MAT I/III deficiency in Portugal: high frequency of R264H mutation in a small area of Douro high lands

Marcão, Ana; Nogueira, Célia; Sousa, Carmen; Fonseca, Helena; Rocha, Hugo; Lopes, Lurdes; Martins, Esmeralda; Vilarinho, Laura

http://hdl.handle.net/10400.18/624

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Introduction: Methionine adenosyltransferase deficiency (MAT I/III deficiency, OMIM 250850) is an inborn error of metabolism resulting in isolated hypermethioninemia and usually inherited as an autosomal recessive trait. A dominant form has been exceptionally reported, associated with a single mutation (R264H). Methods: MAT I/III deficiency is detected by newborn screening (NBS) as a differential diagnosis of classical homocystinuria. Both screenings are based in the methionine measurement by tandem mass spectrometry, and approximately 600,000 newborns were already screened in our laboratory. Suspected cases are confirmed through MAT1A gene analysis. Results: Twenty-three MAT I/III deficient patients were identified through newborn screening. Twelve of them were identified in a small area of Douro high lands, and all revealed to be heterozygous for R264H mutation. Family studies allowed the identification of fifteen additional heterozygotes in this area and seem to indicate a single origin for this allele. Some of the identified heterozygotes present clinical signs which may be related with MAT I/III deficiency. Discussion: The first cause of persistent isolated hypermethioninemia in Portuguese newborns is MAT I/III deficiency due to R264H heterozygosity (21 out of 24 cases). A hot spot for R264H mutation seems to exist in a small area of Douro high lands. Family studies corroborated the importance of carriers identification and counseling.