An unusually high frequency of SCAD deficiency caused by two pathogenic variants in the ACADS gene and its relationship to the ethnic structure in Slovakia

Abstract

BackgroundShort-chain acyl-CoA dehydrogenase deficiency (SCADD) represents a rare autosomal recessive inborn metabolic disorder of mitochondrial β-oxidation of monocarboxylic acids. Clinical symptoms can vary from a severe life-threatening condition to an asymptomatic state, reported in the majority of cases. Since the expansion of newborn screenings, more than three hundred probands were admitted for molecular-genetic analysis, most selected because of elevated values of C4-acylcarnitine detected in newborn screenings in Slovakia. Searching for the principal genomic changes led us to the selection of sixty-two patients in whom the presence of sequence variants in the ACADS gene was analysed and correlated with the available biochemical and clinical data.MethodsBiochemical and molecular genetic tests were performed. Acylcarnitine profiles focused on an elevated level of C4-acylcarnitine, which was analysed via tandem mass spectrometry. Urinary organic acids, specifically a quantity of ethylmalonic acid, were determined by gas chromatography/mass spectrometry. The entire coding region of the ACADS gene was sequenced. A low-cost restriction fragment length polymorphism of PCR amplified fragments analysis (PCR-RFLP) of pathogenic variants was introduced and implemented for the molecular-genetic algorithm appropriate for the Slovak population.ResultsOur molecular genetic study was performed on sixty-two patients with a pathological biochemical pattern related to short-chain acyl-CoA dehydrogenase deficiency. In this cohort, we discovered a high occurrence of two rare pathogenic variants—the deletion c.310_312delGAG and the substitution c.1138C>T, with allelic frequencies of 64% and 31%, respectively. Up to 86% of investigated individuals belong to the Roma ethnic group.ConclusionsAnalogous to other countries, SCADD is not included in the newborn screening programme. Based on the exceeded levels of the specific biomarker C4-acylcarnitine as well as ethylmalonic acid, we revealed a high prevalence of short-chain acyl-CoA dehydrogenase deficiency cases, confirmed by the findings of two rare pathogenic variants. A deletion c.310_312delGAG and c.1138C > T substitution in the ACADS gene appear with a high frequency in the Roma ethnic group of Slovakia. Due to the uncertainty of the pathogenicity and clinical consequences, it is important to follow up the morbidity and mortality in these patients over time and evaluate SCADD in relation to clinical outcomes and preventive healthcare recommendations.

The Roma Population Living in Segregated Settlements in Eastern Slovakia Has a Higher Prevalence of Metabolic Syndrome, Kidney Disease, Viral Hepatitis B and E, and Some Parasitic Diseases Compared to the Majority Population

“…The result of this is a high incidence of hereditary disorders [44]. Some congenital diseases (e.g., congenital glaucoma, congenital hypothyroidism, short-chain acyl-CoA dehydrogenase deficiency) are more common in the Slovak Roma population than in the majority non-Roma population [45][46][47].…”

Temporal metabolic response yields a dynamic biosignature of inflammation

“…As fatty oxidation activity decreases, the initial compounds, like butyryl-CoA, increase in concentration and are degraded to compounds like butyrylglycine via various metabolic processes. Accumulation of short-chain fatty acids is seen in individuals with short-chain acyl-CoA dehydrogenase deficiency as short-chain acyl-dehydrogenase (SCAD) catalyzes the first step in beta-oxidation for small fatty acids with four to six carbon chains ( Lisyová et al., 2018 ). Fatty acid oxidation rates have an inflammation specific outcome in macrophage mitochondria where increases in fatty acid oxidation, indirectly leading to decreases in butyrylglycine, have been indicated in a decreased inflammatory response ( Namgaladze and Brüne, 2016 ).…”

Neonatal Screening on Tandem Mass Spectrometry as a Powerful Tool for the Reassessment of the Prevalence of Underestimated Diseases in Newborns and Their Family Members: A Focus on Short Chain Acyl-CoA Dehydrogenase Deficiency

“…The mutations c.511C>T and c.625G>A have been widely described in exons 5 and 6 of the SCAD gene in European populations and the population of the State of California, U.S.A. [ 11 , 19 , 20 , 21 , 22 ]. Although they modify the structural and catalytic properties of the SCAD protein, these variants are believed to confer susceptibility for developing SCADD [ 12 ].…”

“…Concern abounds for not only patients’ long-term neurodevelopmental status and metabolic crises, but also for understanding disease pathogenesis and effective treatments [ 24 ]. Similarly, Lysiova comments on the importance of early detection this disorder before a severe and/or possible life-threatening manifestation [ 19 ].…”