Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2

Abstract

Glutaric acidemia type 2 (GA2) is an autosomal recessive disorder resulting from a deficiency of electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) that manifests from most severe neonatal to late-onset forms. However, the genetic defect responsible for the disease and clinical severity is not well-characterized. In order to understand the relationship between the phenotype and genetic defect, we investigated the clinical and molecular features of 15 Japanese patients, including 4 previously reported cases. Three patients had the neonatal form and 8 patients had the late-onset form, 1 of whom presented an extremely mild phenotype. Immunoblot analysis showed that either ETFalpha, ETFbeta, or ETFDH was significantly reduced or absent in all patients. However, no specific enzyme deficiency predominated, and there were no associations with the clinical severity. Genetic analyses identified 15 mutations including non-sense, missense, splice site mutations, and small deletions, in ETFA, ETFB and ETFDH genes. Although almost all mutations were unique to Japanese patients and no common mutations were found, some of them appeared to be associated with a specific phenotype. Our results suggest that clinical and mutational spectrums of Japanese GA2 patients are heterogeneous and that genetic diagnoses may help to predict a prognosis and provide more accurate diagnostic information for patients and families with GA2.

Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat

“…The mutation identified in this study has not been reported previously in human cases of MADD (Goodman et al 2002;Olsen et al 2003;Schiff et al 2006;Yotsumoto Er et al 2010;Wolfe et al 2010;Er et al 2011;Wang et al 2011;Trakadis et al 2012) (Fig. 5c).…”

Lipid Storage Myopathy

“…Routine biochemical tests often show mildly to moderately elevated CK levels, especially during the episodes of metabolic decompensation. Mutations in ETFA and ETFB tend to cause neonatalonset forms, whereas ETFDH mutations often present with the later-onset form [23,24], but disease severity may not solely depend upon the primary gene defect but also upon other factors [25•]. It has been long known that a group of MADD patients are riboflavin-responsive but others are not.…”

Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients

“…1,2 According to the onset age, MADD has considerable clinical variations, from neonatal lethal forms to mild late-onset forms. Neonatal-onset MADD is usually lethal and these patients often die from severe acidosis, nonketotic hypoglycemia and cardiomyopathy during the neonatal period.…”