TY  - CHAP
M1  - Book, Section
TI  - Lactic Acidemia: Disorders of Pyruvate Carboxylase and Pyruvate Dehydrogenase
A1  - Robinson, Brian H.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  lactic  acid  that  circulates  in  the  human  body  is  the  product  of  the  anaerobic  metabolism  of  glucose,  which  takes  place  primarily  in  red  cells,  skin,  kidney  medulla,  and  white  skeletal  muscle.  Some  of  it  is  oxidized  by  red  muscle  and  kidney  cortex,  but  the  bulk  of  it  is  taken  up  by  the  liver  and  made  into  glucose.  Lactate  is  always  produced  by  reduction  of  pyruvate  through  lactate  dehydrogenase  and  is  always  removed  by  a  reversal  of  this  process.  Deficiency  of  both  the  H  and  the  M  subunit  forms  of  lactate  dehydrogenase  are  known,  but  they  are  relatively  benign  conditions.  The  oxidative  metabolism  of  pyruvate  proceeds  through  pyruvate  dehydrogenase,  the  Krebs  cycle,  and  the  respiratory  chain,  whereas  anabolic  utilization  proceeds  primarily  through  pyruvate  carboxylase.  A  defect  in  any  of  these  pathways  may  lead  to  inadequate  removal  of  pyruvate  and  lactate  from  the  circulation,  resulting  in  a  condition  of  lactic  acidemia.Deficiency  of  the  pyruvate  dehydrogenase  complex  is  the  most  common  of  the  disorders  leading  to  lactic  acidemia.  It  may  be  due  to  a  defect  in  the  E1  (MIM  312170),  E2  (MIM  245348),  E3  (MIM  246900),  X-lipoate  (MIM  245349),  or  pyruvate  dehydrogenase  phosphatase  component  of  the  complex.  The  most  common  of  these  is  the  defect  in  the  E1  component.  This  particular  defect  can  present  in  three  possible  ways  with  a  graded  spectrum  from  the  most  severe  to  the  least.  In  its  most  severe  form,  it  presents  with  overwhelming  lactic  acidosis  at  birth,  with  death  in  the  neonatal  period.  In  a  second  form  of  presentation,  the  lactic  acidemia  is  moderate,  but  there  is  profound  psychomotor  retardation  with  increasing  age  and,  in  many  cases,  concomitant  damage  to  the  brain  stem  and  basal  ganglia  lead  to  death  in  infancy.  In  the  third  form  of  presentation,  which  is  found  only  in  males,  there  is  carbohydrate-induced  episodic  ataxia,  very  often  coupled  with  mild  developmental  delay.The  E1  defects  are  caused  by  mutations  in  the  E1α  gene  which  is  X-linked  (MIM  312170).  Because  of  its  central  importance  in  central  nervous  system  metabolism,  pyruvate  dehydrogenase  deficiency  is  a  problem  both  in  males  and  in  females  even  though  only  one  E1α  allele  in  the  females  carries  a  mutation.  For  this  reason,  this  form  of  pyruvate  dehydrogenase  complex  deficiency  should  be  classified  as  X-linked  dominant.  Most  defects  in  the  E1α  gene  are  de  novo  mutations  and  are  not  carried  somatically  by  either  parent.  In  males,  the  defects  are  either  missense  mutations  or  mutations  that  affect  only  the  3′  end  of  the  coding  sequence.  In  females,  deletions  and  insertions  that  completely  nullify  one  allele  are  more  common.  The  E2  (MIM  245348)  and  protein  X-lipoate  (MIM  245349)  defects  are  rare  and  result  in  severe  psychomotor  retardation.  A  group  of  X-deficient  patients  has  been  characterized  at  the  molecular  level.The  E3  lipoamide  dehydrogenase  defect  (MIM  246900)  leads  to  deficient  activity  not  only  in  the  pyruvate  dehydrogenase  complex,  but  also  in  the  α-ketoglutarate  and  branched  chain  ketoacid  dehydrogenase  complexes.  Pyruvate  dehydrogenase  phosphatase  deficiency  has  been  documented  in  four  patients,  three  of  them  presenting  with  Leigh  disease  and  the  fourth  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/23
UR  - ommbid.mhmedical.com/content.aspx?aid=1181438297
ER  -