medium chain acyl-CoA dehydrogenase deficiency

disease

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Also known as ACADM deficiencyACADMDacyl-CoA dehydrogenase medium chain deficiency ofAcyl-CoA dehydrogenase, medium chain, deficiency ofacyl-CoA dehydrogenase, medium-chain deficiencyacyl-CoA dehydrogenase, medium-chain, deficiency OFCarnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiencyMCADMCAD deficiencyMCADDmedium chain acyl CoA dehydrogenase deficiencymedium chain acyl-coenzyme A dehydrogenase deficiencymedium-chain acyl-CoA dehydrogenase deficiencymedium-chain acyl-Coenzyme A dehydrogenase deficiency

Summary

medium chain acyl-CoA dehydrogenase deficiency (MONDO:0008721) is a disease caused by ACADM (GenCC Definitive), with 1 cohort gene and 13 clinical trials. Top therapeutic interventions include phenylbutanoic acid, triheptanoin, and glycerin.

At a glance

Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
Causal gene: ACADM (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 979
Phenotypes (HPO): 37
Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

19 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	6.85	Worldwide	Validated
Prevalence at birth	1-5 / 10 000	12	Europe	Validated
Prevalence at birth	1-9 / 100 000	8.5	Portugal	Validated
Prevalence at birth	1-5 / 10 000	11.49	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	4.3	Canada	Validated
Prevalence at birth	1-9 / 100 000	5.26	Australia	Validated
Prevalence at birth	1-9 / 100 000	1.96	Japan	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Taiwan, Province of China	Validated
Prevalence at birth	1-5 / 10 000	11.1	Denmark	Validated
Prevalence at birth	1-9 / 100 000	6.3	Greece	Validated
Prevalence at birth	1-9 / 100 000	4.02	Austria	Validated
Prevalence at birth	1-9 / 100 000	4.35	Italy	Validated
Prevalence at birth	1-9 / 100 000	1	Israel	Validated
Prevalence at birth	1-9 / 1 000 000	0.5	Specific population	Validated
Prevalence at birth	1-9 / 100 000	4.5	Czech Republic	Validated
Prevalence at birth	1-5 / 10 000	16.1	Germany	Not yet validated
Prevalence at birth	1-9 / 100 000	7.25	United Kingdom	Not yet validated
Prevalence at birth	1-9 / 100 000	4.8	Spain	Not yet validated
Prevalence at birth	1-9 / 100 000	5.85	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0003215	Dicarboxylic aciduria	Frequent (30-79%)
HP:0003473	Fatigable weakness	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0011936	Decreased plasma total carnitine	Frequent (30-79%)
HP:0030199	Fatigable weakness of neck muscles	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001640	Cardiomegaly	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0001946	Ketosis	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0005684	Distal arthrogryposis	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0040155	Elevated urinary 3-hydroxybutyric acid	Occasional (5-29%)
HP:0045040	Abnormal lactate dehydrogenase activity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	medium chain acyl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0008721
MeSH	C536038
OMIM	201450
Orphanet	42
DOID	DOID:0080153
ICD-10-CM	E71.311
ICD-11	627734797
NCIT	C84538
SNOMED CT	128596003
UMLS	C0220710
MedGen	65086
GARD	0000540
Is cancer (heuristic)	no

Also known as: ACADM deficiency · ACADMD · acyl-CoA dehydrogenase medium chain deficiency of · Acyl-CoA dehydrogenase, medium chain, deficiency of · acyl-CoA dehydrogenase, medium-chain deficiency · acyl-CoA dehydrogenase, medium-chain, deficiency OF · Carnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiency · MCAD · MCAD deficiency · MCADD · medium chain acyl CoA dehydrogenase deficiency · medium chain acyl-CoA dehydrogenase deficiency · medium chain acyl-coenzyme A dehydrogenase deficiency · medium-chain acyl-CoA dehydrogenase deficiency · medium-chain acyl-Coenzyme A dehydrogenase deficiency

Data availability: 979 ClinVar variants · 5 GenCC gene-disease records · 16 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 › medium chain acyl-CoA dehydrogenase deficiency

Related subtypes (3): short 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

600 retrieved; paginated sample, class counts are floors:

