RT Book, Section
A1 McCabe, Edward R. B.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181437698
T1 Disorders of Glycerol Metabolism
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=1181437698
RD 2024/04/19
AB Glycerol  kinase  (GK)  deficiency  (MIM  307030)  is  an  X-linked  inborn  error  of  metabolism  characterized  by  hyperglycerolemia  and  glyceroluria.  These  individuals  may  evidence  “pseudohypertriglyceridemia”  if  the  laboratory  measures  triglycerides  by  quantitation  of  glycerol  released  after  lipolysis.  Glycerol  kinase  deficiency  has  been  subdivided  into  three  clinical  forms  according  to  phenotype:  (1)  complex  glycerol  kinase  deficiency,  which  is  an  Xp21  contiguous  gene  syndrome  involving  the  GK  locus  together  with  the  adrenal  hypoplasia  congenita  (AHC)  and/or  Duchenne  muscular  dystrophy  (DMD)  loci;  (2)  the  juvenile  form,  associated  with  episodic  vomiting,  acidemia,  and  central  nervous  system  depression,  as  well  as  hypotonia  and  a  Reye-like  illness  in  certain  patients,  presenting  in  the  first  several  years  of  life;  and  (3)  the  benign,  or  adult,  form,  detected  incidentally  with  pseudohypertriglyceridemia.  The  juvenile  and  benign  forms  result  from  isolated  GK  deficiency.The  diagnosis  of  GK  deficiency  may  be  confirmed  by  a  decrease  in  GK  enzymatic  activity  and/or  identification  of  a  GK  gene  mutation  or  deletion.  The  enzyme  activity  may  be  determined  in  leukocytes,  fibroblasts,  liver,  and/or  transformed  lymphoblastoid  cell  lines.  Kidney,  small  intestine,  and  adrenal  gland  are  also  deficient  in  GK  activity  among  affected  individuals.Because  of  the  relatively  high  frequency  of  interstitial  deletions  in  this  chromosomal  region,  all  patients  with  DMD  and  developmental  delay  should  be  evaluated  for  adrenal  hypoplasia  and  insufficiency  and  for  GK  deficiency.Treatment  is  most  critical  for  patients  with  adrenal  hypoplasia  and  insufficiency,  since  all  the  deaths  seem  to  have  resulted  from  Addisonian  crises.  These  patients  require  glucocorticoid  and  mineralocorticoid  treatment.  Patients  with  vomiting,  acidemia,  and  stupor  associated  with  GK  deficiency  or  the  glycerol  intolerance  syndrome  may  be  placed  on  a  low-fat  (i.e.,  glycerol-restricted)  diet,  but  most  important  is  the  avoidance  of  prolonged  fasts.The  gene  order  surrounding  the  GK  locus  is:  Xpter–  AHC  -GK-  DMD  -  ornithine  transcarbamylase  (OTC)–cen.  Human  GK  cDNAs  have  been  isolated  from  testis,  brain,  liver,  and  adrenal  gland,  and  the  deduced  amino  acid  sequences  show  striking  similarities  to  prokaryotic  sequences.Patients  with  the  glycerol  intolerance  syndrome  have  episodes  of  sweating,  irritability,  confusion,  marked  lethargy,  and  coma.  Hypoglycemia  and  seizures  are  variably  observed.  Episodes  can  be  precipitated  by  glycerol  ingestion  or  infusion.  The  patients  may  outgrow  these  episodes.  Each  of  the  three  individuals  investigated  has  a  history  of  prematurity.  Measurements  of  GK  activity  have  been  normal.  Diminished  hepatic  fructose  1,6-bisphosphatase  activity  and  increased  sensitivity  of  this  enzyme  to  inhibition  by  glycerol  3-phosphate  have  been  reported.  These  observations  have  prompted  speculation  that  this  syndrome  may  represent  an  unusual  sensitivity  to  the  hypoglycemic  effects  of  glycerol  3-phosphate,  possibly  due  to  delayed  maturation  of  enzymes  of  the  glycerol  metabolic  pathway.  Similarity  of  symptoms  to  those  of  the  juvenile  form  of  GK  deficiency  has  suggested  alternative  hypotheses  that  include  abnormal  compartmentation  of  a  mutant  GK  gene  with  normal  enzyme  activity  or  a  mutation  in  the  glycerol  facilitator  gene  involved  in  uptake  of  glycerol  across  the  cell  membrane.