RT Book, Section
A1 Donlon, John
A1 Sarkissian, Christineh
A1 Levy, Harvey
A1 Scriver, Charles R.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181421626
T1 Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency
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=1181421626
RD 2024/04/19
AB We  describe  an  inborn  error  of  metabolism  called  phenylketonuria  (PKU;  MIM  No.  261600).  The  disease  has  been  called  an  epitome  of  human  biochemical  genetics  (Scriver  and  Clow,  1980a,  1980b).  The  disorder  reflects  a  disadaptive  interaction  between  nature  and  nurture.  The  component  in  nurture  is  an  essential  amino  acid,  L-phenylalanine;  the  one  in  nature  is  mutation  in  the  phenylalanine  hydroxylase  gene  (PAH)  encoding  the  enzyme  L-phenylalanine  hydroxylase  (EC  1.14.16.1).  The  discordance  between  nature  and  nurture  leads  to  hyperphenylalaninemia  (HPA),  which  can  have  a  toxic  effect  on  brain  development  and  function.  The  “proximal”  phenotype  (phenylalanine  hydroxylase  dysfunction)  is  under  the  control  of  one  locus  encoding  the  phenylalanine  hydroxylase  enzyme  and  additional  loci  encoding  several  other  enzymes  necessary  for  synthesis  and  recycling  of  the  tetrahydrobiopterin  cofactor  essential  for  the  catalytic  reaction;  locus  heterogeneity  thus  enters  the  interpretation  of  HPA.  The  intermediate  (metabolic)  and  distal  (cognitive)  phenotypes  of  PKU  disease  both  behave  as  complex  traits  that  elude  consistent  interindividual  genotype-phenotype  correlations.  The  phenylalanine  hydroxylase  gene  harbors  great  allelic  diversity;  several  hundred  mutations,  both  disease-causing  and  polymorphic,  are  recorded  in  PAHdb,  a  public-locus-specific  mutation  database  (www.pahdb.mcgill.ca).The  HPAs  are  disorders  of  phenylalanine  hydroxylation.  The  minimum  requirements  for  the  normal  reaction,  which  occurs  in  both  liver  and  kidney  in  human  subjects,  are  phenylalanine  hydroxylase  enzyme  (a  monooxygenase,  EC  1.14.16.1),  oxygen,  L-phenylalanine  substrate,  and  the  6R  isomer  of  the  tetrahydrobiopterin  (BH4)  cofactor.  For  the  pterin  cofactor  to  function  as  a  catalyst,  BH4  must  be  regenerated  from  the  carbinolamine  byproduct  (4a-hydroxytetrahydropterin)  of  the  hydroxylation  reaction.  This  is  achieved  by  a  recycling  pathway  in  which  4α-carbinolamine  dehydratase  (formerly  known  as  phenylalanine  hydroxylase–stimulating  protein)  converts  the  carbinolamine  to  the  quinonoid  dihydropterin,  which,  as  the  substrate  for  dihydropteridine  reductase  in  the  presence  of  reduced  pyridine  nucleotide,  is  converted  back  to  BH4.  A  pathway  exists  for  biosynthesis  of  this  obligatory  cofactor  involved  both  here  and  in  the  function  of  other  aromatic  monooxygenases  and  of  nitric  oxide  synthase;  the  enzymes  in  the  pathway  are  guanosine  triphosphate  cyclohydrolase,  6-  pyruvoyltetrahydropterin  synthase,  and  sepiapterin  reductase.  Diseases  of  BH4  synthesis  and  recycling  are  discussed  in  Disorders  of  Tetrahydrobiopterin  and  Related  Biogenic  Amines.Hyperphenylalaninemia  is  defined  as  a  plasma  phenylalanine  value  greater  than  120  µmol/liter  (>2  mg/dl).  Whether  forms  of  HPA  owing  to  altered  integrity  of  the  enzyme  should  be  subdivided  into  different  forms—notably  phenylketonuria  (plasma  phenylalanine  >1000  µmol/liter,  diet  phenylalanine  tolerance    500  mg/day)—is  a  moot  point.  Evidence  suggests  that  mild  degrees  of  persistent  untreated  HPA  (<600  µmol/liter)  may  not  be  harmful  to  cognitive  development  (as  yet  an  unproven  hypothesis).  For  purposes  of  diagnosis,  counseling  and  correct  treatment  of  the  non-PAH  enzyme  deficiencies  affecting  BH4  homeostasis  must  be  ruled  out.The  human  PAH  gene  covers  approximately  100  kb  of  genomic  DNA  on  chromosome  12,  band  region  q23.2,  and  is  embedded  in  a  region  of  1.5  Mbp  harboring  five  other  genes.  The  nucleotide  sequences,  both  genomic  (GenBank  accession  number  AF404777)  and  cDNA  (U49897.1),  are  now  known  (see  www.pahdb.mcgill.ca);  PAH  has  13  exons  and  a  complex  5′  untranslated  region  containing  ...