A Common Mutation Is Associated with a Mild, Potentially Asymptomatic Phenotype in Patients with Isovaleric Acidemia Diagnosed by Newborn Screening

Abstract

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism that can cause significant morbidity and mortality. Since the implementation, in many states and countries, of newborn screening (NBS) by tandem mass spectrometry, IVA can now be diagnosed presymptomatically. Molecular genetic analysis of the IVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C-->T (A282V), in 47% of mutant alleles. Surprisingly, family studies identified six healthy older siblings with identical genotype and biochemical evidence of IVA. Our findings indicate the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA. This has significant consequences for patient management and counseling.

The Risk of Fatty Acid Oxidation Disorders and Organic Acidemias in Children with Normal Newborn Screening

“…The potential high local incidence of false-positive cases in diseases such as of VLCADD, CPT-1, 3-MCC, IVA, citrulinaemia and maternal CUD (Ensenauer et al 2004;Vijay et al 2006;Glamuzina et al 2011;Ryder et al 2016;Rips et al 2016) and the local workforce capacity particularly in the first few years of that contributed to the NMSP adopting relatively high cut-off levels. This results in less work for the screening laboratory, fewer second tests and less false-positive cases, thus limiting unnecessary stressful notifications to families.…”

“…While the clinical details were suggestive of IVA, the lack of specific metabolic investigations at the time of death and the absence of any disease-causing mutations in the IVD gene made the diagnosis of IVA unlikely. IVA is a difficult disease for screening laboratories as there are a number of relatively common variants with elevated screening levels who are at very low or no risk of clinical disease (Ensenauer et al 2004). C5 is also elevated in the very rare disease 2-methylbutyryl-CoA dehydrogenase deficiency but this does not present with a severe hepatic metabolic decompensation as seen in Case B and thus seems unlikely.…”

Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia

“…IVA due to an IVD deficiency has been reported at a frequency of 1:250,000 and 1:365,000 births in the United States and Taiwan, respectively, but is more common in Germany, where the prevalence is 1:62,500 [4,5]. However, recent application of tandem mass spectrometry (MS/MS) for the analysis of the acylcarnitine profile of blood spots obtained for newborn screening has allowed a significant expansion of the recognition of individuals with an IVD deficiency.…”

“…Thus far, over 25 mutations in the IVD gene have been characterized in patients with IVA, including missense/nonsense mutations, splicing mutation and frame shifts [4,9]. A significant proportion of mutant alleles lead to abnormal splicing of the IVD RNA and subsequent complete lack of the IVD protein [10].…”

“…A significant proportion of mutant alleles lead to abnormal splicing of the IVD RNA and subsequent complete lack of the IVD protein [10]. Almost half of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (c.932C>T; Ala282Val) and who have a novel mild and potentially asymptomatic phenotype of IVA [4]. However, most of the biological characteristics of IVA including clinical findings, biochemical features and genetic profiles have been in western populations; no molecular and functional investigations have been performed in Korean patients.…”