| Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine. | |
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MedLine Citation:
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PMID: 22137549 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma. |
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Authors:
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S Harvey Mudd; Conrad Wagner; Zigmund Luka; Sally P Stabler; Robert H Allen; Richard Schroer; Timothy Wood; Jing Wang; Lee-Jun Wong |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-12 |
Journal Detail:
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Title: Molecular genetics and metabolism Volume: - ISSN: 1096-7206 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-12-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9805456 Medline TA: Mol Genet Metab Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD 20892, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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