HIBCH – 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency

3-Hydroxyisobutyryl-CoA hydrolase, encoded by HIBCH (HGNC:4908), is essential for valine catabolism. Biallelic pathogenic variants in HIBCH cause 3-Hydroxyisobutyryl-CoA hydrolase deficiency, a rare autosomal recessive metabolic disorder presenting as a Leigh-like syndrome with basal ganglia lesions, developmental delay, hypotonia, seizures, optic atrophy, dystonia, and ataxia. Brain MRI typically shows bilateral basal ganglia hyperintensities and progressive cerebral atrophy, and enzymatic studies frequently reveal multiple respiratory chain and pyruvate dehydrogenase deficiencies consistent with mitochondrial dysfunction.

To date, over 22 probands from more than 11 unrelated families have been reported, confirming autosomal recessive inheritance and segregation in both consanguineous and outbred pedigrees (PMID:34447000, PMID:25251209). A movement disorder series described 5 adolescent and adult patients from 2 unrelated families, expanding the phenotypic and age spectrum of the disease (PMID:27400804).

The variant spectrum includes frameshift (e.g., c.129dup (p.Gly44ArgfsTer20)), splice-site (c.664-2A>G, c.439-2A>G), and missense changes (c.287C>A (p.Ala96Asp)) affecting enzyme stability or activity (PMID:26163321, PMID:27896122). No clear genotype–phenotype correlations have been established beyond truncating variants tending toward more severe neonatal presentations (PMID:29703962).

Functional assays in patient fibroblasts demonstrate HIBCH activity below detectable limits in loss-of-function alleles, and transfection studies correlate residual activity with clinical severity, supporting a haploinsufficiency mechanism (PMID:27896122). Metabolite profiling consistently shows elevated hydroxy-C4-carnitine, and dietary intervention (low-valine diet) has yielded clinical and radiographic improvements in some cases (PMID:31679561).

Phenotypes range from fatal neonatal presentations with severe high-anion-gap metabolic acidosis and rapid neurodegeneration to childhood and adult-onset movement disorders dominated by dystonia and ataxia. Newborn screening for elevated hydroxy-C4-carnitine may facilitate early diagnosis and management (PMID:26026795).

Key Take-home: HIBCH deficiency is a strongly supported autosomal recessive disorder; early genetic testing combined with enzymatic assays enables diagnosis and guides dietary and supportive interventions.

References

• American Journal of Medical Genetics Part A • 2014 • HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders. PMID:25251209
• Movement Disorders • 2016 • A movement disorder with dystonia and ataxia caused by a mutation in the HIBCH gene. PMID:27400804
• Molecular Genetics and Metabolism Reports • 2014 • Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis. PMID:27896122
• Molecular Genetics and Metabolism • 2015 • Metabolite studies in HIBCH and ECHS1 defects: Implications for screening. PMID:26163321
• Annals of Indian Academy of Neurology • 2021 • 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH) Deficiency Cases Diagnosed by Only HIBCH Gene Analysis and Novel Pathogenic Mutation. PMID:34447000
• Journal of Human Genetics • 2018 • Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review. PMID:29703962
• Case Reports in Genetics • 2020 • A phenotypically severe, biochemically "silent" case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing. PMID:32022391
• European Journal of Paediatric Neurology • 2019 • A therapeutic regimen for 3-hydroxyisobutyryl-CoA hydrolase deficiency with exercise-induced dystonia. PMID:31679561
• Molecular Genetics and Metabolism • 2015 • Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease. PMID:26026795

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