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HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase
Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance...
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| Published in: | Orphanet journal of rare diseases 2013-12, Vol.8 (1), p.188-188, Article 188 |
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| creator | Ferdinandusse, Sacha Waterham, Hans R Heales, Simon J R Brown, Garry K Hargreaves, Iain P Taanman, Jan-Willem Gunny, Roxana Abulhoul, Lara Wanders, Ronald J A Clayton, Peter T Leonard, James V Rahman, Shamima |
| description | Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.
Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.
Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G |
| doi_str_mv | 10.1186/1750-1172-8-188 |
| format | article |
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Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.
Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.
HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.</description><identifier>ISSN: 1750-1172</identifier><identifier>EISSN: 1750-1172</identifier><identifier>DOI: 10.1186/1750-1172-8-188</identifier><identifier>PMID: 24299452</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Brain ; Care and treatment ; Child ; Child, Preschool ; Defects ; Dehydrogenases ; Disease ; Enzymes ; Gene mutations ; Genetic aspects ; Health aspects ; Hospitals ; Humans ; Infant ; Infant, Newborn ; Ketone Oxidoreductases - deficiency ; Ketone Oxidoreductases - genetics ; Leigh disease ; Leigh Disease - enzymology ; Leigh Disease - genetics ; Male ; Mass spectrometry ; Medical equipment and supplies industry ; Medical research ; Medical test kit industry ; Metabolic disorders ; Metabolites ; Mitochondrial Diseases - enzymology ; Mitochondrial Diseases - genetics ; Mitochondrial DNA ; Mutation ; NMR ; Nuclear magnetic resonance ; Patients ; Physiological aspects ; Pyruvate dehydrogenase complex ; Rare diseases ; Risk factors ; Siblings ; Studies ; Thiolester Hydrolases - genetics</subject><ispartof>Orphanet journal of rare diseases, 2013-12, Vol.8 (1), p.188-188, Article 188</ispartof><rights>COPYRIGHT 2013 BioMed Central Ltd.</rights><rights>2013 Ferdinandusse et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2013 Ferdinandusse et al.; licensee BioMed Central Ltd. 2013 Ferdinandusse et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b581t-a711788055c0500d5f6533f9a5880e5add1ebc5f51149348e61653e5b78139513</citedby><cites>FETCH-LOGICAL-b581t-a711788055c0500d5f6533f9a5880e5add1ebc5f51149348e61653e5b78139513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222069/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1467592340?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,25783,27957,27958,37047,37048,44625,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24299452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferdinandusse, Sacha</creatorcontrib><creatorcontrib>Waterham, Hans R</creatorcontrib><creatorcontrib>Heales, Simon J R</creatorcontrib><creatorcontrib>Brown, Garry K</creatorcontrib><creatorcontrib>Hargreaves, Iain P</creatorcontrib><creatorcontrib>Taanman, Jan-Willem</creatorcontrib><creatorcontrib>Gunny, Roxana</creatorcontrib><creatorcontrib>Abulhoul, Lara</creatorcontrib><creatorcontrib>Wanders, Ronald J A</creatorcontrib><creatorcontrib>Clayton, Peter T</creatorcontrib><creatorcontrib>Leonard, James V</creatorcontrib><creatorcontrib>Rahman, Shamima</creatorcontrib><title>HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase</title><title>Orphanet journal of rare diseases</title><addtitle>Orphanet J Rare Dis</addtitle><description>Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.
Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.
Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.
HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.</description><subject>Brain</subject><subject>Care and treatment</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Defects</subject><subject>Dehydrogenases</subject><subject>Disease</subject><subject>Enzymes</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Ketone Oxidoreductases - deficiency</subject><subject>Ketone Oxidoreductases - genetics</subject><subject>Leigh disease</subject><subject>Leigh Disease - enzymology</subject><subject>Leigh Disease - genetics</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Medical equipment and supplies industry</subject><subject>Medical research</subject><subject>Medical test kit industry</subject><subject>Metabolic disorders</subject><subject>Metabolites</subject><subject>Mitochondrial Diseases - enzymology</subject><subject>Mitochondrial Diseases - genetics</subject><subject>Mitochondrial DNA</subject><subject>Mutation</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Pyruvate dehydrogenase complex</subject><subject>Rare diseases</subject><subject>Risk factors</subject><subject>Siblings</subject><subject>Studies</subject><subject>Thiolester Hydrolases - genetics</subject><issn>1750-1172</issn><issn>1750-1172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNp1kk1v1DAQhiMEoqVw5oYscSmHtHYSJ84Fqa2AXWklJD7OluNMNi6JvdhOIfwOfjCz2rLaRUWWZWv8zDv2vE6Sl4xeMCbKS1ZxmjJWZalImRCPktN95PHB_iR5FsItpQXPqXianGRFVtcFz06T34vl9c2CjFNU0TgbiFYW5xSArMCs-3Qw34C0JoDC0A8Te6Ld2BgLLWmhM9qA1TNxHUoM0WwGIKOJTvfOtt6ogXgIG-NVdH4mulfGErC_5hECUbYlm9lPdypiBejn1rs1WKzzPHnSqSHAi_v1LPn6_t2Xm0W6-vhheXO1ShsuWExVhW8TgnKuKae05V3J87yrFccgcNW2DBrNO85YUeeFgJIhALypBMtrzvKz5O1OdzM1I7QabPRqkBtvRuVn6ZSRxyfW9HLt7mSRZRktaxS43gk0xv1H4PgEeye3rsitK1JI9AxFzu9v4d33CUKUowkahkFZcFOQeHla5TTPKKKv_0Fv3eQt9gipsuJ1lhcH1FoNII3tHNbWW1F5xfOiKouMcaQuHqBwtDAa7Syai_GjhDdHCchE-BnX-FmCXH7-dMxe7ljtXQgeun1P2PbtonygC68Ovdjzf79q_gdF1Oln</recordid><startdate>20131204</startdate><enddate>20131204</enddate><creator>Ferdinandusse, Sacha</creator><creator>Waterham, Hans R</creator><creator>Heales, Simon J R</creator><creator>Brown, Garry K</creator><creator>Hargreaves, Iain P</creator><creator>Taanman, Jan-Willem</creator><creator>Gunny, Roxana</creator><creator>Abulhoul, Lara</creator><creator>Wanders, Ronald J A</creator><creator>Clayton, Peter T</creator><creator>Leonard, James V</creator><creator>Rahman, Shamima</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><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>ISR</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20131204</creationdate><title>HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase</title><author>Ferdinandusse, Sacha ; Waterham, Hans R ; Heales, Simon J R ; Brown, Garry K ; Hargreaves, Iain P ; Taanman, Jan-Willem ; Gunny, Roxana ; Abulhoul, Lara ; Wanders, Ronald J A ; Clayton, Peter T ; Leonard, James V ; Rahman, Shamima</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b581t-a711788055c0500d5f6533f9a5880e5add1ebc5f51149348e61653e5b78139513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Brain</topic><topic>Care and treatment</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Defects</topic><topic>Dehydrogenases</topic><topic>Disease</topic><topic>Enzymes</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Ketone Oxidoreductases - deficiency</topic><topic>Ketone Oxidoreductases - genetics</topic><topic>Leigh disease</topic><topic>Leigh Disease - enzymology</topic><topic>Leigh Disease - genetics</topic><topic>Male</topic><topic>Mass spectrometry</topic><topic>Medical equipment and supplies industry</topic><topic>Medical research</topic><topic>Medical test kit industry</topic><topic>Metabolic disorders</topic><topic>Metabolites</topic><topic>Mitochondrial Diseases - enzymology</topic><topic>Mitochondrial Diseases - genetics</topic><topic>Mitochondrial DNA</topic><topic>Mutation</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Patients</topic><topic>Physiological aspects</topic><topic>Pyruvate dehydrogenase complex</topic><topic>Rare diseases</topic><topic>Risk factors</topic><topic>Siblings</topic><topic>Studies</topic><topic>Thiolester Hydrolases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferdinandusse, Sacha</creatorcontrib><creatorcontrib>Waterham, Hans R</creatorcontrib><creatorcontrib>Heales, Simon J R</creatorcontrib><creatorcontrib>Brown, Garry K</creatorcontrib><creatorcontrib>Hargreaves, Iain P</creatorcontrib><creatorcontrib>Taanman, Jan-Willem</creatorcontrib><creatorcontrib>Gunny, Roxana</creatorcontrib><creatorcontrib>Abulhoul, Lara</creatorcontrib><creatorcontrib>Wanders, Ronald J A</creatorcontrib><creatorcontrib>Clayton, Peter T</creatorcontrib><creatorcontrib>Leonard, James V</creatorcontrib><creatorcontrib>Rahman, Shamima</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Orphanet journal of rare diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferdinandusse, Sacha</au><au>Waterham, Hans R</au><au>Heales, Simon J R</au><au>Brown, Garry K</au><au>Hargreaves, Iain P</au><au>Taanman, Jan-Willem</au><au>Gunny, Roxana</au><au>Abulhoul, Lara</au><au>Wanders, Ronald J A</au><au>Clayton, Peter T</au><au>Leonard, James V</au><au>Rahman, Shamima</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase</atitle><jtitle>Orphanet journal of rare diseases</jtitle><addtitle>Orphanet J Rare Dis</addtitle><date>2013-12-04</date><risdate>2013</risdate><volume>8</volume><issue>1</issue><spage>188</spage><epage>188</epage><pages>188-188</pages><artnum>188</artnum><issn>1750-1172</issn><eissn>1750-1172</eissn><notes>ObjectType-Case Study-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-4</notes><notes>content type line 23</notes><notes>ObjectType-Report-1</notes><notes>ObjectType-Article-3</notes><abstract>Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.
Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.
Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.
HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>24299452</pmid><doi>10.1186/1750-1172-8-188</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Brain Care and treatment Child Child, Preschool Defects Dehydrogenases Disease Enzymes Gene mutations Genetic aspects Health aspects Hospitals Humans Infant Infant, Newborn Ketone Oxidoreductases - deficiency Ketone Oxidoreductases - genetics Leigh disease Leigh Disease - enzymology Leigh Disease - genetics Male Mass spectrometry Medical equipment and supplies industry Medical research Medical test kit industry Metabolic disorders Metabolites Mitochondrial Diseases - enzymology Mitochondrial Diseases - genetics Mitochondrial DNA Mutation NMR Nuclear magnetic resonance Patients Physiological aspects Pyruvate dehydrogenase complex Rare diseases Risk factors Siblings Studies Thiolester Hydrolases - genetics |
| title | HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase |
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