3-hydroxyisobutyryl-CoA hydrolase deficiency

Summary

3-hydroxyisobutyryl-CoA hydrolase deficiency (MONDO:0009603) is a disease caused by HIBCH (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HIBCH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 183
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002344	Progressive neurologic deterioration	Very frequent (80-99%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001942	Metabolic acidosis	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0003287	Abnormality of mitochondrial metabolism	Frequent (30-79%)
HP:0003468	Abnormal vertebral morphology	Frequent (30-79%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0011334	Facial shape deformation	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002352	Leukoencephalopathy	Occasional (5-29%)
HP:0012697	Small basal ganglia	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Very rare (<1-4%)
HP:0002599	Head titubation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-hydroxyisobutyryl-CoA hydrolase deficiency
Mondo ID	MONDO:0009603
MeSH	C562803
OMIM	250620
Orphanet	88639
DOID	DOID:0060949
SNOMED CT	722488009
UMLS	C0342738
MedGen	83349
GARD	0013202
Is cancer (heuristic)	no

Also known as: 3-hydroxyisobutyryl-CoA hydrolase deficiency · Beta-hydroxyisobutyryl-CoA deacylase deficiency · HIBCH deficiency · HIBCHD · methacrylic aciduria · neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency

Data availability: 183 ClinVar variants · 6 GenCC gene-disease records.

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 › 3-hydroxyisobutyryl-CoA hydrolase deficiency

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency, isobutyryl-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

183 retrieved; paginated sample, class counts are floors:

62 likely benign, 58 uncertain significance, 19 likely pathogenic, 11 conflicting classifications of pathogenicity, 9 pathogenic, 9 benign, 8 pathogenic/likely pathogenic, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1144	NM_014362.4(HIBCH):c.220-9T>G	HIBCH	Pathogenic	no assertion criteria provided
1146	NM_014362.4(HIBCH):c.79-3C>G	HIBCH	Pathogenic	no assertion criteria provided
1333974	NM_014362.4(HIBCH):c.386-1G>C	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379552	NM_014362.4(HIBCH):c.1012A>T (p.Arg338Ter)	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1938463	NM_014362.4(HIBCH):c.469C>T (p.Arg157Ter)	HIBCH	Pathogenic	criteria provided, multiple submitters, no conflicts
208532	NM_014362.4(HIBCH):c.1033G>A (p.Gly345Ser)	HIBCH	Pathogenic	no assertion criteria provided
2141605	NM_014362.4(HIBCH):c.1010_1011+3del	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2979318	NM_014362.4(HIBCH):c.1000C>T (p.Gln334Ter)	HIBCH	Pathogenic	criteria provided, single submitter
424160	NM_014362.4(HIBCH):c.809+1G>A	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430547	NM_014362.4(HIBCH):c.852del (p.Leu284fs)	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430548	NM_014362.4(HIBCH):c.488G>T (p.Cys163Phe)	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4537294	NC_000002.11:g.(?191068645)(191184553_?)del	HIBCH	Pathogenic	criteria provided, single submitter
654855	NM_014362.4(HIBCH):c.609del (p.Gly204fs)	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689764	NM_014362.4(HIBCH):c.517+1G>A	HIBCH	Pathogenic	criteria provided, single submitter
972925	NM_014362.4(HIBCH):c.835G>T (p.Glu279Ter)	HIBCH	Pathogenic	criteria provided, single submitter
973483	NM_014362.4(HIBCH):c.763C>T (p.Arg255Ter)	HIBCH	Pathogenic	criteria provided, single submitter
987063	NM_014362.4(HIBCH):c.913A>G (p.Thr305Ala)	HIBCH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324532	NM_014362.4(HIBCH):c.439-1G>A	HIBCH	Likely pathogenic	criteria provided, single submitter
1332820	NM_014362.4(HIBCH):c.777T>A (p.Phe259Leu)	HIBCH	Likely pathogenic	criteria provided, single submitter
1492266	NM_014362.4(HIBCH):c.891+1G>A	HIBCH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1522611	NM_014362.4(HIBCH):c.385+2T>A	HIBCH	Likely pathogenic	criteria provided, single submitter
1804879	NM_014362.4(HIBCH):c.860A>G (p.Asp287Gly)	HIBCH	Likely pathogenic	criteria provided, single submitter
187864	NM_014362.4(HIBCH):c.950G>A (p.Gly317Glu)	HIBCH	Likely pathogenic	criteria provided, single submitter
190268	NM_014362.4(HIBCH):c.196C>T (p.Arg66Trp)	HIBCH	Likely pathogenic	criteria provided, single submitter
208531	NM_014362.4(HIBCH):c.129dup (p.Gly44fs)	HIBCH	Likely pathogenic	criteria provided, single submitter
2088137	NM_014362.4(HIBCH):c.664-2A>G	HIBCH	Likely pathogenic	criteria provided, single submitter
217316	NM_014362.4(HIBCH):c.1128dup (p.Lys377Ter)	HIBCH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440721	NM_014362.4(HIBCH):c.556C>T (p.Arg186Ter)	HIBCH	Likely pathogenic	criteria provided, single submitter
2690621	NM_014362.4(HIBCH):c.760_761delinsAT (p.Asp254Ile)	HIBCH	Likely pathogenic	criteria provided, single submitter
3776776	NM_014362.4(HIBCH):c.12_35del (p.Glu5_Arg12del)	HIBCH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · 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
HIBCH	Definitive	Autosomal recessive	3-hydroxyisobutyryl-CoA hydrolase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HIBCH	Orphanet:88639	Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency
MAFB	Orphanet:233	Duane retraction syndrome
MAFB	Orphanet:2774	Multicentric carpo-tarsal osteolysis with or without nephropathy
MAFB	Orphanet:529574	Duane retraction syndrome with congenital deafness
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HIBCH	HGNC:4908	ENSG00000198130	Q6NVY1	3-hydroxyisobutyryl-CoA hydrolase, mitochondrial	gencc,clinvar
MAFB	HGNC:6408	ENSG00000204103	Q9Y5Q3	Transcription factor MafB	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HIBCH	3-hydroxyisobutyryl-CoA hydrolase, mitochondrial	Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite.
MAFB	Transcription factor MafB	Acts as a transcriptional activator or repressor.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	8.0×	0.039
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HIBCH	Enzyme (other)	yes	3.1.2.4	ClpP/crotonase-like_dom_sf, HIBYL-CoA-H, ECH_dom
MAFB	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
nephron tubule	1
renal medulla	1
gingiva	1
renal glomerulus	1
skin of hip	1
adult mammalian kidney	1
apex of heart	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HIBCH	293	ubiquitous	marker	nephron tubule, renal medulla, adrenal tissue
MAFB	277	ubiquitous	marker	renal glomerulus, skin of hip, gingiva
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIFM1	4,780
MAFB	2,671
HIBCH	2,467

