Loading…

Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency

Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia a...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 1996-08, Vol.98 (4), p.1021-1027
Main Authors: Chamberlin, M E, Ubagai, T, Mudd, S H, Wilson, W G, Leonard, J V, Chou, J Y
Format: Article
Language:English
Subjects:
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c400t-13c65eef62de2221f958eb023dd35beeb87bc014080b052b10b28a9103509173
cites
container_end_page 1027
container_issue 4
container_start_page 1021
container_title The Journal of clinical investigation
container_volume 98
creator Chamberlin, M E
Ubagai, T
Mudd, S H
Wilson, W G
Leonard, J V
Chou, J Y
description Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most individuals with isolated hypermethioninemia have been free of major clinical difficulties. Therefore a definitive diagnosis of MAT I/III deficiency, which requires hepatic biopsy, is not routinely made. However, two individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious. In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, including the two with demyelination of the brain. Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eight individuals. Both patients with demyelination are homozygous for mutations that alter the reading frame of the encoded protein such that the predicted MATalpha1 subunits are truncated and enzymatically inactive. The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds including the two major myelin phospholipids, phosphatidylcholine and sphingomyelin. Both are synthesized primarily in the liver. Our findings demonstrate that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities. Therefore, a DNA-based diagnosis should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifestations is warranted.
doi_str_mv 10.1172/JCI118862
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_507518</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>15784457</sourcerecordid><originalsourceid>FETCH-LOGICAL-c400t-13c65eef62de2221f958eb023dd35beeb87bc014080b052b10b28a9103509173</originalsourceid><addsrcrecordid>eNqFkT1PwzAQhj2AoBQGfgCSJySG0rNT187AgMpXEBJLV2TZzoUaJXaJU1D_PalaVTAx3XDP3T26l5BzBteMST5-nhWMKTXlB2QAwNkol5k6JicpfQCwyURMjsiRkhKUFAPydofNGmsfTOdjoLGi3QKpbY0P1CdqUorOmw5L-u27BW2wW_ScD0hNiSGmdd21JqQKW5OQFuOiKGiJlXceg1ufksPK1AnPdnVI5g_389nT6OX1sZjdvozcBKAbscxNBWI15SVyzlmVC4UWeFaWmbCIVknrendQYEFwy8ByZXIGmYCcyWxIbrZrlyvbYOkw9FK1Xra-Me1aR-P1307wC_0ev7QAKZjq5y938238XGHqdOOTw7o2AeMqaam4zPvD_4JMSNV_eGN0tQVdG1NqsdrLMNCbmPQ-pp69-G2_J3cZZT82CJCK</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>15784457</pqid></control><display><type>article</type><title>Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency</title><source>PubMed Central</source><source>EZB Electronic Journals Library</source><creator>Chamberlin, M E ; Ubagai, T ; Mudd, S H ; Wilson, W G ; Leonard, J V ; Chou, J Y</creator><creatorcontrib>Chamberlin, M E ; Ubagai, T ; Mudd, S H ; Wilson, W G ; Leonard, J V ; Chou, J Y</creatorcontrib><description>Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most individuals with isolated hypermethioninemia have been free of major clinical difficulties. Therefore a definitive diagnosis of MAT I/III deficiency, which requires hepatic biopsy, is not routinely made. However, two individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious. In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, including the two with demyelination of the brain. Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eight individuals. Both patients with demyelination are homozygous for mutations that alter the reading frame of the encoded protein such that the predicted MATalpha1 subunits are truncated and enzymatically inactive. The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds including the two major myelin phospholipids, phosphatidylcholine and sphingomyelin. Both are synthesized primarily in the liver. Our findings demonstrate that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities. Therefore, a DNA-based diagnosis should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifestations is warranted.