HIBADH – 3-Hydroxyisobutyric Aciduria

3-Hydroxyisobutyric aciduria is a rare autosomal recessive disorder of valine catabolism resulting in elevated urine L-3-hydroxyisobutyric acid (L-3HIBA) and a spectrum of dysmorphic features and neurodevelopmental delay. The HIBADH gene encodes 3-hydroxyisobutyrate dehydrogenase, which catalyzes the NAD⁺-dependent oxidation of 3-hydroxyisobutyrate to methylmalonate semialdehyde.

Genetic evidence supports a recessive mode of inheritance: five affected individuals from three unrelated families harbor novel, homozygous HIBADH variants, with two additional affected siblings segregating the same alleles in consanguineous kindreds ([PMID:35174513]). No pathogenic variants were detected in HIBADH in three earlier cases, suggesting locus heterogeneity ([PMID:16466957]).

Biochemical assays reveal markedly increased urinary L-3HIBA in patients, and patient fibroblast homogenates exhibit significantly reduced HIBADH enzymatic activity ([PMID:35174513]). Heterologous expression of wild-type HIBADH in Escherichia coli confirms 3-hydroxyisobutyrate dehydrogenase function, substantiating a loss-of-function mechanism.

Early molecular analysis in a small cohort failed to identify HIBADH mutations despite clinical and biochemical features of 3-hydroxyisobutyric aciduria, indicating possible genetic heterogeneity or cryptic variants in regulatory regions ([PMID:16466957]). Subsequent identification of biallelic coding changes with concordant functional deficits has refined the causative role of HIBADH.

HIBADH deficiency leads to accumulation of L-3HIBA and contributes to neurodevelopmental impairment; preliminary reports of valine-restricted dietary intervention suggest potential biochemical improvement in at least one patient ([PMID:35174513]).

Integration of genetic, biochemical, and functional data yields a coherent genotype–phenotype correlation, establishing HIBADH loss-of-function as a moderate strength cause of primary 3-hydroxyisobutyric aciduria. Clinical genetic testing for HIBADH and enzyme activity assays should be considered in patients with unexplained L-3HIBA elevations.

References

• Journal of Inherited Metabolic Disease • 2022 • 3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method PMID:35174513
• Molecular Genetics and Metabolism • 2006 • Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria. PMID:16466957

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