Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency

The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition wh...

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Autores: knerr, Ina, Colombo, Roberto, Urquhart, Jill, Morais, Ana, Merinero, Begoña, Oyarzábal, Alfonso, Pérez, Belén, Jones, Simon A., Perveen, Rahat, Preece, Mary A., Rogers, Yvonne, Treacy, Eileen P., Mayne, Philip, Zampino, Giuseppe, MacKinnon, Sabrina, Wassmer, Evangeline, Yue, Wyatt W., Robinson, Ian, Rodríguez-Pombo, Pilar, Olpin, Simon E., Banka, Siddharth
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2019
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/219551
Acesso em linha:http://hdl.handle.net/10261/219551
Access Level:Acceso aberto
Palavra-chave:Autism spectrum disorder
BCAT2
Branched-chain amino acids
Branched-chain amino transferase 2
Encephalopathy
maple syrup urine disease.
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spelling Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiencyknerr, InaColombo, RobertoUrquhart, JillMorais, AnaMerinero, BegoñaOyarzábal, AlfonsoPérez, BelénJones, Simon A.Perveen, RahatPreece, Mary A.Rogers, YvonneTreacy, Eileen P.Mayne, PhilipZampino, GiuseppeMacKinnon, SabrinaWassmer, EvangelineYue, Wyatt W.Robinson, IanRodríguez-Pombo, PilarOlpin, Simon E.Banka, SiddharthAutism spectrum disorderBCAT2Branched-chain amino acidsBranched-chain amino transferase 2Encephalopathymaple syrup urine disease.The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.Fundación Isabel Gemio; MINECO-FEDER; Fondo Europeo de Desarrollo Regional, Grant/Award Number: PI12/02078; Ministerio de Economía y CompetitividadKluwer Academic PublishersFundación Isabel GemioMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/219551reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1002/jimd.12135Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2195512026-05-22T06:33:51Z
dc.title.none.fl_str_mv Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
title Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
spellingShingle Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
knerr, Ina
Autism spectrum disorder
BCAT2
Branched-chain amino acids
Branched-chain amino transferase 2
Encephalopathy
maple syrup urine disease.
title_short Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
title_full Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
title_fullStr Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
title_full_unstemmed Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
title_sort Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency
dc.creator.none.fl_str_mv knerr, Ina
Colombo, Roberto
Urquhart, Jill
Morais, Ana
Merinero, Begoña
Oyarzábal, Alfonso
Pérez, Belén
Jones, Simon A.
Perveen, Rahat
Preece, Mary A.
Rogers, Yvonne
Treacy, Eileen P.
Mayne, Philip
Zampino, Giuseppe
MacKinnon, Sabrina
Wassmer, Evangeline
Yue, Wyatt W.
Robinson, Ian
Rodríguez-Pombo, Pilar
Olpin, Simon E.
Banka, Siddharth
author knerr, Ina
author_facet knerr, Ina
Colombo, Roberto
Urquhart, Jill
Morais, Ana
Merinero, Begoña
Oyarzábal, Alfonso
Pérez, Belén
Jones, Simon A.
Perveen, Rahat
Preece, Mary A.
Rogers, Yvonne
Treacy, Eileen P.
Mayne, Philip
Zampino, Giuseppe
MacKinnon, Sabrina
Wassmer, Evangeline
Yue, Wyatt W.
Robinson, Ian
Rodríguez-Pombo, Pilar
Olpin, Simon E.
Banka, Siddharth
author_role author
author2 Colombo, Roberto
Urquhart, Jill
Morais, Ana
Merinero, Begoña
Oyarzábal, Alfonso
Pérez, Belén
Jones, Simon A.
Perveen, Rahat
Preece, Mary A.
Rogers, Yvonne
Treacy, Eileen P.
Mayne, Philip
Zampino, Giuseppe
MacKinnon, Sabrina
Wassmer, Evangeline
Yue, Wyatt W.
Robinson, Ian
Rodríguez-Pombo, Pilar
Olpin, Simon E.
Banka, Siddharth
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Isabel Gemio
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Autism spectrum disorder
BCAT2
Branched-chain amino acids
Branched-chain amino transferase 2
Encephalopathy
maple syrup urine disease.
topic Autism spectrum disorder
BCAT2
Branched-chain amino acids
Branched-chain amino transferase 2
Encephalopathy
maple syrup urine disease.
description The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/219551
url http://hdl.handle.net/10261/219551
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1002/jimd.12135
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Kluwer Academic Publishers
publisher.none.fl_str_mv Kluwer Academic Publishers
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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