TY  - CHAP
M1  - Book, Section
TI  - Hypertyrosinemia
A1  - Mitchell, Grant A.
A1  - Grompe, Markus
A1  - Lambert, Marie
A1  - Tanguay, Robert M.
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  - In  humans,  tyrosine  is  obtained  from  two  sources,  dietary  intake  and  hydroxylation  of  phenylalanine.  Tyrosine  degradation  occurs  primarily  in  the  cytoplasm  of  hepatocytes  and  is  both  glucogenic  and  ketogenic.  Under  most  circumstances,  the  rate  of  tyrosine  degradation  is  determined  by  the  activity  of  tyrosine  aminotransferase.Most  inborn  errors  of  tyrosine  catabolism  produce  hypertyrosinemia.  Hypertyrosinemia  is  also  encountered  in  various  acquired  conditions,  in  particular  severe  hepatocellular  dysfunction.Deficiency  of  cytoplasmic  tyrosine  aminotransferase  (TAT)  results  in  oculocutaneous  tyrosinemia,  characterized  by  palmoplantar  keratosis  and  painful  corneal  erosions  with  photophobia  (OMIM  276600).  Half  of  reported  patients  have  mental  retardation.  Ocular  and  cutaneous  symptoms  respond  to  dietary  restriction  of  phenylalanine  and  tyrosine.  Canine  and  mink  models  of  TAT  deficiency  exist.Three  different  conditions  have  been  associated  with  dysfunction  of  4-hydroxyphenylpyruvate  dioxygenase  (4HPPD):  hereditary  4-hydroxyphenylpyruvic  acid  dioxygenase  (4HPPD)  deficiency,  hawkinsinuria,  and  transient  tyrosinemia  of  the  newborn.Primary  4HPPD  deficiency  (OMIM  276710)  has  been  described  in  at  least  three  patients,  all  of  whom  were  neurologically  abnormal.  The  biochemical  phenotype  showed  hypertyrosinemia  and  elevated  urinary  excretion  of  4-hydroxyphenyl  derivatives.  A  mouse  model  of  this  condition  has  been  described.Hawkinsinuria  (OMIM  140350)  is  an  autosomal  dominant  condition  presumably  caused  by  dysfunction  of  4HPPD.  It  results  in  metabolic  acidosis  and  failure  to  thrive  in  infancy.  Hypertyrosinemia  is  minimal  or  absent.  The  presence  in  the  urine  of  hawkinsin,  an  amino  acid  felt  to  be  derived  from  an  intermediate  of  the  4HPPD  reaction,  is  diagnostic  of  this  condition.  Symptoms  respond  to  dietary  protein  restriction  and  to  the  administration  of  ascorbate.Transient  tyrosinemia  (OMIM  276500)  of  the  newborn  results  from  a  combination  of  4HPPD  immaturity,  elevated  dietary  phenylalanine  and  tyrosine  intake,  and  a  relative  ascorbate  deficiency.  Improvement  is  spontaneous  but  can  be  accelerated  by  the  administration  of  ascorbate  and  by  dietary  protein  restriction.  Although  most  children  with  transient  neonatal  tyrosinemia  are  asymptomatic  and  have  normal  development,  some  adverse  effect  on  development  cannot  be  eliminated.A  human  maleylacetoacetate  isomerase  (MAI)  cDNA  has  been  cloned.  No  patients  with  clearly  documented  MAI  deficiency  have  yet  been  identified.Hepatorenal  tyrosinemia  is  an  autosomal  recessive  disease  caused  by  deficiency  of  fumarylacetoacetate  hydrolase  (FAH)  (OMIM  276700).  Symptoms  are  highly  variable  and  include  acute  liver  failure,  cirrhosis,  hepatocellular  carcinoma,  renal  Fanconi  syndrome,  glomerulosclerosis,  and  crises  of  peripheral  neuropathy.  Hypertyrosinemia  is  present  in  most  untreated  patients.  The  presence  of  elevated  levels  of  succinylacetone  in  plasma  or  urine  is  diagnostic  for  this  condition.  Most  patients  show  a  partial  response  to  dietary  restriction  of  phenylalanine  and  tyrosine.  Hepatic  transplantation  cures  the  liver  manifestations  and  prevents  further  neurologic  crises.  Patients  treated  with  NTBC,  an  inhibitor  of  4HPPD,  have  not  developed  acute  hepatic  or  neurologic  crises,  but  current  data  do  not  allow  conclusions  on  the  long-term  risk  of  hepatocellular  carcinoma  in  NTBC-treated  patients.  The  human  FAH  gene  has  been  cloned  and  mapped  to  chromosome  15  q23-q25.  In  hepatocytes  of  many  patients,  disease-causing  mutations  revert  to  the  normal  sequence.  Such  hepatocytes  form  nodules  with  normal  FAH  enzyme  activity.  Thirty-four  different  FAH  mutations  have  been  defined.  Founder  mutations  are  known  in  two  areas  where  hepatorenal  tyrosinemia  is  frequent:  The  splice  mutation  IVS12+5G→A  accounts  for  most  patients  in  ...
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PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181434378
ER  -