HADHA – Mitochondrial Trifunctional Protein Deficiency

Mitochondrial trifunctional protein deficiency is a recessive disorder caused by biallelic mutations in the HADHA gene, encoding the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of the trifunctional protein complex. Affected infants typically present in early infancy with hypoketotic hypoglycemia, cardiomyopathy, hepatic dysfunction, and may develop peripheral neuropathy or sudden death. Female carriers are predisposed to acute fatty liver of pregnancy and HELLP syndrome due to accumulation of 3-hydroxyacyl intermediates in maternal circulation. Diagnosis relies on characteristic elevations of long-chain 3-hydroxyacylcarnitines by tandem mass spectrometry and confirmation by enzyme assay or genetic testing.

Genetic evidence supports autosomal recessive inheritance, with over 70 unrelated probands reported across multiple cohorts, including a large series of 50 patients ([PMID:11773547]) and 11 additional unrelated cases ([PMID:8809345]). The variant spectrum comprises missense, splice-site, and loss-of-function alleles; the common recurrent founder mutation c.1528G>C (p.Glu510Gln) accounts for the majority of alleles in European populations. Segregation analysis demonstrated 19 additional affected relatives with co-segregating HADHA variants, confirming familial transmission of pathogenic alleles.

Functional studies demonstrate that pathogenic HADHA variants abolish LCHAD activity in patient fibroblasts, destabilize the trifunctional protein complex, and impair β-oxidation flux ([PMID:14630990]). Models of the c.1528G>C variant recapitulate cardiomyopathy and altered cardiolipin profiles in murine heart tissue, supporting a mechanism of loss-of-function and secondary mitochondrial dysfunction. Prenatal and newborn screening approaches using acylcarnitine analysis enable early detection and initiation of medium-chain triglyceride–based dietary therapy, which mitigates metabolic crises and improves survival ([PMID:10400133]).

No studies have refuted the HADHA–TFP deficiency association. Collectively, genetic, enzymatic, and model organism data provide a definitive link between HADHA loss-of-function and mitochondrial trifunctional protein deficiency. Key take-home: early genetic diagnosis of HADHA variants is critical for prompt dietary management, carrier counseling, and prevention of maternal complications.

References

• Pediatrics • 2002 • Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. PMID:11773547
• Biochemical and molecular medicine • 1996 • Improved detection of the G1528C mutation in LCHAD deficiency. PMID:8809345
• Pediatric research • 2004 • General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. PMID:14630990
• Pediatric research • 1999 • Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis. PMID:10400133

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