Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Isovaleric acidemia (IVA) is a rare autosomal recessive inborn error of leucine metabolism caused by biallelic pathogenic variants in IVD, encoding mitochondrial isovaleryl-CoA dehydrogenase. Deficiency of IVD leads to toxic accumulation of isovaleryl-CoA derivatives, manifesting as acute metabolic acidosis, hyperammonemia, and “sweaty foot” odor in neonatal presentations, or chronic intermittent and asymptomatic forms later in life (PMID:14534755).
Genetic evidence supports an autosomal recessive inheritance with multiple reports of consanguineous and non-consanguineous families. A six-month-old patient born to second-degree consanguineous parents with homozygous variants exhibited classic neonatal IVA presentation and required metabolic stabilization (PMID:32257695). Segregation of pathogenic alleles has been confirmed in at least 2 additional affected siblings across different pedigrees.
To date, over 60 distinct IVD variants have been described in more than 150 unrelated patients. Missense variants predominate, with notable recurrent alleles including c.932C>T (p.Ala311Val) in asymptomatic newborn-screened individuals (PMID:15486829) and the founder missense variant c.1199A>G (p.Tyr400Cys) in Han Chinese patients (PMID:20519759). Loss-of-function frameshift, splice-site, and nonsense variants further contribute to severe neonatal phenotypes.
Phenotypic spectrum ranges from life-threatening neonatal metabolic crises with severe acidosis and encephalopathy to chronic intermittent decompensation triggered by stress, and even asymptomatic biochemical IVA detected by tandem mass spectrometry. A cohort combining 155 patients revealed 52 asymptomatic cases, 64 neonatal-onset, and 39 chronic-intermittent presentations, highlighting variable expressivity and age of onset (PMID:35968299).
Functional studies of IVD variants demonstrate loss of enzyme stability and activity consistent with haploinsufficiency. In vitro mitochondrial import and kinetic assays of mutant IVD peptides (e.g., Arg21Pro, Ala282Val, Arg363Cys, Arg382Leu) showed rapid degradation or markedly reduced catalytic efficiency compared to wild-type (PMID:9665741). Patient-derived hiPSC lines and CRISPR/Cas9 IVD null HEK293T models further confirmed variant pathogenicity and provided platforms for rapid VUS assessment (PMID:38401345; PMID:34535384).
No robust evidence disputes the IVD–IVA association. The extensive genetic, segregation, and functional concordance across diverse populations meets criteria for a definitive gene–disease relationship. Comprehensive newborn screening combined with molecular diagnosis enables early intervention with protein-restricted diet, carnitine and glycine supplementation, markedly improving outcomes.
Key Take-home: IVD pathogenic variants cause unequivocal autosomal recessive IVA, and integrating genetic and enzymatic data is critical for timely diagnosis, family counseling, and therapeutic management.
Gene–Disease AssociationDefinitiveOver 155 unrelated patients across >25 studies, consistent autosomal recessive inheritance, robust functional data Genetic EvidenceStrong
Functional EvidenceStrongEnzymatic assays, mitochondrial import studies, hiPSC and CRISPR/Cas9 models demonstrate loss of IVD function |