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

BMC Med Genet. 2018 Apr 20;19(1):64. doi: 10.1186/s12881-018-0566-0.


Background: Short-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.

Methods: Biochemical 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.

Results: Our 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.

Conclusions: Analogous 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.

Keywords: C4-acylcarnitine; Ethylmalonic acid; Frequent pathogenic variants in Slovakia; Newborn screening; Roma ethnic group; Short-chain acyl-CoA dehydrogenase deficiency.

MeSH terms

  • Acyl-CoA Dehydrogenase / deficiency*
  • Acyl-CoA Dehydrogenase / genetics
  • Acyl-CoA Dehydrogenase / metabolism
  • Butyryl-CoA Dehydrogenase / genetics*
  • Carnitine / analogs & derivatives*
  • Carnitine / metabolism
  • Ethnicity / genetics*
  • Female
  • Gene Frequency
  • Genetic Testing
  • Humans
  • Infant, Newborn
  • Lipid Metabolism, Inborn Errors / ethnology
  • Lipid Metabolism, Inborn Errors / genetics*
  • Lipid Metabolism, Inborn Errors / metabolism
  • Male
  • Mutation*
  • Neonatal Screening / methods
  • Polymorphism, Restriction Fragment Length
  • Sequence Analysis, DNA
  • Slovakia / ethnology


  • acylcarnitine
  • Butyryl-CoA Dehydrogenase
  • Acyl-CoA Dehydrogenase
  • Carnitine

Supplementary concepts

  • Short chain Acyl CoA dehydrogenase deficiency