Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia.
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.
Mudd
S H
SH
Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland 20892-4034, USA. shm@codon.nih.gov
Cerone
R
R
Schiaffino
M C
MC
Fantasia
A R
AR
Minniti
G
G
Caruso
U
U
Lorini
R
R
Watkins
D
D
Matiaszuk
N
N
Rosenblatt
D S
DS
Schwahn
B
B
Rozen
R
R
LeGros
L
L
Kotb
M
M
Capdevila
A
A
Luka
Z
Z
Finkelstein
J D
JD
Tangerman
A
A
Stabler
S P
SP
Allen
R H
RH
Wagner
C
C
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
D012436:S-Adenosylmethionine; D008715:Methionine; D008780:Methyltransferases; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D012521:Sarcosine