TY  - CHAP
M1  - Book, Section
TI  - Disorders of Tetrahydrobiopterin and Related Biogenic Amines
A1  - Blau, Nenad
A1  - Thöny, Beat
A1  - Cotton, Richard G. H.
A1  - Hyland, Keith
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  - Tetrahydrobiopterin  (BH)deficiencies  are  disorders  affecting  phenylalanine  homeostasis,  and  catecholamine  and  serotonin  biosynthesis.  The  minimum  requirements  for  the  normal  reaction(s)  are  the  apoenzymes,  phenylalanine-4-hydroxylase  (PAH),  tyrosine-3-hydroxylase  (TH),  or  tryptophan-5-hydroxylase  (TPH),  oxygen,  the  corresponding  aromatic  amino  acids,  phenylalanine,  tyrosine,  or  tryptophan,  and  BH4.  The  complete  hydroxylating  system,  in  each  case,  consists  of  the  two  additional  BH4-regenerating  enzymes:  pterin-4α-carbinolamine  dehydratase  (PCD)  and  dihydropteridine  reductase  (DHPR).  BH4  is  synthesized  from  guanosine  triphosphate  (GTP)  catalyzed  sequentially  by  GTP  cyclohydrolase  I  (GTPCH),  6-pyruvoyl-tetrahydropterin  synthase  (PTPS),  and  sepiapterin  reductase  (SR).  The  first  two  steps  are  clinically  relevant.BH  deficiency  comprises  a  heterogeneous  group  of  disorders  caused  by  mutations  at  one  of  the  genes  encoding  enzymes  involved  in  the  biosynthesis  (GTPCH  or  PTPS)  or  regeneration  (PCD  or  DHPR)  of  BH4.  Phenotypically,  it  presents  mostly  with  hyperphenylalaninemia  (HPA)  and  deficiency  of  the  neurotransmitter  precursors,  L-dopa  and  5-hydroxytryptophan,  and  thus  may  be  detected  through  neonatal  phenylketonuria  (PKU)-screening  programs.  However,  some  mutant  variants  may  present  without  HPA  and  some  with  normal  neurotransmitter  homeostasis:  Brain  nitric  oxide  synthase  (NOS)  may  also  be  affected  by  a  deficit  of  the  essential  cofactor  BH4.The  genes  of  the  corresponding  enzymes  are  located  and  characterized  in  normal  and  mutant  genomes.  GTPCH  (six  exons)  is  on  chromosome  14  (region  14q22.1-q22.2)  and  harbors  42  mutations,  most  of  them  associated  with  non-HPAdopa-responsive  dystonia  (DRD).  PTPS  (six  exons)  maps  to  human  chromosome  11  (region  11q22.3-q23.3)  and  harbors  over  28  mutations  associated  with  HPA,  some  having  a  mild  peripheral  phenotype.  PCD  (four  exons)  is  on  chromosome  10  (region  10q22),  with  seven  mutations  described  and  associated  with  benign  transient  HPA.  DHPR  (seven  exons)  maps  to  chromosome  4  (region  4p15.3)  and  harbors  21  mutations,  all  associated  with  HPA  and  neurotransmitter  deficiency.Mutations  of  a  single  allele  of  the  GTPCH  gene  or  of  two  alleles  of  the  tyrosine  hydroxylase  (TH)  gene  can  lead  to  DRD.  The  spectrum  of  clinical  symptoms  in  these  disorders  is  wide  and  does  not  always  include  dystonia.  Therapy  with  low-dose  L-dopa  normally  alleviates  most  symptoms.  Detection  and  differentiation  of  dominantly  inherited  GTPCH  deficiency  from  recessively  inherited  TH  deficiency  requires  measurement  of  pterins  (neopterin  and  biopterin),  and  neurotransmitter  metabolites  in  cerebrospinal  fluid  (CSF).  Confirmation  of  a  diagnosis  requires  enzymatic  and  molecular  analysis  in  the  case  of  dominantly  inherited  GTPCH  deficiency  and  molecular  analysis  for  TH  deficiency  as  no  suitable  tissue  is  available  for  TH  enzyme  assay.Treatment  of  BH  deficiencies  requires  restoration  of  normal  blood  phenylalanine  concentration  by  BH4  supplementation  (2  to  10  mg/kg  per  day)  or  diet  and  replacement  therapy  with  the  neurotransmitter  precursors  L-dopa  (+  carbidopa)  and  5-hydroxytryptophan,  and  supplements  of  folinic  acid  in  DHPR  deficiency.  Treatment  should  be  initiated  as  early  as  possible  (and  perhaps  continued  for  a  lifetime).Detection  and  differentiation  of  BH  deficiencies  among  HPAs  require  measurement  of  pterins  (neopterin  and  biopterin)  in  urine,  DHPR  activity  in  blood  from  a  Guthrie  card,  and  neurotransmitter  metabolites  in  CSF.  If  requested,  prenatal  diagnosis  is  possible  by  enzyme  assay,  measurement  of  metabolites  in  amniotic  fluid,  or  DNA  analysis  in  all  forms  of  BH4  deficiency.The  catecholamines  [dopamine  (DA),  norepinephrine  (NE),  and  epinephrine  (E)],  together  with  serotonin  (5-hydroxytryptamine  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181434093
ER  -