isobutyryl-CoA dehydrogenase deficiency

Summary

isobutyryl-CoA dehydrogenase deficiency (MONDO:0012648) is a disease caused by ACAD8 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ACAD8 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 217
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0003215	Dicarboxylic aciduria	Frequent (30-79%)
HP:0003234	Decreased circulating carnitine concentration	Frequent (30-79%)
HP:0045045	Elevated plasma acylcarnitine levels	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001642	Pulmonic stenosis	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)
HP:0012734	Ketotic hypoglycemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isobutyryl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0012648
MeSH	C535541
OMIM	611283
Orphanet	79159
NCIT	C129975
UMLS	C1969809
MedGen	370754
GARD	0010223
Is cancer (heuristic)	no

Also known as: acyl-CoaA dehydrogenase family, member 8, deficiency of · isobutyric aciduria · isobutyryl-CoA dehydrogenase deficiency

Data availability: 217 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › isobutyryl-CoA dehydrogenase deficiency

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylglutaconic aciduria, 3-methylcrotonyl-CoA carboxylase 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

217 retrieved; paginated sample, class counts are floors:

103 uncertain significance, 45 likely benign, 24 conflicting classifications of pathogenicity, 16 pathogenic, 12 benign, 10 likely pathogenic, 4 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069419	NM_014384.3(ACAD8):c.1092+1G>C	ACAD8	Pathogenic	criteria provided, single submitter
1452755	NM_014384.3(ACAD8):c.286G>A (p.Gly96Ser)	ACAD8	Pathogenic	criteria provided, multiple submitters, no conflicts
1452933	NM_014384.3(ACAD8):c.1092+1G>A	ACAD8	Pathogenic	criteria provided, single submitter
1459900	NC_000011.9:g.(?133778964)(134134854_?)del	ACAD8	Pathogenic	criteria provided, single submitter
1954125	NM_014384.3(ACAD8):c.589G>T (p.Glu197Ter)	ACAD8	Pathogenic	criteria provided, single submitter
2074051	NM_014384.3(ACAD8):c.616C>T (p.Arg206Ter)	ACAD8	Pathogenic	criteria provided, multiple submitters, no conflicts
2716443	NM_014384.3(ACAD8):c.886C>T (p.Arg296Ter)	ACAD8	Pathogenic	criteria provided, multiple submitters, no conflicts
2954661	NM_014384.3(ACAD8):c.473A>C (p.Tyr158Ser)	ACAD8	Pathogenic	criteria provided, single submitter
3625901	NM_014384.3(ACAD8):c.567+2del	ACAD8	Pathogenic	criteria provided, single submitter
4692000	NM_014384.3(ACAD8):c.172C>T (p.Arg58Ter)	ACAD8	Pathogenic	criteria provided, single submitter
4748047	NM_014384.3(ACAD8):c.522del (p.Ser175fs)	ACAD8	Pathogenic	criteria provided, single submitter
5356	NM_014384.3(ACAD8):c.1129G>A (p.Gly377Ser)	ACAD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5358	NM_014384.3(ACAD8):c.867C>A (p.His289Gln)	ACAD8	Pathogenic	no assertion criteria provided
566782	NM_014384.3(ACAD8):c.2T>C (p.Met1Thr)	ACAD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632056	NM_014384.3(ACAD8):c.730C>T (p.Arg244Ter)	ACAD8	Pathogenic	criteria provided, single submitter
645496	NM_014384.3(ACAD8):c.133C>T (p.Gln45Ter)	ACAD8	Pathogenic	criteria provided, single submitter
658754	NM_014384.3(ACAD8):c.1000C>T (p.Arg334Cys)	ACAD8	Pathogenic	criteria provided, single submitter
848313	NM_014384.3(ACAD8):c.348C>A (p.Cys116Ter)	ACAD8	Pathogenic	criteria provided, single submitter
95585	NM_014384.3(ACAD8):c.384G>A (p.Met128Ile)	ACAD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323839	NM_014384.3(ACAD8):c.1195+1G>A	ACAD8	Likely pathogenic	criteria provided, single submitter
1499156	NM_014384.3(ACAD8):c.845C>T (p.Ser282Phe)	ACAD8	Likely pathogenic	criteria provided, single submitter
2047520	NM_014384.3(ACAD8):c.3G>C (p.Met1Ile)	ACAD8	Likely pathogenic	criteria provided, single submitter
2439095	NM_014384.3(ACAD8):c.205C>T (p.Gln69Ter)	ACAD8	Likely pathogenic	criteria provided, single submitter
2844227	NM_014384.3(ACAD8):c.939+1G>T	ACAD8	Likely pathogenic	criteria provided, single submitter
2998335	NM_014384.3(ACAD8):c.1A>G (p.Met1Val)	ACAD8	Likely pathogenic	criteria provided, single submitter
3061797	NM_014384.3(ACAD8):c.758T>G (p.Val253Gly)	ACAD8	Likely pathogenic	criteria provided, single submitter
3709269	NM_014384.3(ACAD8):c.568-2A>T	ACAD8	Likely pathogenic	criteria provided, single submitter
4086061	NM_014384.3(ACAD8):c.1240C>T (p.Gln414Ter)	ACAD8	Likely pathogenic	criteria provided, single submitter
939292	NM_014384.3(ACAD8):c.989G>A (p.Arg330Gln)	ACAD8	Likely pathogenic	criteria provided, single submitter
1001998	NM_014384.3(ACAD8):c.822C>A (p.Asn274Lys)	ACAD8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
ACAD8	Definitive	Autosomal recessive	isobutyryl-CoA dehydrogenase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAD8	Orphanet:79159	Isobutyryl-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
ACAD8	HGNC:87	ENSG00000151498	Q9UKU7	Isobutyryl-CoA dehydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACAD8	Isobutyryl-CoA dehydrogenase, mitochondrial	Isobutyryl-CoA dehydrogenase which catalyzes the conversion of 2-methylpropanoyl-CoA to (2E)-2-methylpropenoyl-CoA in the valine catabolic pathway.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACAD8	Other/Unknown	no		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
cerebellar hemisphere	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACAD8	273	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAD8	2,360

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAD8	Q9UKU7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Branched-chain amino acid catabolism	1	475.8×	0.011	ACAD8
Mitochondrial protein degradation	1	114.2×	0.022	ACAD8
Metabolism of amino acids and derivatives	1	67.6×	0.025	ACAD8
Metabolism of proteins	1	12.4×	0.086	ACAD8
Metabolism	1	11.6×	0.086	ACAD8

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-valine catabolic process	1	3370.4×	6e-04	ACAD8
lipid metabolic process	1	91.6×	0.011	ACAD8

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACAD8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACAD8

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)
ACAD8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan