RT Book, Section
A1 von Figura, Kurt
A1 Hanefeld, Folker
A1 Isbrandt, Dirk
A1 Stöckler-Ipsiroglu, Sylvia
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181435128
T1 Guanidinoacetate Methyltransferase 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=1181435128
RD 2024/04/20
AB Guanidinoacetate  methyltransferase  (GAMT)-deficiency  (MIM  601240)  is  a  disease  of  creatine  biosynthesis.  Creatine  is  synthesized  in  a  two-step  mechanism  from  glycine,  arginine,  and  methionine.  In  the  first  reaction,  guanidinoacetate  and  ornithine  are  formed  by  arginine:  glycine  aminidinotransferase.  In  the  second  reaction,  catalyzed  by  GAMT,  S-adenosylmethionine  donates  the  methyl  group  for  formation  of  creatine  from  guanidinoacetate.GAMT-deficiency  manifests  during  the  first  months  of  life  as  developmental  delay  or  arrest.  Neurologic  symptoms  are  heterogeneous,  including  muscular  hypotonia  and  weakness,  poor  head  control,  involuntary  extrapyramidal  movements,  epilepsy,  and,  in  older  patients,  autistic  behavior.  Abnormal  signals  in  the  globus  pallidus,  as  observed  on  MRI  scans,  may  provide  an  important  clue  for  diagnosis.Diagnosis  of  the  disease  is  based  on  the  demonstration  of  excessive  amounts  of  guanidinoacetate  in  body  fluids,  the  deficiency  of  creatine/phosphocreatine  in  brain,  and  the  absence  of  GAMT  activity  in  fibroblasts,  lymphocytes,  or  amniotic  fluid  cells.GAMT  deficiency  is  an  autosomal  recessive  disorder.  Two  GAMT  deficiency  alleles  have  been  characterized,  which  account  for  four  of  the  six  alleles  in  the  three  patients  analyzed  so  far.  The  two  alleles  give  rise  to  transcripts  that  encode  truncated  or  elongated,  presumably  nonfunctional  polypeptides.The  bulk  of  creatine  is  synthesized  in  liver,  pancreas,  and  kidney;  released  into  the  blood;  and  taken  up  by  cells  via  creatine  transporters.  In  tissues  with  highly  fluctuating  demand  for  energy,  such  as  muscle  and  brain,  the  creatine/phosphocreatine  system  serves  as  a  temporal  and  spatial  energy  buffering  system.  Some  of  the  abnormalities  observed  in  GAMT  deficiency  can  be  explained  by  the  deficiency  of  high-energy  phosphate  in  such  cells,  while  others  appear  to  be  related  to  the  accumulation  of  guanidinoacetate.Oral  supplementation  of  creatine  in  GAMT  deficiency  patients  partially  restores  the  creatine/phosphocreatine  in  brain  and  has  beneficial  effects  on  the  clinical  manifestations.  The  elevation  of  guanidinoacetate  in  plasma  is  largely  refractory  to  oral  supplementation  of  creatine,  which  may  explain  the  persistence  of  some  of  the  clinical  symptoms.