223 likely benign, 92 uncertain significance, 75 likely pathogenic, 71 pathogenic, 69 pathogenic/likely pathogenic, 42 conflicting classifications of pathogenicity, 18 benign, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066760	NM_000016.6(ACADM):c.217-2A>G	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067387	NM_000016.6(ACADM):c.1010A>C (p.Tyr337Ser)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068571	NM_000016.6(ACADM):c.1045C>G (p.Arg349Gly)	ACADM	Pathogenic	criteria provided, single submitter
1068759	NM_000016.6(ACADM):c.203del (p.Asp68fs)	ACADM	Pathogenic	criteria provided, single submitter
1070356	NM_000016.6(ACADM):c.799_803del (p.Gly267fs)	ACADM	Pathogenic	criteria provided, single submitter
1070530	NM_000016.6(ACADM):c.377del (p.Asn126fs)	ACADM	Pathogenic	criteria provided, single submitter
1071806	NM_000016.6(ACADM):c.1120C>T (p.Gln374Ter)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072109	NM_000016.6(ACADM):c.849+2T>C	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073714	NM_000016.6(ACADM):c.243_250del (p.Glu83fs)	ACADM	Pathogenic	criteria provided, single submitter
1076157	NM_000016.6(ACADM):c.554T>C (p.Ile185Thr)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331078	NM_000016.6(ACADM):c.232dup (p.Ile78fs)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356922	NM_000016.6(ACADM):c.1067T>C (p.Ile356Thr)	ACADM	Pathogenic	criteria provided, multiple submitters, no conflicts
1368883	NM_000016.6(ACADM):c.801del (p.Ala268fs)	ACADM	Pathogenic	criteria provided, single submitter
1369032	NM_000016.6(ACADM):c.30+2T>G	ACADM	Pathogenic	criteria provided, single submitter
1371575	NM_000016.6(ACADM):c.652del (p.Ala218fs)	ACADM	Pathogenic	criteria provided, single submitter
1374259	NM_000016.6(ACADM):c.614C>T (p.Ala205Val)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380272	NM_000016.6(ACADM):c.468+2T>C	ACADM	Pathogenic	criteria provided, single submitter
1396357	NC_000001.10:g.(?76211473)(76228458_?)del	ACADM	Pathogenic	criteria provided, single submitter
1404546	NM_000016.6(ACADM):c.653C>G (p.Ala218Gly)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420172	NM_000016.6(ACADM):c.24C>A (p.Cys8Ter)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420985	NM_000016.6(ACADM):c.1042del (p.Arg348fs)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1428164	NM_000016.6(ACADM):c.1A>T (p.Met1Leu)	ACADM	Pathogenic	criteria provided, single submitter
1431508	NM_000016.6(ACADM):c.1175G>A (p.Arg392Lys)	ACADM	Pathogenic	criteria provided, single submitter
1433388	NM_000016.6(ACADM):c.1046G>A (p.Arg349Gln)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1438490	NM_000016.6(ACADM):c.727C>T (p.Arg243Ter)	ACADM	Pathogenic	criteria provided, multiple submitters, no conflicts
1451625	NM_000016.6(ACADM):c.342_343dup (p.Gly115fs)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451991	NM_000016.6(ACADM):c.168del (p.Arg57fs)	ACADM	Pathogenic	criteria provided, single submitter
1452587	NM_000016.6(ACADM):c.253G>C (p.Gly85Arg)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453591	NM_000016.6(ACADM):c.741_742dup (p.Arg248fs)	ACADM	Pathogenic	criteria provided, single submitter
1453649	NM_000016.6(ACADM):c.383dup (p.Leu128fs)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
ACADM	Definitive	Autosomal recessive	medium chain acyl-CoA dehydrogenase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACADM	Orphanet:42	Medium chain acyl-CoA dehydrogenase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACADM	HGNC:89	ENSG00000117054	P11310	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
ACADM	292	ubiquitous	marker	jejunal mucosa, skeletal muscle tissue of rectus abdominis, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACADM	3,245

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACADM	P11310	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	2284.0×	0.002	ACADM
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	1903.3×	0.002	ACADM
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	1903.3×	0.002	ACADM
mitochondrial fatty acid beta-oxidation of saturated fatty acids	1	1631.4×	0.002	ACADM
Mitochondrial Fatty Acid Beta-Oxidation	1	380.7×	0.005	ACADM
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.011	ACADM
Fatty acid metabolism	1	131.3×	0.011	ACADM
PPARA activates gene expression	1	94.4×	0.013	ACADM
Metabolism of lipids	1	31.6×	0.035	ACADM
Metabolism	1	11.6×	0.086	ACADM

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
carnitine metabolic process, CoA-linked	1	5617.3×	0.001	ACADM
carnitine biosynthetic process	1	3370.4×	0.001	ACADM
medium-chain fatty acid catabolic process	1	3370.4×	0.001	ACADM
medium-chain fatty acid metabolic process	1	2808.7×	0.001	ACADM
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	1404.3×	0.002	ACADM
regulation of gluconeogenesis	1	1123.5×	0.002	ACADM
glycogen biosynthetic process	1	936.2×	0.002	ACADM
cardiac muscle cell differentiation	1	674.1×	0.002	ACADM
response to cold	1	561.7×	0.003	ACADM
response to starvation	1	468.1×	0.003	ACADM
fatty acid beta-oxidation	1	374.5×	0.003	ACADM
liver development	1	221.7×	0.005	ACADM
post-embryonic development	1	205.5×	0.005	ACADM

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACADM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACADM	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACADM	1.3.8.7	medium-chain acyl-CoA dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACADM	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE2	4
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06773026	PHASE2	RECRUITING	Study of Sodium Phenylbutyrate (ACER-001) for the Treatment of Pediatric and Adults Patients With Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
NCT07097311	PHASE2	RECRUITING	Study to Evaluate the Use of Triheptanoin in Patients With Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
NCT06067802	PHASE2	SUSPENDED	Study of Triheptanoin for the Prevention of Hypoglycemia in Patients With Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
NCT06069375	PHASE2	SUSPENDED	Study of Sodium Phenylbutyrate (ACER-001) for the Treatment of Patients With Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
NCT01881984	PHASE1	COMPLETED	Use of Ravicti™ in Patients With MCAD Deficiency With the 985A>G (K304E) Mutation
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06623032	Not specified	RECRUITING	Metabolic Effects of Medium-Chain Fatty Acids in Patients With Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Healthy Individuals
NCT02517307	Not specified	COMPLETED	Fatty Acid Oxidation Defects and Insulin Sensitivity
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT03761693	Not specified	UNKNOWN	Fasting Tolerance in MCADD-infants
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT06796530	Not specified	COMPLETED	High Intensity Exercise in Children With MCADD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYLBUTANOIC ACID	4	4
TRIHEPTANOIN	4	2
GLYCERIN	4	1
GLYCEROL PHENYLBUTYRATE	4	1

Cohort genes: ACADM
Drugs: Phenylbutanoic Acid, Triheptanoin, Glycerin, Glycerol Phenylbutyrate