TY  - CHAP
M1  - Book, Section
TI  - Primary Hyperoxaluria
A1  - Danpure, Christopher J.
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  term  primary  hyperoxaluria  includes  two  rare,  well-characterized  autosomal  recessive  diseases,  primary  hyperoxaluria  type  1  (PH1,  MIM  259900)  and  primary  hyperoxaluria  type  2  (PH2,  MIM  260000).  The  clinical  phenotype  of  PH1,  which  is  the  more  common  of  the  two,  is  one  of  progressive  renal  deposition  of  calcium  oxalate  (CaOx)  as  urolithiasis  and/or  nephrocalcinosis  leading  to  renal  failure.  Decreasing  renal  function  is  accompanied  by  increasing  deposition  of  CaOx  throughout  the  body  as  systemic  oxalosis.  In  PH2,  which  is  often  considered  to  be  a  milder  disease  than  PH1,  renal  failure  is  less  common.  At  the  biochemical  level,  PH1  is  characterized  by  concomitant  hyperoxaluria  and  hyperglycolic  aciduria  and  PH2  by  hyperoxaluria  and  hyper-L-glyceric  aciduria.PH1  is  caused  by  a  functional  deficiency  of  the  liver-specific  peroxisomal  enzyme  alanine:glyoxylate  aminotransferase  (AGT)  and  PH2  by  a  deficiency  of  the  cytosolic  enzyme  D-glycerate  dehydrogenase/glyoxylate  reductase  (DGDH/GR).  One-third  of  PH1  patients  have  significant  levels  of  AGT  catalytic  activity,  which  in  some  cases  is  similar  to  the  levels  found  in  asymptomatic  obligate  heterozygotes.  These  patients  have  disease  due  to  a  unique  intracellular  protein  trafficking  defect  in  which  AGT  is  erroneously  localized  to  the  mitochondria  instead  of  the  peroxisomes.The  AGT  gene  (AGXT)  has  been  cloned  and  sequenced  both  at  the  cDNA  and  the  genomic  levels.  The  gene  consists  of  11  exons  spanning  about  10  kb  and  has  been  localized  to  chromosome  2q37.3.  At  least  18  mutations  have  been  identified,  many  of  which  are  associated  with  specific  enzymic  PH1  phenotypes,  including  the  peroxisome-to-mitochondrion  targeting  defect,  intraperoxisomal  AGT  aggregation,  absence  of  AGT  catalytic  activity,  and  absence  of  both  AGT  catalytic  activity  and  immunoreactivity.AGT  is  targeted  to  peroxisomes  via  the  peroxisomal  targeting  sequence  type  1  (PTS1)  import  pathway,  even  though  its  C-terminal  tripeptide  (Lys-Lys-Leu)  does  not  fit  the  conservative  PTS1  consensus  motif.  AGT  mistargeting  to  mitochondria  is  caused  by  a  combination  of  a  common  polymorphism  that  generates  a  functionally  weak  mitochondrial  targeting  sequence  (MTS)  and  a  disease-specific  mutation  that,  together  with  the  polymorphism,  enhances  the  efficiency  of  the  MTS  by  inhibiting  AGT  dimerization.A  canine  analogue  of  PH1  and  a  feline  analogue  of  PH2  have  been  identified,  but  their  clinical  usefulness  has  yet  to  be  determined.Recent  years  have  seen  the  development  of  new  strategies  for  diagnosis,  prenatal  diagnosis,  and  treatment  of  PH1.  The  disease  can  be  diagnosed  definitively  by  AGT  assay  of  percutaneous  liver  needle  biopsies.  Such  a  procedure  can  diagnose  PH1  even  in  patients  who  present  in  renal  failure  and  in  whom  urinalysis  is  not  available.  PH1  also  can  be  diagnosed  prenatally  by  AGT  analysis  of  fetal  liver  biopsies  obtained  in  the  second  trimester  and  DNA  analysis  of  chorionic  villus  samples  or  amniocytes  in  the  first  trimester.  The  greatest  change  in  the  clinical  management  of  PH1  over  the  past  decade  has  been  the  introduction  of  liver  transplantation  as  a  form  of  enzyme-replacement  therapy.  Combined  hepatorenal  transplantation  replaces  not  only  the  enzymically  defective  organ  (i.e.,  the  liver)  but  also  the  pathophysiologically  defective  organ  (i.e.,  the  kidney).  Such  treatment  can  correct  the  clinical  and  metabolic  sequelae  of  PH1  and  lead  to  resolution  of  some  of  the  long-term  ravages  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - ommbid.mhmedical.com/content.aspx?aid=1181453346
ER  -