short chain acyl-CoA dehydrogenase deficiency

Summary

short chain acyl-CoA dehydrogenase deficiency (MONDO:0008722) is a disease caused by ACADS (GenCC Definitive), with 4 cohort genes and 8 clinical trials. Top therapeutic interventions include clopidogrel and edoxaban.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ACADS (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 453
• Phenotypes (HPO): 24
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0003219	Ethylmalonic aciduria	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0045045	Elevated plasma acylcarnitine levels	Frequent (30-79%)
HP:0410153	Increased level of methylsuccinic acid in urine	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0006929	Hypoglycemic encephalopathy	Occasional (5-29%)
HP:0012734	Ketotic hypoglycemia	Occasional (5-29%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0001276	Hypertonia	Very rare (<1-4%)
HP:0001511	Intrauterine growth retardation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	short chain acyl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0008722
MeSH	C537596
OMIM	201470
Orphanet	26792
DOID	DOID:0080154
ICD-10-CM	E71.312
ICD-11	180018315
NCIT	C84539
UMLS	C0342783
MedGen	90998
GARD	0004822
NORD	1709
Is cancer (heuristic)	no

Also known as: ACADS deficiency · ACADSD · acyl-CoA dehydrogenase, short-chain deficiency · acyl-CoA dehydrogenase, short-chain, deficiency OF · SCAD · SCAD deficiency · SCADD · Short Chain Acyl CoA Dehydrogenase Deficiency · short chain acyl-CoA dehydrogenase deficiency · short-chain acyl-CoA dehydrogenase deficiency · short-chain acyl-CoA dehydrogenase deficiency (SCAD) · short-chain acyl-coenzyme A dehydrogenase deficiency · short-chain acyl-Coenzyme A dehydrogenase deficiency (SCAD)

Data availability: 453 ClinVar variants · 6 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of energy metabolism › disorder of fatty acid and ketone body metabolism › disorder of fatty acid oxidation and ketogenesis › acyl-CoA dehydrogenase deficiency › short chain acyl-CoA dehydrogenase deficiency

Related subtypes (3): medium chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, transient neonatal multiple acyl-CoA dehydrogenase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

453 retrieved; paginated sample, class counts are floors:

