Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain...

Descripción completa

Detalles Bibliográficos
Autores principales: Zinnanti, William J., Lazovic, Jelena, Griffin, Kathleen, Skvorak, Kristen J., Paul, Harbhajan S., Homanics, Gregg E., Bewley, Maria C., Cheng, Keith C., LaNoue, Kathryn F., Flanagan, John M.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668944/
https://www.ncbi.nlm.nih.gov/pubmed/19293241
http://dx.doi.org/10.1093/brain/awp024
_version_ 1782166220305334272
author Zinnanti, William J.
Lazovic, Jelena
Griffin, Kathleen
Skvorak, Kristen J.
Paul, Harbhajan S.
Homanics, Gregg E.
Bewley, Maria C.
Cheng, Keith C.
LaNoue, Kathryn F.
Flanagan, John M.
author_facet Zinnanti, William J.
Lazovic, Jelena
Griffin, Kathleen
Skvorak, Kristen J.
Paul, Harbhajan S.
Homanics, Gregg E.
Bewley, Maria C.
Cheng, Keith C.
LaNoue, Kathryn F.
Flanagan, John M.
author_sort Zinnanti, William J.
collection PubMed
description Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.
format Text
id pubmed-2668944
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-26689442009-04-20 Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease Zinnanti, William J. Lazovic, Jelena Griffin, Kathleen Skvorak, Kristen J. Paul, Harbhajan S. Homanics, Gregg E. Bewley, Maria C. Cheng, Keith C. LaNoue, Kathryn F. Flanagan, John M. Brain Original Articles Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress. Oxford University Press 2009-04 2009-03-17 /pmc/articles/PMC2668944/ /pubmed/19293241 http://dx.doi.org/10.1093/brain/awp024 Text en © 2009 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zinnanti, William J.
Lazovic, Jelena
Griffin, Kathleen
Skvorak, Kristen J.
Paul, Harbhajan S.
Homanics, Gregg E.
Bewley, Maria C.
Cheng, Keith C.
LaNoue, Kathryn F.
Flanagan, John M.
Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title_full Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title_fullStr Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title_full_unstemmed Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title_short Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
title_sort dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668944/
https://www.ncbi.nlm.nih.gov/pubmed/19293241
http://dx.doi.org/10.1093/brain/awp024
work_keys_str_mv AT zinnantiwilliamj dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT lazovicjelena dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT griffinkathleen dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT skvorakkristenj dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT paulharbhajans dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT homanicsgregge dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT bewleymariac dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT chengkeithc dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT lanouekathrynf dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease
AT flanaganjohnm dualmechanismofbraininjuryandnoveltreatmentstrategyinmaplesyrupurinedisease