Zahra Nochi, Sarah Fogh, Rikke Katrine Jentoft Olsen & Niels Gregersen
Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
Corresponding Author contact information:
Zahra Nochi, PhD
Research Unit for Molecular Medicine (MMF) Department of Clinical Medicine
Aarhus University Hospital Palle Juul-Jensens Boulevard 99 8200 Aarhus N, Denmark
BACKGROUND: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation, characterized by increased level of butyrylcarnitine and ethylmalonic acid (EMA) in plasma and urine. The majority of individuals with SCADD, who are identified through newborn screening programs, may remain clinically insignificant, while those with symptomatic SCADD may show relatively severe phenotype, such as metabolic or neuromuscular disabilities.
METHODS: We performed a comprehensive literature review and collected our own unpublished data (presented at SSIEM meetings in 2016 & 2017) to gain a greater understanding of SCADD.
RESULTS: Two common gene variations, c.511C > T and c.625G > A and a large number of rare gene variations, along with a modifier gene ethylmalonyl-CoA decarboxylase 1 (ECHDC1) have been identified in affected individuals with SCADD. The common variations – as well as the great majority of rare variations – impair folding that cause toxic accumulation of the encoded protein and/or metabolites. These and possibly in combination with SCAD modifier genes, such as ECHDC1, which its protein deficiency increases EMA level, initiate production of reactive oxygen species at a pathogenic level and consequently creates chronic oxidative stress. Interestingly, we found no bi-allelic loss-of-function (LOF) variations among 357 SCAD deficient patients studied over the last 20 years at the Research Unit for molecular Medicine, Aarhus University. This may indicate that SCAD LOF variations are incompatible with life and may raise the question whether human cells can survive with total lack of SCAD protein. In fact, the number of heterozygous LOF variations in the genomic databases is under-represented in relation to the expected.
DISCUSSION: Today, SCADD is not included as a newborn screening target in most countries, since the exact molecular mechanisms that link ACADS variations and elevated levels of butyrate/EMA with significant clinical symptoms are still uncertain. Consequently, many patients with SCAD gene variations do not get a diagnosis and the possibilities to be followed up during development. Pursuing efforts to follow outcomes in SCADD-patients and clarifying possible cellular and genetic mechanisms of SCADD, e.g. by extended genomic screening studies to map SCADD modifier genes should be done.