Naslov
S-Adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

Autori
Barić, Ivo ; Fumić, Ksenija ; Glen, Byron ; Ćuk, Mario ; Schulze, Andreas ; Finkelstein, James D. ; James, Jill S. ; Mejaški-Bošnjak, Vlatka ; Pažanin, Leo ; Pogribny, Igor P. ; Radoš, Marko ; Sarnavka, Vladimir ; Šćukanec-Špoljar, Mira ; Allen, Robert H. ; Stabler, Sally ; Uzelac, Lidija ; Vugrek, Oliver ; Wagner, Conrad ; Zeisel, Steven ; Mudd, Harvey S.

Izvornik
Proceedings of the National Academy of Sciences of the United States of America (0027-8424) 101 (2004), 12; 4234-4239

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Hypermethioninemia ; S-adenosylhomocysteine ; AdoHcy ; homocysteine ; gene mutations

Sažetak
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 μM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5–15.9 μM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was ≈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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Kliničke medicinske znanosti

POVEZANOST RADA