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26
HIBCH	Q6NVY1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAFB	Q9Y5Q3	63.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
3-hydroxyisobutyryl-CoA hydrolase deficiency	1	5710.0×	9e-04	HIBCH
Branched-chain amino acid catabolism	1	237.9×	0.008	HIBCH
Activation of HOX genes during differentiation	1	219.6×	0.008	MAFB
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.027	MAFB
Developmental Biology	1	7.2×	0.134	MAFB

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
rhombomere 6 development	1	5617.3×	0.004	MAFB
rhombomere 5 development	1	2808.7×	0.004	MAFB
abducens nerve formation	1	2808.7×	0.004	MAFB
brain segmentation	1	1872.4×	0.004	MAFB
protein import into mitochondrial intermembrane space	1	1872.4×	0.004	AIFM1
protein import into the intermembrane space via the disulfide relay system	1	1872.4×	0.004	AIFM1
L-valine catabolic process	1	1123.5×	0.004	HIBCH
regulation of myeloid cell differentiation	1	1123.5×	0.004	MAFB
mitochondrial respiratory chain complex assembly	1	936.2×	0.004	AIFM1
positive regulation of necroptotic process	1	936.2×	0.004	AIFM1
cornified envelope assembly	1	936.2×	0.004	MAFB
cellular response to aldosterone	1	802.5×	0.004	AIFM1
segment specification	1	702.2×	0.005	MAFB
response to L-glutamate	1	561.7×	0.005	AIFM1
negative regulation of erythrocyte differentiation	1	510.7×	0.006	MAFB
branched-chain amino acid catabolic process	1	351.1×	0.008	HIBCH
cellular response to nitric oxide	1	312.1×	0.008	AIFM1
integrated stress response signaling	1	234.1×	0.010	MAFB
sensory organ development	1	224.7×	0.010	MAFB
respiratory gaseous exchange by respiratory system	1	208.1×	0.010	MAFB
negative regulation of osteoclast differentiation	1	181.2×	0.011	MAFB
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	160.5×	0.012	AIFM1
T cell differentiation in thymus	1	137.0×	0.013	MAFB
cellular response to estradiol stimulus	1	137.0×	0.013	AIFM1
thymus development	1	112.3×	0.015	MAFB
inner ear morphogenesis	1	100.3×	0.016	MAFB
response to nutrient	1	98.5×	0.016	MAFB
positive regulation of neuron apoptotic process	1	90.6×	0.017	AIFM1
response to ischemia	1	83.8×	0.017	AIFM1
keratinocyte differentiation	1	82.6×	0.017	MAFB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIBCH	0	0
MAFB	0	0
AIFM1	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
HIBCH	4	ADMET:2, Binding:2
AIFM1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HIBCH	3.1.2.4	3-hydroxyisobutyryl-CoA hydrolase
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	HIBCH, AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MAFB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HIBCH	4	—
MAFB	0	—
AIFM1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.