TY  - CHAP
M1  - Book, Section
TI  - Maple Syrup Urine Disease (Branched-Chain Ketoaciduria)
A1  - Chuang, David T.
A1  - Shih, Vivian E.
A1  - Max Wynn, R.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/Ommbid.400
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Maple  syrup  urine  disease  (MSUD)  or  branched-chain  ketoaciduria  is  caused  by  a  deficiency  in  activity  of  the  branched-chain  α-keto  acid  dehydrogenase  (BCKD)  complex.  This  metabolic  block  results  in  the  accumulation  of  the  branched-chain  amino  acids  (BCAAs)  leucine,  isoleucine,  and  valine,  and  the  corresponding  branched-chain  α-keto  acids  (BCKAs).  Based  on  the  clinical  presentation  and  biochemical  responses  to  thiamine  administration,  MSUD  patients  can  be  divided  into  five  phenotypes:  classic,  intermediate,  intermittent,  thiamine-responsive,  and  dihydrolipoyl  dehydrogenase  (E3)-deficient.  Classic  MSUD  has  a  neonatal  onset  of  encephalopathy  and  is  the  most  severe  and  most  common  form.  Variant  forms  of  MSUD  generally  have  the  initial  symptoms  by  2  years  of  age.  The  levels  of  the  BCAAs,  particularly  leucine,  are  greatly  increased  in  plasma  and  urine.  The  presence  of  alloisoleucine  is  diagnostic  of  MSUD.  Activity  of  the  BCKD  complex  in  skin  fibroblasts  or  lymphoblast  cultures  is  reduced,  and  ranges  from  less  than  2  percent  of  normal  in  the  classic  form  to  30  percent  of  normal  in  the  variant  forms.  The  E3-deficient  MSUD  presents  a  combined  deficiency  of  BCKD,  pyruvate  dehydrogenase,  and  α-ketoglutarate  dehydrogenase  complexes.  This  is  the  result  of  E3  being  a  common  component  of  the  three  mitochondrial  multienzymes.  An  animal  model  in  Polled  Hereford  calves  has  been  described.MSUD  is  an  autosomal  recessive  metabolic  disorder  of  panethnic  distribution.  The  worldwide  frequency  based  on  routine  screening  data  from  26.8  million  newborns  is  approximately  1  in  185,000.  In  the  inbred  Old  Order  Mennonite  population  of  Lancaster  and  Lebanon  Counties,  Pennsylvania,  MSUD  occurs  in  approximately  1  in  176  newborns.The  BCAAs  comprise  about  35  percent  of  the  indispensable  amino  acids  in  muscle,  and  40  percent  of  the  performed  amino  acids  required  by  mammals.  The  catabolic  pathways  for  BCAAs  begin  with  the  transport  of  these  amino  acids  into  cells  by  the  system  L  transporter  located  in  the  cytosolic  membrane.  Inside  the  cell,  BCAAs  undergo  reversible  transamination  by  the  cytosolic  or  mitochondrial  isoforms  of  the  branched-chain  amino  acid  aminotransferase  (BCAT)  in  the  respective  compartment  to  produce  the  BCKAs  α-ketoisocaproate  (KIC)  from  leucine,  α-keto-β-methylvalerate  (KMV)  from  isoleucine,  and  α-ketoisovalerate  (KIV)  from  valine.  BCKAs  synthesized  in  the  cytosol  are  translocated  by  the  specific  BCKA  transporter  into  mitochondria,  where  oxidative  decarboxylation  of  the  three  BCKAs  is  catalyzed  by  the  single  BCKD  multienzyme  complex.  These  reactions  generate  the  respective  branched-chain  acyl-CoAs  that  are  further  metabolized  via  separate  pathways.  The  end  products  of  leucine  catabolism  are  acetyl-CoA  and  acetoacetate.  BCAAs,  as  a  group,  are  both  ketogenic  and  glucogenic.  They  are  the  precursor  for  fatty  acids  and  cholesterol  synthesis  through  acetyl-CoA.  These  amino  acids  are  also  substrates  for  energy  production  via  succinyl-CoA  and  acetoacetate.The  oxidation  of  BCAAs  occurs  primarily  in  liver,  kidney  muscle,  heart,  brain,  and  adipose  tissue.  There  is  evidence  that  transamination  is  rate  limiting  in  the  catabolism  of  BCAAs  in  rat  liver,  where  BCAT  activity  is  low.  Based  on  the  rat  model,  a  significant  proportion  of  BCKAs  appears  to  originate  from  skeletal  muscle,  and  circulates  to  the  liver  where  it  is  oxidized.  However,  recent  studies  confirm  that  the  BCKD  complex  activity  in  human  liver  is  markedly  lower  than  that  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/Ommbid.400
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181435741
ER  -