Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles

Abstract

Classical neonatal-onset glutaric aciduria type 2 (MAD deficiency) is a severe disorder of mitochondrial fatty acid oxidation associated with poor survival. Secondary dysfunction of acyl-CoA dehydrogenases may result from deficiency for riboflavin transporters, leading to severe disorders that, nevertheless, are treatable by riboflavin supplementation. In the last 10 years, we identified nine newborns with biochemical features consistent with MAD deficiency, only four of whom survived past the neonatal period. A likely iatrogenic cause of riboflavin deficiency was found in two premature newborns having parenteral nutrition, one of whom recovered upon multivitamin supplementation, whereas the other died before diagnosis.Four other patients had demonstrated mutations involving ETF or ETF-DH flavoproteins, whereas the remaining three patients presumably had secondary deficiencies of unknown mechanism. Interestingly, six newborns among the seven tested for plasma amino acids had pronounced hyperprolinemia. In one case, because the initial diagnostic workup did not include organic acids and acylcarnitine profiling, clinical presentation and hyperprolinemia suggested the diagnosis. Analysis of our full cohort of >50,000 samples from >30,000 patients suggests that the proline/ alanine ratio may be a good marker of MAD deficiency and could contribute to a more effective management of the treatable forms.

Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity

“…In pregnancy, it is passed from the mother to the child via the placenta probably using the riboflavin transporter RFVT1 ( SLC52A1 ) 26 . Transient MADD‐like biochemical profiles have been reported previously in healthy infants of whom the mothers were (suspected to be) riboflavin deficient during pregnancy 15,16,27 . Medical history taking of the infants' mothers described in our case report revealed that all of them either followed an imbalanced or lactose‐free diet or were (temporarily) vegan or vegetarian during pregnancy.…”

Induced Hyperproteinemia and Its Effects on the Remodeling of Fat Bodies in Silkworm, Bombyx mori

“…In the AM group, the levels of His, Phe, Thr, Glu, Met, and Gly were all abnormal. Abnormalities of single amino acids in circulating blood are closely related to the prevalence of diseases such as histidinemia (Rojas et al, 2012 ), hyperphenylalaninemia and hyperprolinemia (Pontoizeau et al, 2016 ), as well as other amino-acid-related metabolic diseases. These results suggest that the amino acid composition in the hyperproteinemic silkworm FBs were altered, implying that they have adverse effects on tissues and their related functions.…”

Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

“…Thus, another supporting evidence of FAD scarcity in this patient is the hyperprolinemia we detected at the time of first decompensation, consistent with a mitochondrial flavoenzyme proline dehydrogenase deficiency. 51 Indeed, an alimentary maternal Rf deficiency has been described in other infants as responsible for transient and moderate VLCAD deficiency. 52…”