported occasionally, but unlike other FAO disorders it is
    uncommon and, when present, is typically accompanied by ketonuria (i.e., not
    hypoketotic), consistent with largely preserved ketogenesis.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 14 month old with SCADD was reported to have hypoglycemia, but ketonuria was also present, suggesting that ketone body formation is not significantly impacted in SCADD
    explanation: >-
      Documents that hypoglycemia in SCADD is accompanied by ketonuria, unlike the
      hypoketotic hypoglycemia of other FAO disorders.
- name: Metabolic acidosis
  description: >
    Metabolic acidosis has been reported in symptomatic SCADD, chiefly as a risk
    during metabolic stress, and is among the phenotypes ascribed to primary SCADD.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A range of phenotypes has now been ascribed to primary SCADD including failure to thrive, metabolic acidosis, ketotic hypoglycemia, developmental delay, seizures, and neuromuscular symptoms such as myopathy and hypotonia.
    explanation: >-
      Lists metabolic acidosis among phenotypes ascribed to primary SCADD.
biochemical:
- name: Butyrylcarnitine (C4)
  presence: INCREASED
  context: >
    Increased plasma butyrylcarnitine (C4 acylcarnitine) is the primary
    tandem-mass-spectrometry marker used to detect SCADD on newborn screening. It
    is not specific (isobutyryl-CoA dehydrogenase deficiency also elevates C4) and
    may be normal except during physiologic stress.
  biomarker_term:
    preferred_term: O-butanoylcarnitine
    term:
      id: CHEBI:7676
      label: O-butanoylcarnitine
  readouts:
  - target: Toxic metabolite accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated C4 acylcarnitine reports the accumulation of butyryl-CoA when SCAD
      activity is deficient.
    evidence:
    - reference: PMID:21938826
      reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in individuals with SCADD include increased butyrylcarnitine (C4 acylcarnitine)
      explanation: >-
        GeneReviews identifies increased butyrylcarnitine (C4) as a defining
        biochemical finding of SCADD.
  evidence:
  - reference: PMID:21938826
    reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in individuals with SCADD include increased butyrylcarnitine (C4 acylcarnitine)
    explanation: >-
      GeneReviews lists increased butyrylcarnitine (C4 acylcarnitine) as a
      characteristic biochemical finding.
- name: Ethylmalonic acid (urine)
  presence: INCREASED
  context: >
    Increased urinary ethylmalonic acid (EMA) is the hallmark organic-acid finding
    in SCADD. It is characteristic but not diagnostic, as EMA is also elevated in
    glutaric acidemia type II, ethylmalonic encephalopathy, and some oxidative
    phosphorylation defects, and may be normal when the individual is well.
  biomarker_term:
    preferred_term: ethylmalonic acid
    term:
      id: CHEBI:741548
      label: ethylmalonic acid
  readouts:
  - target: Toxic metabolite accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased urinary EMA reports diversion of accumulated butyryl-CoA through
      carboxylation to ethylmalonic acid.
    evidence:
    - reference: PMID:21938826
      reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        concentration in plasma and/or increased ethylmalonic acid concentration in
      explanation: >-
        GeneReviews identifies increased ethylmalonic acid concentration as a
        defining biochemical finding of SCADD.
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
    explanation: >-
      Identifies increased urinary EMA as a defining biochemical marker of SCADD.
- name: SCAD enzyme activity
  presence: DECREASED
  context: >
    Decreased SCAD activity in skin fibroblasts or muscle supports the diagnosis,
    although some enzymatic assays lack sufficient sensitivity for reliable
    measurement, and molecular testing is the preferred confirmatory step.
  readouts:
  - target: ACADS molecular function deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reduced SCAD enzyme activity in fibroblasts or muscle directly reports the
      ACADS molecular-function defect.
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
      explanation: >-
        Lists decreased SCAD activity in fibroblasts or muscle as a biochemical
        marker of SCADD.
  evidence:
  - reference: PMID:18977676
    reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle
    explanation: >-
      Documents decreased SCAD enzyme activity as a biochemical marker.
genetic:
- name: ACADS gene variants
  gene_term:
    preferred_term: ACADS
    term:
      id: hgnc:90
      label: ACADS
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:21938826
      reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SCADD is inherited in an autosomal recessive manner.
      explanation: >-
        GeneReviews states autosomal recessive inheritance for SCADD.
  variants:
  - name: ACADS - rare inactivating missense variants
    description: >
      Most SCADD-associated ACADS variants are rare, largely private missense
      mutations. For alleles tested, these lead to complete inactivation, impaired
      biogenesis, or intramitochondrial aggregation of misfolded protein, and the
      degree of dysfunction correlates with biochemical (EMA) but not clinical
      phenotype.
