RT Book, Section
A1 Sahota, Amrik S.
A1 Tischfield, Jay A.
A1 Kamatani, Naoyuki
A1 Anne Simmonds, H.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181440861
T1 Adenine Phosphoribosyltransferase Deficiency and 2,8-Dihydroxyadenine Lithiasis
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181440861
RD 2024/04/19
AB Adenine  phosphoribosyltransferase  (APRT)  catalyzes  the  synthesis  of  AMP  from  adenine  and  5-phosphoribosyl-1-pyrophosphate  (PP-ribose-P).  An  inherited  deficiency  of  this  enzyme  (MIM  1026000)  results  in  inability  to  utilize  adenine,  which,  in  the  absence  of  any  other  significant  pathway  of  metabolism  in  humans,  is  oxidized  by  xanthine  dehydrogenase  (XDH)  via  the  8-hydroxy  intermediate  to  2,8-dihydroxyadenine  (2,8-DHA).  2,8-DHA  is  extremely  insoluble,  and  its  accumulation  in  the  kidney  can  lead  to  crystalluria  and  the  formation  of  urinary  stones.  Adenine  and  2,8-DHA  are  secreted  by  the  human  kidney,  and  2,8-DHA  is  protein-bound  in  the  circulation.  Both  these  factors  tend  to  minimize  toxicity  in  tissues  other  than  the  kidney.  Administration  of  exogenous  adenine  itself  has  produced  2,8-DHA  nephrotoxicity  in  a  variety  of  animal  systems  and  also  in  humans  with  normal  APRT  activity  given  massive  transfusions  of  adenine-containing  blood.Clinical  symptoms,  which  include  renal  colic,  hematuria,  urinary  tract  infection,  and  dysuria,  are  due  to  2,8-DHA  stone  formation  or  crystalluria  and  may  be  present  from  birth.  Age  at  diagnosis  has  ranged  from  5  months  to  74  years,  and  approximately  60  percent  of  patients  have  been  male.  As  many  as  50  percent  of  APRT-deficient  individuals  may  be  asymptomatic.  Acute  renal  failure  may  occur  as  the  presenting  symptom  and  can  be  reversible.  Some  patients  have  developed  chronic  renal  failure,  requiring  dialysis  or  transplantation,  and  in  a  subset  of  these,  2,8-DHA  crystals  were  first  detected  during  biopsy  analysis  of  the  native  or  the  transplanted  kidney.  Homozygotes  do  not  show  any  evidence  of  immunodeficiency.Except  for  the  excretion  of  adenine  and  its  metabolites,  no  biochemical  abnormalities  have  been  recorded.  Purine  production  and  excretion  are  normal,  indicating  that,  unlike  the  companion  enzyme  hypoxanthine-guanine  phosphoribosyltransferase,  APRT  is  not  vital  for  the  overall  control  of  purine  metabolism  in  humans.  Adenine  metabolites  in  the  urine  account  for  20–30  percent  of  total  purine  excretion,  even  on  a  low-purine  diet.  The  main  source  of  endogenous  adenine  is  probably  polyamine  synthesis,  of  which  adenine  is  a  metabolic  byproduct.  Adenine-rich  foods  may  be  a  contributing  factor  in  precipitating  urolithiasis.Two  types  of  APRT  deficiency  have  been  recognized,  based  on  the  level  of  residual  enzyme  activity  in  erythrocyte  lysates.  Patients  with  type  I  deficiency  have  no  detectable  activity  in  erythrocyte  lysates.  Approximately  140  such  patients  have  been  identified  in  many  countries,  including  45  in  Japan.  These  patients  are  homozygotes  or  compound  heterozygotes  for  null  alleles.  Patients  with  type  II  deficiency  have  significant  enzyme  activity  (5–25  percent  of  wild-type  in  hemolysates)  and  have  been  found  only  in  Japan  to  date  (138  cases).  Approximately  75  percent  of  the  patients  in  Japan  have  the  type  II  defect.  The  type  II  enzyme  has  reduced  affinity  for  PP-ribose-P  compared  with  the  wild-type  enzyme.  In  both  types  of  deficiency,  APRT  activity  is  neither  demonstrable  in  intact  cells  nor  functional  in  vivo.  Intact  cells  are  resistant  to  the  toxic  effects  of  2,6-diaminopurine  (DAP)  and  other  adenine  analogues  that  depend  on  APRT  for  their  metabolism.APRT  deficiency  is  inherited  in  an  autosomal  recessive  manner.  The  frequency  of  heterozygosity  is  quite  high  (0.4–1.2  per  100),  but  the  number  of  identified  cases  is  smaller  than  expected,  especially  in  ...