Abstract
Homocystinuria due to cystathionine β-synthase deficiency or “classical homocystinuria” is a rare autosomal recessive condition resulting in altered sulfur metabolism with elevated methionine and homocysteine in plasma and homocystine in urine. This condition is characterized by a high clinical heterogeneity, which contributes to late clinical diagnosis, usually only made after irreversible damage has occurred. Treatment is effective if started before clinical symptoms. The analysis of methionine levels by tandem mass spectrometry (MS/MS) allows the newborn screening for homocystinuria, but false-positive results can be frequently obtained and lead to the unwanted identification of methionine adenosyl transferase (MAT I/III) deficiency. This latter condition is biochemically characterized by isolated persistent hypermethioninemia, accompanied in some individuals with slightly elevated levels of homocysteine in plasma. A dominant form of MAT I/III deficiency, associated with mutation p.R264H, seems to be very frequent in the Iberian Peninsula and usually has a clinically benign course. Both these metabolic disorders are screened in Galicia and Portugal since the introduction of the MS/MS technology, in 2000 and 2004, respectively, resulting in the identification of three patients with classical homocystinuria and 44 patients with MAT I/III deficiency. All but one heterozygous parent of MAT I/III patients, identified with the p.R264H mutation, are healthy adults around the age of 30/40. The implementation of a second-tier test for homocysteine in dried blood spots would considerably reduce the number of MAT I/III-deficient patients identified and improve the specificity and positive predictive value for classical homocystinuria screening.
Competing interests: None declared
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Acknowledgments
We are grateful to the clinicians from Portuguese Treatment Centers for the clinical evaluation and follow-up of these patients: Esmeralda Martins and Anabela Bandeira (Centro Hospitalar do Porto), Elisa Leão Teles and Esmeralda Rodrigues (Centro Hospitalar S. João), Luísa Diogo and Paula Garcia (Centro Hospitalar de Coimbra), and Ana Gaspar, Patricia Janeiro, and Cláudia Costa (Centro Hospitalar Lisboa Norte).
We also give thanks to the European network and Registry for Homocystinurias and Methylation Defects – EHOD project (N°2012_12_02) – for the partial support of this work.
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Communicated by: Bridget Wilcken
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Synopsis
MS/MS-based NBS in Galicia and Portugal, through the analysis of methionine, revealed a very low birth prevalence for classical homocystinuria (approximately 1:400,000) and a high birth prevalence for MAT I/III deficiency (approximately : 1:28,000).
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Ana Marcão, María L. Couce, Célia Nogueira, Helena Fonseca, Filipa Ferreira, José M. Fraga, M. Dolores Bóveda, and Laura Vilarinho declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
Additional informed consent was obtained from all patients for which identifying information is included in this article.
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Ana Marcão – Planned, conducted, and reported the work described in the article.
María L. Couce – Planned and reported the work described in the article.
Célia Nogueira – Planned, conducted, and reported the work described in the article.
Helena Fonseca – Conducted the work described in the article.
Filipa Ferreira – Conducted the work described in the article.
M. Dolores Bóveda – Planned the work described in the article.
José M. Fraga – Planned the work described in the article.
Laura Vilarinho – Planned and reported the work described in the article.
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Marcão, A. et al. (2014). Newborn Screening for Homocystinuria Revealed a High Frequency of MAT I/III Deficiency in Iberian Peninsula. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 20. JIMD Reports, vol 20. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_400
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DOI: https://doi.org/10.1007/8904_2014_400
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