191 uncertain significance, 110 likely benign, 44 likely pathogenic, 40 conflicting classifications of pathogenicity, 26 pathogenic/likely pathogenic, 23 pathogenic, 12 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3588	NM_000016.6(ACADM):c.799G>A (p.Gly267Arg)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1060209	NM_000017.4(ACADS):c.812del (p.Gly271fs)	ACADS	Pathogenic	criteria provided, single submitter
1193318	NM_000017.4(ACADS):c.795+1G>A	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453349	NM_000017.4(ACADS):c.362_363CT[2] (p.Tyr123fs)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1485321	NM_000017.4(ACADS):c.937A>G (p.Lys313Glu)	ACADS	Pathogenic	criteria provided, single submitter
1509542	NC_000012.11:g.(?121172765)(121176235_?)del	ACADS	Pathogenic	criteria provided, single submitter
189087	NM_000017.4(ACADS):c.409C>T (p.Gln137Ter)	ACADS	Pathogenic	criteria provided, single submitter
189093	NM_000017.4(ACADS):c.682_683del (p.Glu228fs)	ACADS	Pathogenic	criteria provided, multiple submitters, no conflicts
1948098	NM_000017.4(ACADS):c.1086+2T>G	ACADS	Pathogenic	criteria provided, single submitter
203556	NM_000017.4(ACADS):c.815G>A (p.Arg272His)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203557	NM_000017.4(ACADS):c.988C>T (p.Arg330Cys)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203560	NM_000017.4(ACADS):c.1095G>T (p.Gln365His)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203569	NM_000017.4(ACADS):c.988_990delinsTGT (p.Arg330Cys)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2039130	NM_000017.4(ACADS):c.88C>T (p.Gln30Ter)	ACADS	Pathogenic	criteria provided, single submitter
2422134	NC_000012.11:g.(?121174454)(121176447_?)del	ACADS	Pathogenic	criteria provided, single submitter
2501121	NM_000017.4(ACADS):c.2T>C (p.Met1Thr)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2709405	NM_000017.4(ACADS):c.3G>A (p.Met1Ile)	ACADS	Pathogenic	criteria provided, single submitter
3010236	NM_000017.4(ACADS):c.931C>T (p.Gln311Ter)	ACADS	Pathogenic	criteria provided, single submitter
30611	NM_000017.4(ACADS):c.164C>T (p.Pro55Leu)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30612	NM_000017.4(ACADS):c.1031A>G (p.Glu344Gly)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244257	NC_000012.11:g.(?121163689)(121438995_?)del	ACADS	Pathogenic	criteria provided, single submitter
3646036	NM_000017.4(ACADS):c.105dup (p.Glu36fs)	ACADS	Pathogenic	criteria provided, single submitter
3648925	NM_000017.4(ACADS):c.762_911del150 (p.Gly255_Leu304del)	ACADS	Pathogenic	criteria provided, single submitter
370099	NM_000017.4(ACADS):c.1084C>T (p.Gln362Ter)	ACADS	Pathogenic	criteria provided, single submitter
370351	NM_000017.4(ACADS):c.1164_1165del (p.Glu389fs)	ACADS	Pathogenic	criteria provided, single submitter
370525	NM_000017.4(ACADS):c.369C>G (p.Tyr123Ter)	ACADS	Pathogenic	criteria provided, single submitter
370584	NM_000017.4(ACADS):c.910dup (p.Leu304fs)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370741	NM_000017.4(ACADS):c.125_135del (p.Leu42fs)	ACADS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370891	NM_000017.4(ACADS):c.527C>A (p.Ser176Ter)	ACADS	Pathogenic	criteria provided, single submitter
3727600	NM_000017.4(ACADS):c.561_568del (p.Asn188fs)	ACADS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACADS	Definitive	Autosomal recessive	short chain acyl-CoA dehydrogenase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACADS	Orphanet:26792	Short chain acyl-CoA dehydrogenase deficiency
COX6A1	Orphanet:435998	Autosomal recessive intermediate Charcot-Marie-Tooth disease type D
ACADM	Orphanet:42	Medium chain acyl-CoA dehydrogenase deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACADS	HGNC:90	ENSG00000122971	P16219	Short-chain specific acyl-CoA dehydrogenase, mitochondrial	gencc,clinvar
ECHDC1	HGNC:21489	ENSG00000093144	Q9NTX5	Ethylmalonyl-CoA decarboxylase	clinvar
COX6A1	HGNC:2277	ENSG00000111775	P12074	Cytochrome c oxidase subunit 6A1, mitochondrial	clinvar
ACADM	HGNC:89	ENSG00000117054	P11310	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACADS	Short-chain specific acyl-CoA dehydrogenase, mitochondrial	Short-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the produc…
ECHDC1	Ethylmalonyl-CoA decarboxylase	Decarboxylates ethylmalonyl-CoA, a potentially toxic metabolite, to form butyryl-CoA, suggesting it might be involved in metabolite proofreading.
COX6A1	Cytochrome c oxidase subunit 6A1, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
ACADM	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial	Medium-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of ener…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACADS	Other/Unknown	no		Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
ECHDC1	Enzyme (other)	yes	4.1.1.94	Enoyl-CoA_hydra/iso, Enoyl-CoA_hyd/isom_CS, ClpP/crotonase-like_dom_sf
COX6A1	Other/Unknown	no		Cyt_c_oxidase_su6a, Cyt_c_oxidase_su6a_CS, Cyt_c_oxidase_su6a_sf
ACADM	Enzyme (other)	yes	1.3.8.7	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
mucosa of transverse colon	1
right lobe of liver	1
palpebral conjunctiva	1
parotid gland	1
pigmented layer of retina	1
frontal cortex	1
prefrontal cortex	1
primary visual cortex	1
biceps brachii	1
jejunal mucosa	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACADS	234	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, apex of heart
ECHDC1	280	ubiquitous	marker	pigmented layer of retina, palpebral conjunctiva, parotid gland
COX6A1	145	ubiquitous	marker	prefrontal cortex, primary visual cortex, frontal cortex
ACADM	292	ubiquitous	marker	jejunal mucosa, skeletal muscle tissue of rectus abdominis, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACADM	3,245
ECHDC1	2,382
ACADS	2,343
COX6A1	1,887

