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.