</description><identifier>ISSN: 0021-9738</identifier><identifier>DOI: 10.1172/JCI118862</identifier><identifier>PMID: 8770875</identifier><language>eng</language><publisher>United States</publisher><subject>Adolescent ; Amino Acid Metabolism, Inborn Errors - enzymology ; Amino Acid Metabolism, Inborn Errors - genetics ; Brain Diseases - enzymology ; Brain Diseases - genetics ; Child ; Child, Preschool ; Chromosomes, Human, Pair 10 ; Demyelinating Diseases - enzymology ; Demyelinating Diseases - genetics ; Female ; Genes ; Humans ; Infant ; Male ; Methionine - metabolism ; Methionine Adenosyltransferase - deficiency ; Methionine Adenosyltransferase - genetics ; Point Mutation ; Polymorphism, Single-Stranded Conformational</subject><ispartof>The Journal of clinical investigation, 1996-08, Vol.98 (4), p.1021-1027</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-13c65eef62de2221f958eb023dd35beeb87bc014080b052b10b28a9103509173</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC507518/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC507518/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8770875$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chamberlin, M E</creatorcontrib><creatorcontrib>Ubagai, T</creatorcontrib><creatorcontrib>Mudd, S H</creatorcontrib><creatorcontrib>Wilson, W G</creatorcontrib><creatorcontrib>Leonard, J V</creatorcontrib><creatorcontrib>Chou, J Y</creatorcontrib><title>Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most individuals with isolated hypermethioninemia have been free of major clinical difficulties. Therefore a definitive diagnosis of MAT I/III deficiency, which requires hepatic biopsy, is not routinely made. However, two individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious. In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, including the two with demyelination of the brain. Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eight individuals. Both patients with demyelination are homozygous for mutations that alter the reading frame of the encoded protein such that the predicted MATalpha1 subunits are truncated and enzymatically inactive. The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds including the two major myelin phospholipids, phosphatidylcholine and sphingomyelin. Both are synthesized primarily in the liver. Our findings demonstrate that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities. Therefore, a DNA-based diagnosis should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifestations is warranted.</description><subject>Adolescent</subject><subject>Amino Acid Metabolism, Inborn Errors - enzymology</subject><subject>Amino Acid Metabolism, Inborn Errors - genetics</subject><subject>Brain Diseases - enzymology</subject><subject>Brain Diseases - genetics</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromosomes, Human, Pair 10</subject><subject>Demyelinating Diseases - enzymology</subject><subject>Demyelinating Diseases - genetics</subject><subject>Female</subject><subject>Genes</subject><subject>Humans</subject><subject>Infant</subject><subject>Male</subject><subject>Methionine - metabolism</subject><subject>Methionine Adenosyltransferase - deficiency</subject><subject>Methionine Adenosyltransferase - genetics</subject><subject>Point Mutation</subject><subject>Polymorphism, Single-Stranded Conformational</subject><issn>0021-9738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><recordid>eNqFkT1PwzAQhj2AoBQGfgCSJySG0rNT187AgMpXEBJLV2TZzoUaJXaJU1D_PalaVTAx3XDP3T26l5BzBteMST5-nhWMKTXlB2QAwNkol5k6JicpfQCwyURMjsiRkhKUFAPydofNGmsfTOdjoLGi3QKpbY0P1CdqUorOmw5L-u27BW2wW_ScD0hNiSGmdd21JqQKW5OQFuOiKGiJlXceg1ufksPK1AnPdnVI5g_389nT6OX1sZjdvozcBKAbscxNBWI15SVyzlmVC4UWeFaWmbCIVknrendQYEFwy8ByZXIGmYCcyWxIbrZrlyvbYOkw9FK1Xra-Me1aR-P1307wC_0ev7QAKZjq5y938238XGHqdOOTw7o2AeMqaam4zPvD_4JMSNV_eGN0tQVdG1NqsdrLMNCbmPQ-pp69-G2_J3cZZT82CJCK</recordid><startdate>19960815</startdate><enddate>19960815</enddate><creator>Chamberlin, M E</creator><creator>Ubagai, T</creator><creator>Mudd, S H</creator><creator>Wilson, W G</creator><creator>Leonard, J V</creator><creator>Chou, J Y</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19960815</creationdate><title>Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency</title><author>Chamberlin, M E ; Ubagai, T ; Mudd, S H ; Wilson, W G ; Leonard, J V ; Chou, J Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-13c65eef62de2221f958eb023dd35beeb87bc014080b052b10b28a9103509173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Adolescent</topic><topic>Amino Acid Metabolism, Inborn Errors - enzymology</topic><topic>Amino Acid Metabolism, Inborn Errors - genetics</topic><topic>Brain Diseases - enzymology</topic><topic>Brain Diseases - genetics</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromosomes, Human, Pair 10</topic><topic>Demyelinating Diseases - enzymology</topic><topic>Demyelinating Diseases - genetics</topic><topic>Female</topic><topic>Genes</topic><topic>Humans</topic><topic>Infant</topic><topic>Male</topic><topic>Methionine - metabolism</topic><topic>Methionine Adenosyltransferase - deficiency</topic><topic>Methionine Adenosyltransferase - genetics</topic><topic>Point Mutation</topic><topic>Polymorphism, Single-Stranded Conformational</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chamberlin, M E</creatorcontrib><creatorcontrib>Ubagai, T</creatorcontrib><creatorcontrib>Mudd, S H</creatorcontrib><creatorcontrib>Wilson, W G</creatorcontrib><creatorcontrib>Leonard, J V</creatorcontrib><creatorcontrib>Chou, J Y</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chamberlin, M E</au><au>Ubagai, T</au><au>Mudd, S H</au><au>Wilson, W G</au><au>Leonard, J V</au><au>Chou, J Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>1996-08-15</date><risdate>1996</risdate><volume>98</volume><issue>4</issue><spage>1021</spage><epage>1027</epage><pages>1021-1027</pages><issn>0021-9738</issn><abstract>Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most individuals with isolated hypermethioninemia have been free of major clinical difficulties. Therefore a definitive diagnosis of MAT I/III deficiency, which requires hepatic biopsy, is not routinely made. However, two individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious. In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, including the two with demyelination of the brain. Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eight individuals. Both patients with demyelination are homozygous for mutations that alter the reading frame of the encoded protein such that the predicted MATalpha1 subunits are truncated and enzymatically inactive. The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds including the two major myelin phospholipids, phosphatidylcholine and sphingomyelin. Both are synthesized primarily in the liver. Our findings demonstrate that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities. Therefore, a DNA-based diagnosis should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifestations is warranted.</abstract><cop>United States</cop><pmid>8770875</pmid><doi>10.1172/JCI118862</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-9738
ispartof The Journal of clinical investigation, 1996-08, Vol.98 (4), p.1021-1027
issn 0021-9738
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_507518
source PubMed Central; EZB Electronic Journals Library
subjects Adolescent
Amino Acid Metabolism, Inborn Errors - enzymology
Amino Acid Metabolism, Inborn Errors - genetics
Brain Diseases - enzymology
Brain Diseases - genetics
Child
Child, Preschool
Chromosomes, Human, Pair 10
Demyelinating Diseases - enzymology
Demyelinating Diseases - genetics
Female
Genes
Humans
Infant
Male
Methionine - metabolism
Methionine Adenosyltransferase - deficiency
Methionine Adenosyltransferase - genetics
Point Mutation
Polymorphism, Single-Stranded Conformational
title Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T22%3A18%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Demyelination%20of%20the%20brain%20is%20associated%20with%20methionine%20adenosyltransferase%20I/III%20deficiency&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Chamberlin,%20M%20E&rft.date=1996-08-15&rft.volume=98&rft.issue=4&rft.spage=1021&rft.epage=1027&rft.pages=1021-1027&rft.issn=0021-9738&rft_id=info:doi/10.1172/JCI118862&rft_dat=%3Cproquest_pubme%3E15784457%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c400t-13c65eef62de2221f958eb023dd35beeb87bc014080b052b10b28a9103509173%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=15784457&rft_id=info:pmid/8770875&rfr_iscdi=true