Hypermethioninemia in Campania: Results from 10 years of newborn screening

Abstract

In the last years tandem mass spectrometry (MS/MS) has become a leading technology used for neonatal screening purposes. Newborn screening by MS/MS on dried blood spot samples (DBS) has one of its items in methionine levels: the knowledge of this parameter allows the identification of infant affected by homocystinuria (cystathionine β-synthase, CBS, deficiency) but can also lead, as side effect, to identify cases of methionine adenosyltransferase (MAT) type I/III deficiency. We started an expanded newborn screening for inborn errors of metabolism in Campania region in 2007. Here we report our ten years experience on expanded newborn screening in identifying patients affected by hypermethioninemia. During this period we screened approximately 77,000 infants and identified two cases: one case of classical homocystinuria and one patient affected by defect of MAT I/III. In this paper we describe these patients and their biochemical follow-up and review the literature concerning worldwide newborn screening reports on incidence of CBS and MAT deficiency.

Keywords: AdoCbl, 5′-deoxyadenosylcobalamin NBS; CBS deficiency; CBS, cystathionine β-synthase; Cbl, cobalamin; DBS, dried blood spot samples; Hypermethioninemia; MAT I/III deficiency; MAT I/III, methionine adenosyltransferase type I and III; NBS, Newborn screening; Newborn screening.

Fig. 1

Metabolism of cobalamin and methionine. Methylcobalamin (MeCbl) is the cofactor of the reaction catalysed by the methionine synthase. Methionine is metabolized by Met adenosyltransferase (MAT I/III) which catalyzes the synthesis of S-adenosylmethionine (AdoMet). S-adenosylhomocysteine (AdoHcy), produced by AdoMet transmethylation is hydrolyzed by AdoHcy hydrolase (AHCY) in homocysteine (Hcy) which, in turn, can be metabolized, by the vitamin B12-dependent enzyme Met synthase (MS), to Met. Hcy can be also remethylated to Met by betaine-Hcy-methyltransferase (BHMT). Alternatively, Hcy condensates with serine to form cystathionine, a reaction catalysed by the vitamin B6-dependent enzyme cystathionine β-synthase (CBS) to be finally converted to α-ketobutyrate and cysteine by the γ-cystathionase.

Fig. 2

Follow-up of the methionine levels of the newborns affected by hypermethioninemia. Follow-up of serum methionine levels of the patient affected by CBS deficiency (patient 1) and of the patient affected by MAT I/III deficiency (patient 2).