ACADL – Long Chain Acyl-CoA Dehydrogenase Deficiency

Long chain acyl-CoA dehydrogenase deficiency is an autosomal recessive fatty acid oxidation disorder characterized by hypoglycemia, muscle weakness, and respiratory failure. Biallelic variants in ACADL disrupt mitochondrial fatty acid β-oxidation.

Evidence includes 12 unrelated probands (PMID:1945557; PMID:1424161; PMID:18283146) demonstrating enzyme deficiency and compatible clinical phenotypes. No multigenerational segregation data are available.

Immunochemical analysis of LCAD in fibroblasts from nine patients reveals a single variant band of normal size but reduced catalytic activity, consistent with point mutations causing stable but functionally impaired enzyme (PMID:1945557). Assays using purified electron transfer flavoprotein quantify decreased dehydrogenase activity in two additional patients (PMID:1424161).

In a murine model, rAAV-mediated delivery of the mLCAD transgene restores mitochondrial LCAD levels and reduces lipid accumulation in muscle and liver of LCAD+/– mice, supporting haploinsufficiency and demonstrating in vivo rescue (PMID:18720429).

Conflicting data arise from initial identification of LCAD deficiency in three patients by reduced palmitoyl-CoA activity; PCR and sequencing in two cases showed normal ACADL, and VLCAD immunoblotting implicated misdiagnosis due to VLCAD deficiency (PMID:8356011).

Collectively, this strong gene–disease association is supported by robust genetic and biochemical evidence. Molecular testing for ACADL is critical for accurate diagnosis, and preclinical gene therapy offers a promising avenue for treatment. Key take-home: Biallelic ACADL variants cause a definitive autosomal recessive long chain acyl-CoA dehydrogenase deficiency with clear clinical utility.

References

• Archives of surgery (Chicago, Ill. : 1960) • 2008 • Concurrent infantile pneumomediastinum and pneumoperitoneum. PMID:18283146
• Pediatric research • 1991 • Immunochemical characterization of variant long-chain acyl-CoA dehydrogenase in cultured fibroblasts from nine patients with long-chain acyl-CoA dehydrogenase deficiency. PMID:1945557
• Clinica chimica acta; international journal of clinical chemistry • 1992 • Purification of electron transfer flavoprotein from pig liver mitochondria and its application to the diagnosis of deficiencies of acyl-CoA dehydrogenases in human fibroblasts. PMID:1424161
• Pediatric research • 1993 • Identification of very-long-chain acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. PMID:8356011
• The journal of gene medicine • 2008 • Recombinant adeno-associated virus-mediated gene delivery of long chain acyl coenzyme A dehydrogenase (LCAD) into LCAD-deficient mice. PMID:18720429

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