Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders.
Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings.
Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, Rebro, 10000, Zagreb, Croatia. ibaric@kbc-zagreb.hr.|University of Zagreb, School of Medicine, Zagreb, Croatia. ibaric@kbc-zagreb.hr.
Ivo
I
Barić
Department of General Pediatrics, Division of Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120, Heidelberg, Germany.
Christian
C
Staufner
1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Persephone
P
Augoustides-Savvopoulou
Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Yin-Hsiu
YH
Chien
Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre University Hospital and RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364 CHRU Lille, 59037, Lille, France.
Dries
D
Dobbelaere
University Medical Centre Freiburg, Freiburg, Germany.
Sarah C
SC
Grünert
Department of General Pediatrics, Division of Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120, Heidelberg, Germany.
Thomas
T
Opladen
Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, Rebro, 10000, Zagreb, Croatia.
Danijela
D
Petković Ramadža
Biochemical Genetics Laboratory, BC Children's Hospital, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.
Bojana
B
Rakić
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Anna
A
Wedell
Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics Adolescent Medicine and Neonatology, University Medical Centre Freiburg, Freiburg, Germany.
Henk J
HJ
Blom
D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000378:metabolism; D008715:Methionine / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000172:deficiency; D008745:Methylation; D015997:Neonatal Screening / Q000379:methods; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D008716:Methionine Adenosyltransferase
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