ACADVL, encoding very long-chain acyl-CoA dehydrogenase, is crucial for mitochondrial fatty acid oxidation. It catalyzes the initial step in the beta-oxidation of very long-chain fatty acids, a key process in energy production. This function is essential for maintaining normal physiological function, especially during periods of fasting or increased energy demands [1,3,4].

Mutations in ACADVL cause very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), an autosomal recessive inborn error of fatty acid oxidation [1,2,3]. In a study of 693 unrelated patients with a positive newborn screen for VLCADD, 94 different pathogenic ACADVL variants (40 novel) and 134 variants of unknown clinical significance were identified. The c.848T>C (p.V283A) pathogenic variant was relatively frequent, and patients homozygous for this allele had a mild phenotype responsive to standard treatment but were still at risk of hypoglycemia [1]. A South Asian pediatric patient with a novel homozygous frameshift variant in ACADVL presented with severe, early-onset VLCADD, highlighting the importance of early diagnosis [3]. Six novel missense variants in ACADVL led to mild VLCAD deficiency, causing mitochondrial defects such as reduced fatty acid oxidation, mitochondrial respiratory-chain function, ATP production, increased ROS, and higher apoptosis levels under glucose-limited stress [4].

In conclusion, ACADVL is essential for mitochondrial fatty acid oxidation, and its dysfunction due to genetic variants causes VLCADD. Understanding the molecular basis of ACADVL-related disorders through studies of genetic variants can potentially guide early diagnosis and treatment strategies for VLCADD patients [1,3,4].

References:

1. Miller, Marcus J, Burrage, Lindsay C, Gibson, James B, Zhang, Victor Wei, Wong, Lee-Jun C. 2015. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. In Molecular genetics and metabolism, 116, 139-45. doi:10.1016/j.ymgme.2015.08.011. https://pubmed.ncbi.nlm.nih.gov/26385305/

2. Flowers, May, Dickson, Alexa, Miller, Marcus J, Graham, Brett H, Mao, Rong. 2023. Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation. In Molecular genetics and metabolism, 140, 107668. doi:10.1016/j.ymgme.2023.107668. https://pubmed.ncbi.nlm.nih.gov/37549443/

3. Arunath, Visvalingam, Liyanarachchi, Manoj Sanjeewa, Gajealan, Sundararajah, Weerasekara, Kumudu, Moheb, Lia Abbasi. 2021. A novel mutation in ACADVL causing very long-chain acyl-coenzyme-A dehydrogenase deficiency in a South Asian pediatric patient: a case report and review of the literature. In Journal of medical case reports, 15, 441. doi:10.1186/s13256-021-03013-y. https://pubmed.ncbi.nlm.nih.gov/34465376/

4. Chen, Ting, Tong, Fan, Wu, Xiao-Yu, Shu, Qiang, Jiang, Ping-Ping. . Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency. In Journal of Zhejiang University. Science. B, 21, 885-896. doi:10.1631/jzus.B2000339. https://pubmed.ncbi.nlm.nih.gov/33150772/