TY  - CHAP
M1  - Book, Section
TI  - Pyruvate Kinase Deficiency and Other Enzymopathies of the Erythrocyte
A1  - Hirono, Akira
A1  - Kanno, Hitoshi
A1  - Miwa, Shiro
A1  - Beutler, Ernest
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  - Pyruvate  kinase  (PK)  deficiency  (MIM  266200)  is  the  most  common  enzyme  deficiency  resulting  in  hereditary  hemolytic  anemia.  The  disorder  has  a  worldwide  distribution  and  is  characterized  clinically  by  lifelong  chronic  hemolysis  of  variable  severity.  Splenectomy  often  results  in  amelioration  of  the  hemolytic  process  in  more  severely  affected  patients,  but  is  less  effective  in  milder  cases.  Defective  PK  catalysis  in  affected  erythrocytes  generally  results  in  elevated  concentrations  of  2,3-diphosphoglycerate  (2,3-DPG)  and  decreased  ATP  levels  relative  to  cells  of  comparable  age.PK  is  encoded  by  two  genes,  gene  symbol  for  PK  locus  encoding  L  and  R  isozymes  (PKLR)  and  gene  symbol  for  PK  locus  encoding  M  isozymes  (PKM).  PKLR  is  expressed  in  the  liver  and  in  red  cells;  different  splice  forms  are  found  in  liver  and  in  erythrocytes.  PKM  is  expressed  in  muscle,  leukocytes,  and  many  other  tissues.  Allosteric  (M2)  and  nonallosteric  (M1)  splice  forms  of  PKM  exist.  The  erythrocyte  enzyme  deficiency  is  due  to  mutations  of  the  PKLR  gene.  Many  different  mutations  have  been  identified,  but  more  than  one-half  of  the  PK  deficiency  mutations  among  Europeans  are  1529G→A  (Arg510Gln).  PK  deficiency  is  inherited  as  an  autosomal  recessive  disorder.  The  red  cells  of  heterozygotes  usually  have  40  to  60  percent  of  the  PK  activity  of  normal  red  cells,  and  heterozygotes  are  almost  always  clinically  normal.Deficiencies  of  other  red  cell  glycolytic  enzymes  are  less  common  than  is  PK  deficiency.  Severe  deficiencies  of  hexokinase  (MIM  235700),  glucosephosphate  isomerase  (GPI)  (MIM  172400),  phosphofructokinase  (PFK)  (MIM  171850),  aldolase  (MIM  103850),  triosephosphate  isomerase  (TPI)  (MIM  190450),  phosphoglycerate  kinase  (PGK)  (MIM  311800),  bisphosphoglycerate  mutase/phosphatase  (BPGM/BPGP)  (MIM  222800),  and  lactate  dehydrogenase  (LDH)  (MIM  150100)  have  been  documented,  and  in  most  cases,  mutations  have  been  identified  at  the  DNA  level.  All  of  these  enzyme  deficiencies  are  autosomal  except  for  PGK,  which  is  X-linked.  Deficiencies  of  BPGM  and  bisphosphoglycerate  phosphatase  are  associated  with  mild  erythrocytosis  secondary  to  virtual  absence  of  2,3-DPG.  LDH  deficiency  is  also  not  associated  with  hemolysis,  but  in  one  form  there  is  myopathy.  All  others  are  associated  with  hemolytic  anemia  of  variable  severity  with  partial  response  to  splenectomy,  except  for  PFK  deficiency,  which  usually  has  a  compensated  hemolytic  process.GPI  deficiency  is  second  to  PK  deficiency  in  frequency;  all  tissues  have  decreased  GPI  activity,  but  clinical  manifestations  are  usually  limited  to  a  chronic  hemolytic  process,  although  in  some  instances,  mental  retardation  and  myopathy  may  occur.  In  PFK  deficiency  (glycogen  storage  disease  type  VII),  clinical  hallmarks  are  male  predominance  with  early  onset  gout,  compensated  hemolytic  process,  and  prominent  myopathy.  Severe  deficiency  of  aldolase  activity  has  been  documented  in  only  four  patients.  TPI  deficiency  is  clinically  usually  the  most  severe  of  the  enzymatic  defects  of  the  glycolytic  pathway;  it  is  characterized  by  multisystem  disease,  including  progressive  neurologic  dysfunction,  increased  susceptibility  to  infections,  cardiomyopathy,  and  death  usually  during  early  childhood.  All  body  tissues  investigated  are  deficient  in  TPI.  Hemolytic  anemia  and  a  variety  of  neurologic  abnormalities  most  frequently  accompany  PGK  deficiency  in  hemizygous  males;  the  phenotypic  picture  is  variable.  Heterozygous  females  may  exhibit  only  hemolytic  anemia  of  variable  degree  depending  on  random  X  inactivation.Glucose-6-phosphate  dehydrogenase  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181457229
ER  -