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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...
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Published in: | The Journal of clinical investigation 1996-08, Vol.98 (4), p.1021-1027 |
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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. |
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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> |
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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 |
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