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        no correlation was found between the clinical phenotype and the degree of SCAD dysfunction
      explanation: >-
        Documents the lack of genotype-clinical-phenotype correlation for ACADS
        variants.
  - name: ACADS - c.511C>T (p.Arg147Trp) and c.625G>A (p.Gly185Ser) common variants
    description: >
      Two common ACADS variants, c.511C>T (R147W) and c.625G>A (G185S), have little
      effect on catalytic kinetics but impair folding and stability. They are
      relatively common in the general population (allele frequencies ~22% and ~3%
      in one U.S. study), are overrepresented among individuals with ethylmalonic
      aciduria, and are considered susceptibility/variant alleles of uncertain
      clinical significance rather than fully penetrant pathogenic mutations.
    evidence:
    - reference: PMID:28516284
      reference_title: "Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        individuals has identified rare gene variants along with two common gene
      explanation: >-
        Identifies the two common ACADS variants alongside rare variants.
    - reference: PMID:16926354
      reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        c.511C>T or c.625G>A susceptibility variants
      explanation: >-
        The Dutch study explicitly designates c.511C>T and c.625G>A as
        susceptibility variants.
  features: >
    SCADD results from biallelic ACADS variants. Genotypes are described as
    mutation/mutation, mutation/variant, or variant/variant combinations; the
    ACADS genotype correlates with biochemical (EMA, C4) levels but not with
    clinical characteristics, and asymptomatic relatives with the same genotype as
    affected probands are frequently identified.
  evidence:
  - reference: PMID:16926354
    reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACADS genotype showed a statistically significant association with EMA and C4-C
    explanation: >-
      Documents that ACADS genotype correlates with biochemical (EMA, C4-C) levels.
  - reference: PMID:16926354
    reference_title: "Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were free of symptoms.
    explanation: >-
      Documents that SCADD relatives sharing the proband genotype were largely
      asymptomatic, underscoring uncertain clinical significance.
treatments:
- name: No specific treatment (biochemical phenotype)
  description: >
    Because SCADD is generally a biochemical phenotype without clinical
    manifestations, GeneReviews recommends no treatment and gives no dietary or
    supplement recommendations; surveillance is likewise not recommended.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:21938826
    reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      without clinical manifestations, no treatment is recommended and there are no
    explanation: >-
      GeneReviews states that no treatment is recommended for SCADD.
- name: Avoidance of fasting
  description: >
    If preventive measures are undertaken, they likely include only avoidance of
    fasting to reduce catabolic drive; the need for a low-fat diet has not been
    substantiated.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired short-chain fatty acid beta-oxidation
    treatment_effect: MODULATES
    description: Avoiding fasting reduces reliance on the impaired short-chain fatty acid oxidation pathway during catabolic stress.
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Preventive measures, if necessary, likely include only avoidance of fasting. The need for a low fat diet has not been substantiated.
      explanation: >-
        Supports avoidance of fasting as the main preventive measure and notes
        low-fat diet is unsubstantiated.
  notes: >-
    Clinical course does not seem to be altered significantly by chronic therapies,
    and there is no consensus on the need to treat SCADD.
- name: Riboflavin supplementation (unproven)
  description: >
    Because FAD is an essential cofactor for SCAD, riboflavin has been suggested as
    a possible chemical-chaperone therapy to stabilize misfolded mutant enzyme. Its
    need and efficacy in SCADD remain unproven.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: riboflavin
      term:
        id: CHEBI:17015
        label: riboflavin
  target_mechanisms:
  - target: Protein misfolding, aggregation and oxidative stress
    treatment_effect: MODULATES
    description: Riboflavin (FAD precursor) is proposed to act as a chemical chaperone to stabilize misfolded SCAD, but evidence is anecdotal.
    evidence:
    - reference: PMID:18977676
      reference_title: "Short-chain acyl-coenzyme A dehydrogenase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        riboflavin supplementation has been suggested as a possible therapy for SCADD due to its potential ability to act as a chemical chaperone and stabilize mutant enzyme.
      explanation: >-
        States the proposed chemical-chaperone rationale for riboflavin in SCADD.
  notes: >-
    The mini-review concludes the need and efficacy of carnitine and riboflavin
    supplementation in SCADD remains unproven.
