HADHA – Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD; MONDO:0012173) is an autosomal recessive disorder caused by biallelic pathogenic variants in the HADHA gene (HGNC:4801). Affected infants typically present in the first year of life with hypoketotic hypoglycemia, cardiomyopathy, skeletal myopathy and, in some cases, pigmentary retinopathy.

A total of 28 probands with pathogenic HADHA variants have been reported across eight independent studies ([PMID:2284166], [PMID:9535636], [PMID:35782617], [PMID:11241049], [PMID:23430857], [PMID:33107778], [PMID:8809345], [PMID:37549033]). Family studies including molecular prenatal diagnosis in eight families ([PMID:11241049]) and an affected sibling pair in Estonia ([PMID:23430857]) confirmed autosomal recessive segregation.

The variant spectrum includes missense, splice-site and frameshift alleles. The common c.1528G>C (p.Glu510Gln) founder variant accounts for ~87.5% of disease alleles in Estonia, where the carrier frequency is 1:173 ([PMID:23430857]). Additional alleles include c.1690-2A>G (splice) and c.1108G>A (p.Gly370Arg) in trans with p.Glu510Gln in a late‐onset case ([PMID:35782617]).

Functional assays in patient fibroblasts demonstrate selective loss of long-chain 3-hydroxyacyl-CoA dehydrogenase activity with preserved acyl-CoA dehydrogenase and thiolase functions ([PMID:2284166]). A nested PCR/PstI assay reliably detects the G1528C allele in 11 unrelated LCHADD patients, revealing compound heterozygosity in 7 of 11 cases ([PMID:8809345]). More recently, a knock-in mouse model of the c.1528G>C variant recapitulates eccentric hypertrophic cardiomyopathy and altered cardiolipin profiles, supporting a key role for HADHA in both fatty acid oxidation and cardiolipin remodeling ([PMID:40164334]).

Pathogenicity arises via loss of dehydrogenase activity leading to accumulation of medium- and long-chain 3-hydroxyacyl intermediates, causing energy failure in heart, liver, muscle and retina. Early diagnosis through newborn screening, enzymatic assay and targeted HADHA gene testing is critical.

Key Take-Home: Autosomal recessive HADHA variants cause LCHAD deficiency with a strong gene–disease association; early genetic and biochemical testing enables timely dietary and triheptanoin therapy to mitigate cardiac and retinal damage.

References

• Pediatric research • 1990 • Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. PMID:2284166
• American journal of ophthalmology • 1997 • Pigmentary retinopathy in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. PMID:9535636
• Molecular genetics and metabolism reports • 2022 • A novel HADHA variant associated with an atypical moderate and late-onset LCHAD deficiency. PMID:35782617
• The Journal of pediatrics • 2001 • Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations. PMID:11241049
• JIMD reports • 2012 • Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia. PMID:23430857
• Ophthalmic Genetics • 2020 • Long-term retinal follow-up of LCHADD patients diagnosed by newborn screening. PMID:33107778
• Biochemical and molecular medicine • 1996 • Improved detection of the G1528C mutation in LCHAD deficiency. PMID:8809345
• The American journal of forensic medicine and pathology • 2023 • An Autopsy Analysis of a Patient With Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Caused by Compound Heterozygous HADHA Gene Mutations. PMID:37549033

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