Clear relationship betweenETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency

Abstract

Mutations in electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) are the molecular basis of multiple acyl-CoA dehydrogenation deficiency (MADD), an autosomal recessively inherited and clinically heterogeneous disease that has been divided into three clinical forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD. We report the genomic structures of the ETFA, ETFB, and ETFDH genes and the identification and characterization of seven novel and three previously reported disease-causing mutations. Our molecular genetic investigations of these nine patients are consistent with three clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of disease. Interestingly, our data suggest that homozygosity for two null mutations causes fetal development of congenital anomalies resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be rescued up to 59% of that of wild-type activity when ETFB-D128N-transformed E. coli cells were grown at low temperature. This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature.

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).…”

“…4b). In humans, most cases of MADD are attributable to a zygotic effect on different mutations in ETF or ETFDH (Olsen et al 2003), although the majority of patients with late-onset MADD recorded in southern China carried a homozygous mutation of c.250G>A in ETFDH (Wang et al 2011). According to the owner, the present cat is derived from a group of dozens of stray cats, which were fed by a particular person.…”

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

“…ETF is a dimeric mitochondrial matrix protein composed of ␣ -and ␤ -subunits, and a mutation in either subunit or in ETFDH will result in MADD ( 213 ). Null mutations in either ETFB or ETFDH appear to be associated with the neonatal onset (type 1) of the disease ( 213,214 ). Its mode of inheritance follows an autosomal-recessive pattern.…”

A Case of Late Onset Riboflavin-responsive Multiple Acyl-CoA Dehydrogenase Deficiency Manifesting as Recurrent Rhabdomyolysis and Acute Renal Failure

“…The severity and age at onset of MADD is speculated to correlate with the genotype and residual enzyme activity. Olsen et al described that the clinical phenotype can be explained by ETF/ETFDH genotype that results in different levels of residual enzyme activity (13). That is, null mutations, which would not be expected to result in any residual ETF/ETFDH enzyme activity, result in the development of congenital anomalies and thereby type 1, and even small amounts of residual activity is sufficient to give rise to the type 2 phenotype.…”

“…That is, null mutations, which would not be expected to result in any residual ETF/ETFDH enzyme activity, result in the development of congenital anomalies and thereby type 1, and even small amounts of residual activity is sufficient to give rise to the type 2 phenotype. And the type 3 phenotype is caused by at least one allele with a single missense mutation, which is not directly involved in the active site and has no apparent effect on mRNA processing or stability, and shows significant residual enzyme activity (13). In the Japanese population, though some missense mutations have been reported to be associated with the mild/late onset form (14), no obvious clustering of mutations has been established.…”