- name: Genetic counseling
  description: >
    Counseling regarding autosomal recessive inheritance and recurrence risk. Because
    SCADD is not thought to be clinically significant, prenatal and preimplantation
    genetic testing are considered medically unnecessary.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:21938826
    reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCADD is inherited in an autosomal recessive manner.
    explanation: >-
      Autosomal recessive inheritance supports the role of genetic counseling for
      recurrence-risk assessment.
notes: >
  SCADD exemplifies the interpretive challenge of expanded newborn screening: an
  elevated C4 acylcarnitine reliably flags reduced SCAD activity, but the majority
  of individuals so identified remain asymptomatic, and the two common ACADS
  variants (c.511C>T, c.625G>A) behave as susceptibility alleles rather than
  fully penetrant mutations. The disorder is deliberately curated with UNKNOWN
  causal links from metabolite/protein-aggregation mechanisms to the nonspecific
  neuromuscular and developmental features, reflecting the unresolved debate over
  whether ACADS gene variants are disease-associated at all. Ethylmalonic aciduria
  is characteristic but not specific (also seen in glutaric acidemia type II,
  ethylmalonic encephalopathy, and some OXPHOS defects), and isobutyryl-CoA
  dehydrogenase deficiency must be distinguished as another cause of elevated C4
  on newborn screening.
datasets:
- accession: geo:GSE296978
  title: "H4K16 acylations fine-tune transcriptional response to short-chain acyl-CoA dehydrogenase deficiency (RNA-seq)"
  description: "Bulk RNA-seq of wild-type versus Acads-deficient (SCADD) mouse liver, linking accumulating short-chain acyl-CoAs to histone H4K16 acylation and transcriptional remodeling — an epigenetic consequence of the SCAD metabolic block."
  data_type: BULK_RNA_SEQ
  publication: PMID:41421336
  notes: "Organism: mouse (Mus musculus), male liver. NCBI GEO subseries (companion GSE296977 ChIP-seq, GSE296976 ATAC-seq)."
- accession: geo:GSE35180
  title: "Effects of diet and Acads genotype on transcriptional response in brain and liver"
  description: "Microarray transcriptomics of Acads-deficient versus wild-type mouse brain and liver under high- versus low-fat diet, revealing AMPK/energy-sensing transcriptional rewiring under dietary fat challenge."
  data_type: MICROARRAY
  publication: PMID:22936979
  notes: "Organism: mouse (Mus musculus). ABI Mouse Genome Survey microarray."
- accession: massive:MSV000094418
  title: "Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies"
  description: "Targeted metabolomics, organic acids, and lipidomics (LC-MS/MS) of serum and urine from SCAD-deficient patients (n=11), ATP-synthase-deficient, combined, and control groups, showing glycerophospholipid/sphingolipid depletion alongside butyrylcarnitine elevations — membrane and complex-lipid remodeling beyond the diagnostic acylcarnitine signature."
  data_type: METABOLOMICS
  publication: PMID:41477503
  notes: "Organism: human (serum and urine). MassIVE MSV000094418 (DOI 10.25345/C5D50G81T)."
diagnosis:
- name: Biochemical and molecular diagnosis of SCADD
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis rests on characteristic increased plasma butyrylcarnitine (C4
    acylcarnitine) and/or increased urinary ethylmalonic acid under non-stressed
    conditions, confirmed by biallelic ACADS variants on molecular genetic
    testing.
  results: Increased C4 acylcarnitine and/or ethylmalonic acid under non-stressed conditions plus biallelic ACADS variants.
  evidence:
  - reference: PMID:21938826
    reference_title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SCADD is established in an individual with characteristic
      increased butyrylcarnitine (C4 acylcarnitine) concentration in plasma
      and/or increased ethylmalonic acid concentration in urine under
      non-stressed conditions (on at least two occasions) and biallelic
      SCADD-related variants in ACADS identified by molecular genetic testing.
    explanation: >-
      GeneReviews diagnosis/testing criteria for SCADD (biochemical markers under
      non-stressed conditions plus biallelic ACADS variants).
references:
- reference: PMID:21938826
  title: "Short-Chain Acyl-CoA Dehydrogenase Deficiency."
  tags:
  - GeneReviews
  findings: []

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PMID:21938826

Short-Chain Acyl-CoA Dehydrogenase Deficiency.

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Short-Chain Acyl-CoA Dehydrogenase Deficiency

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