Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B

Abstract

Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant. Two recently-identified riboflavin transporters G protein-coupled receptor 172B (GPR172B or RFT1) and riboflavin transporter 2 (C20orf54 or RFT2) were screened for mutations. Two missense sequence variations, c.209A>G [p.Q70R] and c.886G>A [p.V296M] were found in GPR172B. In vitro functional studies of both missense variations showed that riboflavin transport was unaffected by these variations. Quantitative real-time PCR revealed a de novo deletion in GPR172B spanning exons 2 and 3 in one allele from the mother. We postulate that haploinsufficiency of this riboflavin transporter causes mild riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, resulted in the transient riboflavin-responsive disease seen in her newborn infant. This is the first report of a genetic defect in riboflavin transport in humans.

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

“…Thus, maternal MCADD (Leydiker et al 2011), CTD (De Biase et al 2012;El-Hattab et al 2010;Lee et al 2010;Lund et al 2012;Schimmenti et al 2007;Vijay et al 2006), glutaric acidemia type I (Crombez et al 2008), and combined homocystinuria and methylmalonic aciduria (Lin et al 2009) have all been detected through NBS by the finding of decreased free carnitine in the newborn. In addition, elevated specific acylcarnitines in newborns have revealed maternal 3-methylcrotonyl-CoA carboxylase deficiency (Gibson et al 1998;Koeberl et al 2003;Lund et al 2012), very long-chain acyl-CoA dehydrogenase deficiency (McGoey and Marble 2011), holocarboxylase synthetase deficiency (Nyhan et al 2009), and multiple acyl-CoA dehydrogenation deficiency due to a riboflavin transporter gene defect (Chiong et al 2007;Ho et al 2011). These cases illustrate the importance of taking a detailed maternal history and performing biochemical evaluation with acylcarnitine profile and urine organic acids and when appropriate molecular genetic follow-up in mothers of newborns with abnormal screening results if confirmatory testing shows that the newborn is normal.…”

Molecular Basis of Transient Neonatal Zinc Deficiency

“…In fact, there is ample evidence that haploinsufficiency in heterozygous mutated transporter genes occurs in various diseases: (a) maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in a single allele of the riboflavin transporter gene GPR172B (30). The authors postulated that haploinsufficiency of this riboflavin transporter causes riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, could result in the transient riboflavin-responsive disease observed in the newborn infant.…”

Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles

“…A few of these patients have congenital anomalies, such as renal cystic dysplasia, facial dysmorphism, rocker bottom feet, and abnormalities of external genitalia (Frerman and Goodman 2001), while the others often develop severe cardiomyopathy during the neonatal period. Cases of secondary MADD related to riboflavin deficiency have been described in neonates of mothers carrying heterozygous mutations in a riboflavin transporter (deficiency for GPR172B/SLC52A1) and showed a good response to transient riboflavin supplementation (Chiong et al 2007;Harpey et al 1983;Ho et al 2011). A different entity with later presentation, Brown-Vialetto-Van Laere syndrome, is caused by mutations in two related riboflavin transporters SLC52A2 and SLC52A3 (Bosch et al 2011;Green et al 2010;Johnson et al 2012).…”