Intra-cohort edges

A	B	Sources
ACADS	ECHDC1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACADM	P11310	7
ACADS	P16219	4
COX6A1	P12074	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ECHDC1	Q9NTX5	90.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial fatty acid beta-oxidation of saturated fatty acids	2	1087.6×	2e-05	ACADS, ACADM
Mitochondrial Fatty Acid Beta-Oxidation	2	253.8×	2e-04	ACADS, ACADM
Fatty acid metabolism	2	87.5×	9e-04	ACADS, ACADM
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	761.3×	0.003	ACADM
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	761.3×	0.003	ACADS
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	761.3×	0.003	ACADS
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	634.4×	0.003	ACADM
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	634.4×	0.003	ACADM
Metabolism of lipids	2	21.0×	0.005	ACADS, ACADM
Complex IV assembly	1	76.1×	0.021	COX6A1
Cytoprotection by HMOX1	1	61.4×	0.024	COX6A1
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.026	ACADM
Metabolism	2	7.7×	0.026	ACADS, ACADM
TP53 Regulates Metabolic Genes	1	43.3×	0.026	COX6A1
Respiratory electron transport	1	31.7×	0.031	COX6A1
PPARA activates gene expression	1	31.5×	0.031	ACADM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fatty acid beta-oxidation	3	280.9×	1e-06	ACADS, ECHDC1, ACADM
fatty acid beta-oxidation using acyl-CoA dehydrogenase	2	702.2×	2e-05	ACADS, ACADM
butyrate catabolic process	1	4213.0×	0.001	ACADS
carnitine metabolic process, CoA-linked	1	1404.3×	0.003	ACADM
carnitine biosynthetic process	1	842.6×	0.003	ACADM
medium-chain fatty acid catabolic process	1	842.6×	0.003	ACADM
medium-chain fatty acid metabolic process	1	702.2×	0.003	ACADM
regulation of gluconeogenesis	1	280.9×	0.008	ACADM
glycogen biosynthetic process	1	234.1×	0.008	ACADM
mitochondrial electron transport, cytochrome c to oxygen	1	191.5×	0.009	COX6A1
cardiac muscle cell differentiation	1	168.5×	0.009	ACADM
response to cold	1	140.4×	0.010	ACADM
response to starvation	1	117.0×	0.011	ACADM
cellular respiration	1	108.0×	0.011	COX6A1
generation of precursor metabolites and energy	1	86.0×	0.013	COX6A1
liver development	1	55.4×	0.019	ACADM
post-embryonic development	1	51.4×	0.019	ACADM

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACADS	0	0
ECHDC1	0	0
COX6A1	0	0
ACADM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACADM	3	Binding:3
COX6A1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ECHDC1	4.1.1.94	ethylmalonyl-CoA decarboxylase
ACADM	1.3.8.7	medium-chain acyl-CoA dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACADM
D	Druggable family + AlphaFold only, no drug	1	ECHDC1
E	Difficult family or no structure, no drug	2	ACADS, COX6A1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACADS	0	—
ECHDC1	0	—
COX6A1	1	—
ACADM	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE4	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06759272	PHASE4	NOT_YET_RECRUITING	Impact of CYP2C19 Genotype-guided Approach in Antiplatelet Therapy on Platelet Reactivity Index Among Coronary Artery Disease (CAD) Patients
NCT05122455	PHASE2/PHASE3	COMPLETED	Effects of Edoxaban on Platelet Aggregation
NCT01427179	Not specified	RECRUITING	Genetic Investigations in Spontaneous Coronary Artery Dissection (SCAD)
NCT01429727	Not specified	RECRUITING	The Virtual Multicenter Spontaneous Coronary Artery Dissection (SCAD) Registry
NCT04906356	Not specified	RECRUITING	Canadian SCAD Study
NCT04936438	Not specified	ACTIVE_NOT_RECRUITING	Clinical Cohort Study - INTERCATH
NCT07317323	Not specified	RECRUITING	Norwegian Spontaneous Coronary Artery Dissection Study
NCT03941184	Not specified	COMPLETED	Spontaneous Coronary Artery Dissection (SCAD) and Autoimmunity

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLOPIDOGREL	4	1
EDOXABAN	4	1
CHEMBL4303203	0	1
CHEMBL4643136	0	1