title: Hyperhomocysteinemia: related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues.
abstract: Homocysteine, a sulfur-containing amino acid derived from the methionine metabolism, is located at the branch point of two pathways of the methionine cycle, i.e. remethylation and transsulfuration. Gene abnormalities in the enzymes catalyzing reactions in both pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is associated with increased risk for congenital disorders, including neural tube closure defects, heart defects, cleft lip/palate, Down syndrome, and multi-system abnormalities in adults. Since hyperhomocysteinemia is known to affect the extent of DNA methylation, it is likely that abnormal DNA methylation during embryogenesis, may be a pathogenic factor for these congenital disorders. In this review we highlight the importance of homocysteinemia by describing the genes encoding for enzymes of homocysteine metabolism relevant to the clinical practice, especially cystathionine-β-synthase and methylenetetrahydrofolate reductase mutations, and the impairment of related metabolites levels. Moreover, a possible correlation between hyperhomocysteine and congenital disorders through the involvement of abnormal DNA methylation during embryogenesis is discussed. Finally, the relevance of present and future diagnostic tools such as tandem mass spectrometry and next generation sequencing in newborn screening is highlighted.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125 Bari, Italy; Center of Excellence in Comparative Genomics, University of Bari, via Orabona 4, 70125 Bari, Italy; CNR Institute of Biomembranes and Bioenergetics, Bari, Italy. Electronic address: vito.iacobazzi@uniba.it.
authors.forename: Vito
authors.initials: V
authors.lastname: Iacobazzi
authors.affiliation: Department of Science, University of Basilicata, 85100 Potenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Infantino
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125 Bari, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
authors.affiliation: Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
mesh_terms: D019175:DNA Methylation; D006801:Humans; D020138:Hyperhomocysteinemia / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D007231:Infant, Newborn; D008403:Mass Screening; D015997:Neonatal Screening / Q000379:methods; D012307:Risk Factors
keywords: Cobalamin; Folate cycle; Homocysteine; Hyperhomocysteine; Methionine cycle; Newborn screening