Abstract 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 defi ciencies. This paper provides the first consensus recommenda tions for the diagnosis and management of methylation disor ders.
Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provid ed in a structured way comprising diagnosis (clinical presenta tion, biochemical abnormalities, differential diagnosis, new born 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 con centrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S adenosylhomocysteine hydrolase and adenosine kinase defi ciencies.
S-adenosylmethionine supplementation may be use ful in patients with methionine adenosyltransferase I/III defi ciency. Recommendations given in this article are based on general principles and in practice should be adjusted individu ally according to patient’s age, severity of the disease, clinical and laboratory findings.