Isovaleric acidemia

Summary

Isovaleric acidemia (MONDO:0009475) is a disease caused by IVD (GenCC Definitive), with 1 cohort gene and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: IVD (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 743
• Phenotypes (HPO): 29
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.28	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.63	Italy	Validated
Prevalence at birth	1-9 / 100 000	1.55	Germany	Not yet validated
Prevalence at birth	1-9 / 1 000 000	0.53	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002919	Ketonuria	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0031962	Elevated serum anion gap	Frequent (30-79%)
HP:0033111	3-hydroxyisovaleric aciduria	Frequent (30-79%)
HP:0033447	Elevated circulating isovalerylcarnitine concentration	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001735	Acute pancreatitis	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0001994	Renal Fanconi syndrome	Very rare (<1-4%)
HP:0002453	Abnormal globus pallidus morphology	Very rare (<1-4%)
HP:0011675	Arrhythmia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isovaleric acidemia
Mondo ID	MONDO:0009475
MeSH	C538167
OMIM	243500
Orphanet	33
DOID	DOID:14753
ICD-10-CM	E71.110
NCIT	C98964
SNOMED CT	87827003
UMLS	C0268575
MedGen	82822
GARD	0000465
NORD	712
Is cancer (heuristic)	no

Also known as: isovaleric acid CoA dehydrogenase deficiency · isovaleric acidemia · Isovalericacidemia · isovaleryl CoA carboxylase deficiency · isovaleryl-CoA dehydrogenase deficiency · IVA

Data availability: 743 ClinVar variants · 6 GenCC gene-disease records · 6 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 amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › isovaleric acidemia

Related subtypes (14): beta-ketothiolase deficiency, 3-hydroxyisobutyric aciduria, 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, 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

600 retrieved; paginated sample, class counts are floors:

314 likely benign, 94 uncertain significance, 76 likely pathogenic, 35 pathogenic, 28 pathogenic/likely pathogenic, 24 benign, 23 conflicting classifications of pathogenicity, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100060	NM_002225.5(IVD):c.932C>T (p.Ala311Val)	IVD	Pathogenic	criteria provided, multiple submitters, no conflicts
1057882	NM_002225.5(IVD):c.467G>C (p.Gly156Ala)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066603	NM_002225.5(IVD):c.1138+1G>A	IVD	Pathogenic	criteria provided, single submitter
1072234	NC_000015.9:g.(?40699827)(40710472_?)del	IVD	Pathogenic	criteria provided, single submitter
1321422	NM_002225.5(IVD):c.205G>A (p.Asp69Asn)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331437	NM_002225.5(IVD):c.1123G>A (p.Gly375Ser)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339075	NM_002225.5(IVD):c.287-2A>G	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1351489	NM_002225.5(IVD):c.150del (p.Gln51fs)	IVD	Pathogenic	criteria provided, single submitter
1393907	NM_002225.5(IVD):c.541G>T (p.Glu181Ter)	IVD	Pathogenic	criteria provided, single submitter
1432608	NM_002225.5(IVD):c.242G>A (p.Trp81Ter)	IVD	Pathogenic	criteria provided, single submitter
1452780	NM_002225.5(IVD):c.838_841del (p.Leu280fs)	IVD	Pathogenic	criteria provided, single submitter
1453786	NM_002225.5(IVD):c.225del (p.Asn76fs)	IVD	Pathogenic	criteria provided, single submitter
1454153	NM_002225.5(IVD):c.109G>A (p.Asp37Asn)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459787	NC_000015.9:g.(?40698010)(40698182_?)del	IVD	Pathogenic	criteria provided, single submitter
167199	NM_002225.5(IVD):c.358G>A (p.Gly120Arg)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705327	NM_002225.5(IVD):c.127dup (p.Ser43fs)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188720	NM_002225.5(IVD):c.457-2A>G	IVD	Pathogenic	criteria provided, multiple submitters, no conflicts
188724	NM_002225.5(IVD):c.457-3_457-2delinsGG	IVD	Pathogenic	criteria provided, multiple submitters, no conflicts
188922	NM_002225.5(IVD):c.149G>C (p.Arg50Pro)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188993	NM_002225.5(IVD):c.1179del (p.Leu394fs)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198480	NM_002225.5(IVD):c.784+1G>A	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203788	NM_002225.5(IVD):c.286+2T>C	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203792	NM_002225.5(IVD):c.890C>T (p.Ala297Val)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2083374	NM_002225.5(IVD):c.1030G>A (p.Ala344Thr)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137648	NM_002225.5(IVD):c.506_507insT (p.Gly170fs)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2190902	NM_002225.5(IVD):c.1204_1210del (p.Ile402fs)	IVD	Pathogenic	criteria provided, single submitter
2424376	NC_000015.9:g.(?40698010)(40710472_?)del	IVD	Pathogenic	criteria provided, single submitter
265202	NM_002225.5(IVD):c.1174C>T (p.Arg392Cys)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676185	NM_002225.5(IVD):c.1186G>C (p.Asp396His)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676194	NM_002225.5(IVD):c.631A>G (p.Thr211Ala)	IVD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
IVD	Definitive	Autosomal recessive	isovaleric acidemia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IVD	Orphanet:33	Isovaleric acidemia

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
IVD	HGNC:6186	ENSG00000128928	P26440	Isovaleryl-CoA dehydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IVD	Isovaleryl-CoA dehydrogenase, mitochondrial	A mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism, where isovaleryl-CoA (3-methylbutanoyl-CoA) is metabolized to 3-methylbut-2-enoyl-CoA.

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)
IVD	Enzyme (other)	yes	1.3.8.4	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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IVD	267	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IVD	2,067

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IVD	P26440	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Isovaleric acidemia	1	11420.0×	6e-04	IVD
Diseases of branched-chain amino acid catabolism	1	1903.3×	0.002	IVD
Branched-chain amino acid catabolism	1	475.8×	0.005	IVD
Diseases of metabolism	1	80.4×	0.021	IVD
Metabolism of amino acids and derivatives	1	67.6×	0.021	IVD
Disease	1	13.1×	0.086	IVD
Metabolism	1	11.6×	0.086	IVD

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-leucine catabolic process	1	2407.4×	9e-04	IVD
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	1404.3×	9e-04	IVD
branched-chain amino acid catabolic process	1	1053.2×	9e-04	IVD

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
IVD	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IVD	1.3.8.4	isovaleryl-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	IVD
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)
IVD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
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