S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.
We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 microM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 microM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was approximately equal to 3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.
Baric
Ivo
I
Department of Pediatrics, University Hospital Center, Kispatićeva 12, 10000 Zagreb, Croatia. ibaric@kbc-zagreb.hr
Fumic
Ksenija
K
Glenn
Byron
B
Cuk
Mario
M
Schulze
Andreas
A
Finkelstein
James D
JD
James
S Jill
SJ
Mejaski-Bosnjak
Vlatka
V
Pazanin
Leo
L
Pogribny
Igor P
IP
Rados
Marko
M
Sarnavka
Vladimir
V
Scukanec-Spoljar
Mira
M
Allen
Robert H
RH
Stabler
Sally
S
Uzelac
Lidija
L
Vugrek
Oliver
O
Wagner
Conrad
C
Zeisel
Steven
S
Mudd
S Harvey
SH
D043383:Adenosylhomocysteinase / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging; D030342:Genetic Diseases, Inborn / Q000178:diet therapy / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000000981:diagnostic imaging; D008279:Magnetic Resonance Imaging; D008297:Male; D008715:Methionine / Q000097:blood / Q000378:metabolism*; D011859:Radiography; D014463:Ultrasonography
D008715:Methionine; D043383:Adenosylhomocysteinase