TY  - CHAP
M1  - Book, Section
TI  - Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism
A1  - Webster, Dianne R.
A1  - Becroft, David M. O.
A1  - van Gennip, Albert H.
A1  - Van Kuilenburg, André B. P.
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  - Pyrimidines  and  purines  are  the  building  blocks  of  DNA  and  RNA  and  are  thus  required  for  the  retention  and  transmission  of  genetic  information.  In  addition  they  function  in  the  formation  of  coenzymes  and  active  intermediates  in  carbohydrate  and  phospholipid  metabolism.  Purines  and  pyrimidines  have  two  routes  for  nucleotide  formation,  the  de  novo  pathway,  which  begins  with  ribose  phosphate,  amino  acids,  CO2,  and  ammonia;  and  the  salvage  pathway,  which  takes  free  bases  and  nucleosides  back  to  nucleotides.  De  novo  and  salvage  pathways  are  balanced  and  connected  through  the  enzymes,  which  degrade  the  nucleotides  to  β-amino  acids,  CO2,  and  ammonia.In  contrast  to  the  well-known  defects  of  purine  metabolism,  most  of  the  seven  defects  of  pyrimidine  metabolism  are  recently  discovered:  hereditary  orotic  aciduria  (UMP  synthase  deficiency;  MIM  25890,  25892),  pyrimidine  5′-nucleotidase  deficiency  (MIM  26612),  dihydropyrimidine  dehydrogenase  deficiency  (MIM  27427),  dihydropyrimidinase  (dihydropyrimidinuria,  MIM),  ureidopropionase  deficiency,  thymidine  phosphorylase  deficiency,  and  pyrimidine  5′-superactivity.  Purine  metabolism  has  an  easily  recognizable,  easily  measurable  endpoint  in  uric  acid.  There  is  no  equivalent  compound  in  pyrimidine  metabolism.The  first  defect,  hereditary  orotic  aciduria,  is  in  the  de  novo  synthetic  pathway.  This  autosomal  recessive  disorder  results  from  a  severe  deficiency  of  the  last  two  activities  in  the  pathway,  orotate  phosphoribosyltransferase  and  orotidine-5′-monophosphate  decarboxylase.  Although  orotic  aciduria  was  thought  to  be  unique  because  of  the  loss  of  two  enzymes,  it  is  now  known  that  these  activities  reside  in  separate  domains  of  a  single  polypeptide  coded  by  a  single  gene.  This  bifunctional  protein,  uridine-5′-monophosphate  synthase,  has  been  purified,  the  amino  acid  sequence  determined  by  cDNA  sequencing,  and  the  gene  localized  to  chromosome  3q13.  Two  point  mutations  resulting  in  amino  acid  substitutions  and  loss  of  enzyme  activity  have  been  identified  in  one  orotic  aciduria  patient.There  are  15  known  patients  with  hereditary  orotic  aciduria.  All  have  had  a  macrocytic  hypochromic  megaloblastic  anemia  and  orotic  acid  crystalluria.  Thirteen  have  been  treated  with  uridine  with  good  effect  in  the  majority.  Five  young  adults  remain  well  but  require  continued  therapy.  One  adult  has  not  received  uridine  therapy  and  is  well  despite  persisting  anemia.  Other  features  have  included  renal  tract  obstruction  by  crystals,  cardiac  malformations,  and  strabismus.  Infections  have  been  a  problem  in  some,  associated  with  various  abnormalities  of  in  vitro  tests  of  immune  function.  One  patient  had  severe  congenital  abnormalities.  Mild  intellectual  impairment  has  been  an  inconstant  feature  prior  to  treatment.  The  progressive  neurologic  deterioration  in  one  young  adult  may  be  unrelated  to  the  metabolic  error.The  other  disorders  involve  defects  in  the  pyrimidine  degradative  pathway.  Deficiency  of  pyrimidine-5′-nucleotidase  causes  hemolytic  anemia,  possibly  due  to  accumulation  in  erythrocytes  of  pyrimidine  nucleotides,  mostly  uridine  triphosphate  (UTP)  and  cytidine  triphosphate  (CTP).  The  disorder  is  transmitted  in  an  autosomal  recessive  manner,  and  there  is  no  specific  treatment  available.  Pyrimidine  5′-nucleotidase  superactivity  has  been  described  in  four  unrelated  patients  with  developmental  delay  and  neurologic  abnormalities.  The  patients  were  treated  with  uridine  with  good  effect.  Deficiency  of  dihydropyrimidine  dehydrogenase  causes  an  increase  in  blood  and  urine  levels  of  uracil  and  thymine.  This  deficiency  is  detected  in  a  variety  of  clinical  situations  including  pediatric  metabolic  screens  for  neurologic  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/24
UR  - ommbid.mhmedical.com/content.aspx?aid=1181441759
ER  -