title: Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia.
abstract: This paper reports clinical and metabolic studies of two Italian siblings with a novel form of persistent isolated hypermethioninaemia, i.e. abnormally elevated plasma methionine that lasted beyond the first months of life and is not due to cystathionine beta-synthase deficiency, tyrosinaemia I or liver disease. Abnormal elevations of their plasma S-adenosylmethionine (AdoMet) concentrations proved they do not have deficient activity of methionine adenosyltransferase I/III. A variety of studies provided evidence that the elevations of methionine and AdoMet are not caused by defects in the methionine transamination pathway, deficient activity of methionine adenosyltransferase II, a mutation in methylenetetrahydrofolate reductase rendering this activity resistant to inhibition by AdoMet, or deficient activity of guanidinoacetate methyltransferase. Plasma sarcosine (N-methylglycine) is elevated, together with elevated plasma AdoMet in normal subjects following oral methionine loads and in association with increased plasma levels of both methionine and AdoMet in cystathionine beta-synthase-deficient individuals. However, plasma sarcosine is not elevated in these siblings. The latter result provides evidence they are deficient in activity of glycine N-methyltransferase (GNMT). The only clinical abnormalities in these siblings are mild hepatomegaly and chronic elevation of serum transaminases not attributable to conventional causes of liver disease. A possible causative connection between GNMT deficiency and these hepatitis-like manifestations is discussed. Further studies are required to evaluate whether dietary methionine restriction will be useful in this situation.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland 20892-4034, USA. shm@codon.nih.gov
authors.forename: S H
authors.initials: SH
authors.lastname: Mudd
authors.forename: R
authors.initials: R
authors.lastname: Cerone
authors.forename: M C
authors.initials: MC
authors.lastname: Schiaffino
authors.forename: A R
authors.initials: AR
authors.lastname: Fantasia
authors.forename: G
authors.initials: G
authors.lastname: Minniti
authors.forename: U
authors.initials: U
authors.lastname: Caruso
authors.forename: R
authors.initials: R
authors.lastname: Lorini
authors.forename: D
authors.initials: D
authors.lastname: Watkins
authors.forename: N
authors.initials: N
authors.lastname: Matiaszuk
authors.forename: D S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: B
authors.initials: B
authors.lastname: Schwahn
authors.forename: R
authors.initials: R
authors.lastname: Rozen
authors.forename: L
authors.initials: L
authors.lastname: LeGros
authors.forename: M
authors.initials: M
authors.lastname: Kotb
authors.forename: A
authors.initials: A
authors.lastname: Capdevila
authors.forename: Z
authors.initials: Z
authors.lastname: Luka
authors.forename: J D
authors.initials: JD
authors.lastname: Finkelstein
authors.forename: A
authors.initials: A
authors.lastname: Tangerman
authors.forename: S P
authors.initials: SP
authors.lastname: Stabler
authors.forename: R H
authors.initials: RH
authors.lastname: Allen
authors.forename: C
authors.initials: C
authors.lastname: Wagner
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004032:Diet; D005260:Female; D050938:Glycine N-Methyltransferase; D006529:Hepatomegaly; D006801:Humans; D008099:Liver / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage / Q000097:blood*; D008780:Methyltransferases / Q000172:deficiency*; D012436:S-Adenosylmethionine / Q000097:blood; D012521:Sarcosine / Q000097:blood
chemical_list: D012436:S-Adenosylmethionine; D008715:Methionine; D008780:Methyltransferases; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D012521:Sarcosine