Molecular analysis using targeted next generation DNA sequencing and clinical spectrum of Mexican patients with isovaleric acidemia

•tNGS improves understanding of the genotypes and phenotypes associated with IVA.•Novel pathogenic variants found in IVD are reported along with patient phenotypes.•IVA NBS with molecular studies identifies forms of IVA; drives treatment decisions. Isovaleric acidemia (IVA) is an inborn error of metabolism caused by deficiency of isovaleryl-CoA dehydrogenase. IVA clinical picture includes gastroenterological and progressive neurological symptoms which can lead to permanent disability and death. Early detection by newborn screening (NBS) and treatment promotes normal development. In this study, clinical summaries, biochemical measurements and targeted next generation sequencing (tNGS) data from the IVD gene were compared in 13 Mexican patients. The main symptoms were vomiting, feeding refusal, abdominal pain, impaired alertness, lethargy, stupor, coma; hypotonia, ataxia, hallucinations, seizures; anemia, neutropenia and pancytopenia. Mean blood concentration of isovalerylcarnintine was above the reference value (0.5 µM) in symptomatic patients (8.78 µM), as well as in the screen positive newborns (2.23 µM). The molecular spectrum of this cohort was heterogeneous, with 14 different variants identified, seven were previously-described, and seven were novel. The most frequent variant was c.158G > C (p.R53P). In this study, we found a long diagnostic delay (average of 44 months). Thus, it is essential to increase physician awareness of this treatable condition. Biochemical IVA NBS accompanied by molecular studies (e.g. tNGS) will permit identification of potentially asymptomatic forms of the disease, and improve genotype-phenotype relationship, management decisions and follow-up.