RT Book, Section
A1 Goodman, Stephen I.
A1 Frerman, Frank E.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181437407
T1 Organic Acidemias Due to Defects in Lysine Oxidation: 2-Ketoadipic Acidemia and Glutaric Acidemia
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=1181437407
RD 2024/04/19
AB 2-Ketoadipic  acid,  an  intermediate  in  the  metabolism  of  L-lysine,  hydroxy-L-lysine,  and  L-tryptophan,  undergoes  successive  oxidative  decarboxylations  by  2-ketoadipic  dehydrogenase  and  glutaryl-CoA  dehydrogenase  to  form  glutaryl-CoA  and  crotonyl-CoA,  respectively.Deficiency  of  2-ketoadipic  dehydrogenase  causes  2-ketoadipic  acidemia  (MIM  245130),  a  condition  characterized  by  accumulation  and  excretion  of  2-ketoadipic,  2-aminoadipic,  and  2-hydroxyadipic  acids,  probably  without  adverse  phenotypic  effects.Deficiency  of  glutaryl-CoA  dehydrogenase  causes  glutaric  acidemia  type  I  (MIM  231670),  a  disorder  characterized  clinically  by  dystonia  and  dyskinesia  appearing  during  the  first  years  of  life,  chemically  by  excretion  of  glutaric  and  3-hydroxyglutaric  acids  in  urine,  and  pathologically  by  neuronal  degeneration  of  the  caudate  and  putamen.  CT  and  MRI  scans  often  show  frontotemporal  atrophy  and/or  arachnoid  cysts  before  the  onset  of  symptoms.Glutaryl-CoA  dehydrogenase  deficiency  is  inherited  as  an  autosomal  recessive  trait.  More  than  60  pathogenic  mutations  have  been  identified  in  the  GCD  gene  (19p13.2),  and  because  no  one  mutation  is  prominent  outside  of  inbred  groups,  most  GA1  patients  are  heterozygous  for  two  different  mutant  alleles.  Identification  of  heterozygous  carriers,  while  possible  by  demonstration  of  activity  of  intermediate  enzymes  in  cultured  fibroblasts  and  peripheral  leukocytes,  is  most  accurately  done  by  mutation  analysis.Striatal  damage  and  neurologic  phenotype  do  not  develop  in  all  patients,  and  there  is  evidence  that  early  supplementation  with  L-carnitine,  vigorous  treatment  of  intercurrent  infections  with  fluids,  glucose  and  insulin,  and  (perhaps)  dietary  restriction  of  lysine  and  tryptophan  can  prevent  their  development  in  most  instances.Prenatal  diagnosis  is  possible  and  is  based  on  demonstrating  increased  concentrations  of  glutaric  acid  in  amniotic  fluid,  deficiency  of  glutaryl-CoA  dehydrogenase  in  cultured  amniocytes  or  (probably)  material  obtained  by  CVS,  or,  in  appropriate  families,  by  mutation  analysis.