TY  - CHAP
M1  - Book, Section
TI  - Inborn Errors of Ketone Body Metabolism
A1  - Mitchell, Grant A.
A1  - Fukao, Toshiyuki
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.130
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  ketone  bodies  acetoacetate  (AcAc)  and  R-3-hydroxybutyrate  (3HB)  are  important  vectors  of  energy  transport  from  hepatocyte  mitochondria  to  extrahepatic  tissues  during  fasting  and  other  lipolytic  stress.  AcAc  is  the  product  of  ketogenesis  and  the  substrate  for  ketolysis.  3HB  is  derived  from  AcAc.  A  third  compound,  acetone,  arises  from  decarboxylation  of  AcAc  and  accounts  for  the  distinct  odor  of  ketotic  individuals.Ketogenesis  is  fueled  by  fatty  acids  or  ketogenic  amino  acids,  principally  leucine.  Two  mitochondrial  enzymes  mediate  ketogenesis  from  fatty  acids:  mitochondrial  HMG-CoA  synthase  (mHS)  and  HMG-CoA  lyase  (HL).  Circulating  levels  of  ketone  bodies  fluctuate  greatly  with  age,  nutrition,  lipolytic  stress,  and  other  factors.Ketolysis  occurs  in  mitochondria  of  extrahepatic  tissues,  particularly  heart,  kidney,  and  brain,  via  reversible  reactions  catalyzed  by  succinyl-CoA:  3-ketoacid  CoA  transferase  (SCOT)  and  mitochondrial  AcAc-CoA  thiolase  (T2).  Ketolytic  rate  is  determined  by  the  circulating  concentration  of  ketone  bodies.  The  ketolytic  capacity  of  tissues  is  proportional  to  their  level  of  SCOT  activity.Inborn  errors  of  ketogenesis  (mHS  or  HL  deficiencies)  cause  episodes  of  hypoketotic  hypoglycemia,  often  with  coma.  Ketolytic  (T2  or  SCOT)  deficiencies  cause  episodes  of  ketoacidosis.  All  four  disorders  are  autosomal  recessive.  Infancy  is  the  period  of  highest  risk  for  decompensation.  Death  or  neurologic  complications  can  occur,  but  with  early  diagnosis  and  treatment,  many  patients  are  clinically  normal.  The  mainstay  of  treatment  in  these  disorders  is  suppression  of  ketogenesis.  Enzyme  and  molecular  diagnosis  is  possible  for  each  of  these  conditions.mHS  undergoes  intricate  transcriptional  and  posttranscriptional  regulation  to  control  the  rate  of  ketogenesis.  In  mHS  deficiency,  the  urinary  organic  acid  pattern  is  not  diagnostic.  Diagnosis  depends  upon  enzyme  assay  in  liver  and/or  molecular  studies.HL  is  located  in  mitochondria  and  peroxisomes  of  all  tissues  studied  to  date.  HL  deficiency  is  characterized  by  high  levels  of  3-hydroxy-3-methylglutaric  acid  (HMG)  and  related  leucine  metabolites  in  urine.  Enzymatic  confirmation  is  recommended,  since  rare  patients  excrete  these  compounds  but  have  normal  HL  activity.  Mental  retardation,  epilepsy,  and  white  matter  changes  may  occur  following  hypoglycemic  episodes.SCOT  is  extrahepatic  in  distribution.  The  ketolytic  capacity  of  tissues  is  proportional  to  their  levels  of  SCOT  activity.  In  SCOT  deficiency,  ketoacidosis  develops  rapidly  on  fasting  and  ketonuria  is  often  present  in  the  fed  state.  Urine  organic  acids  show  only  a  nonspecific  increase  of  AcAc  and  3HB.T2  functions  in  both  ketolysis  and  ketogenesis.  T2  deficiency  presents  as  infantile  ketoacidosis.  Coma  and  basal  ganglia  abnormalities  may  occur.  A  diagnostic  metabolite  profile  including  2-methyl-3HB,  2-methylAcAc  and  tiglylglycine  is  present  in  most  patients.3HB  dehydrogenase  (3HBD)  catalyzes  the  reversible  reduction  of  AcAc  to  3HB,  functioning  in  both  ketogenesis  and  ketolysis.  3HBD  deficiency  has  not  been  described.A  distinct  cytoplasmic  AcAc-CoA  thiolase  (CT)  functions  in  lipogenesis  and  cholesterol  synthesis.  It  was  reportedly  deficient  in  two  girls  with  progressive  mental  retardation.  Enzyme  and  molecular  diagnosis  is  possible.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.130
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181439262
ER  -