Researchers from the University of Pittsburgh generated a new cell line that can be used for functional studies and to assess the pathogenicity of different ACADVL gene variants causing VLCAD deficiency, a type of long-chain fatty acid oxidation disorder (LCFAOD), without the need for invasive skin biopsies.

The new tool was presented by Meena Sethuraman, a second-year medical student at the University of Pittsburgh School of Medicine at the first lecture in the International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series. 

VLCAD deficiency is an autosomal recessive disorder caused by bi-allelic mutations in the ACADVL gene. This gene normally encodes an enzyme that plays a crucial role in mitochondrial beta-oxidation of long-chain fatty acids. When the enzyme cannot function properly because of the mutations, the body cannot generate energy from long-chain fatty acids.


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Read more about the etiology of LCFAOD.

Inborn errors of metabolism such as VLCAD deficiency can be identified through newborn screening. This is usually followed by DNA sequencing to confirm the diagnosis. However, there may sometimes be so-called variants of uncertain significance, which can lead to uncertainty in terms of disease severity and treatment plan. The ACADVL gene is known to have more than 300 variants of unknown significance and many patients have at least one of these variants. 

The cell line presented here was developed to determine the pathogenicity of ACADVL variants of uncertain significance.  

The HEK293T cell line was ACADVL null and expressed no VLCAD protein. It also had reduced activity towards C16-CoA and C21-CoA substrates.

These cells can help determine the pathogenicity of individual ACADVL variants, which is not possible with fibroblast samples obtained from patients, Sethuraman said. This is important because many patients with VLCAD deficiency have unique combinations of variants.

“Overall, this will facilitate better diagnostic and therapeutic outcomes for patients with VLCAD deficiency,” according to Sethuraman.

Reference

Sethuraman M. Testing variants of uncertain significance in a HEK293T model for very-long-chain acyl-CoA dehydrogenase deficiency. Lecture presented as part of International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series: January 24, 2022; Virtual.