HIBCH – Leigh Syndrome

HIBCH encodes 3-hydroxyisobutyryl-CoA hydrolase, a valine catabolic enzyme whose loss leads to autosomal recessive Leigh syndrome characterized by early-onset neurodegeneration and basal ganglia lesions. Initial identification in a child with compound heterozygous HIBCH variants (c.410C>T (p.Ala137Val) and c.517+1G>A) established the gene–disease link through whole exome sequencing and clinical improvement on a valine-restricted diet ([PMID:25591832]). Subsequent cohort screening in 89 Leigh syndrome patients uncovered six additional HIBCH-deficient probands, all presenting with similar neurodegenerative features and paroxysmal dystonia, and recurrent basal ganglia cysts on MRI ([PMID:32677093]).

Segregation analysis in consanguineous pedigrees demonstrated biallelic inheritance: two brothers homozygous for c.950G>A (p.Gly317Glu) showed absent HIBCH activity in fibroblasts, and novel variants segregated with disease in independent families ([PMID:24299452]; [PMID:26026795]). Functional assays across multiple studies confirmed that missense mutations (e.g., c.287C>A (p.Ala96Asp), c.365A>G (p.Tyr122Cys)) yield residual enzyme activities correlating with clinical severity, while truncating alleles produce more severe phenotypes ([PMID:27896122]; [PMID:29703962]).

Metabolite profiling revealed elevated hydroxy-C4-carnitine detectable in newborn screening cards, suggesting HIBCH deficiency as a treatable target in MS/MS-based neonatal programs ([PMID:26163321]).

Key Take-home

Robust genetic and biochemical evidence supports HIBCH as a definitive autosomal recessive Leigh syndrome gene; early molecular diagnosis enables dietary intervention and inclusion in newborn screening panels.

References

• Pediatric Neurology • 2015 • Identification of HIBCH gene mutations causing autosomal recessive Leigh syndrome: a gene involved in valine metabolism. PMID:25591832
• Journal of Inherited Metabolic Disease • 2021 • Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene. PMID:32677093
• Orphanet Journal of Rare Diseases • 2013 • HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. PMID:24299452
• 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 • 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
• 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
• Molecular Genetics and Metabolism • 2015 • Metabolite studies in HIBCH and ECHS1 defects: Implications for screening. PMID:26163321

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