TY  - CHAP
M1  - Book, Section
TI  - I-Cell Disease and Pseudo-Hurler Polydystrophy: Disorders of Lysosomal Enzyme Phosphorylation and Localization
A1  - Braulke, Thomas
A1  - Raas-Rothschild, Annick
A1  - Kornfeld, Stuart
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  - I-cell  disease  (mucolipidosis  II,  or  ML-II  alpha/beta)  and  pseudo-Hurler  polydystrophy  (mucolipidosis  III,  or  ML-III  alpha/beta  and  ML-III  gamma)  are  related  genetic  diseases,  with  rare  occurrence  and  autosomal  recessive  inheritance.I-cell  disease  shows  many  of  the  clinical  and  radiographic  features  of  Hurler  syndrome  but  presents  earlier  and  does  not  show  mucopolysacchariduria.  There  is  severe  progressive  developmental  delay,  and  death  usually  occurs  in  the  first  decade.  Pseudo-Hurler  polydystrophy  is  milder  and  presents  later,  and  survival  into  adulthood  is  possible.In  both  diseases,  there  is  abnormal  lysosomal  enzyme  transport  in  cells  of  mesenchymal  origin.  In  these  cells,  newly  synthesized  lysosomal  enzymes  are  secreted  instead  of  being  targeted  correctly  to  lysosomes.  Affected  cells  show  dense  inclusions  filled  with  storage  material,  and  lysosomal  enzymes  are  present  at  elevated  levels  in  the  plasma  and  body  fluids  of  affected  patients.In  normal  cells,  targeting  of  lysosomal  enzymes  to  lysosomes  is  mediated  by  receptors  that  bind  mannose  6-phosphate  recognition  markers  on  the  enzymes.  The  recognition  marker  is  synthesized  in  a  two-step  reaction  in  the  Golgi  complex,  and  it  is  the  enzyme  that  catalyzes  the  first  step  in  this  process,  UDP-N-acetylglucosamine:lysosomal  enzyme  N-acetylglucosamine-1-phosphotransferase,  which  is  defective  in  ML-II  and  ML-III.The  phosphotransferase  is  a  low-abundance,  membrane-bound  enzyme  complex  of  three  subunits  (α2β2γ2)  that  are  the  products  of  two  genes.  Biochemical  studies  suggest  that  the  α/β  subunits  mediate  the  catalytic  activity  and  the  specific  recognition  of  lysosomal  enzymes,  while  the  γ  subunits  facilitate  the  phosphorylation  of  a  subset  of  lysosomal  enzymes.Over  125  mutations  in  the  GNPTAB  gene  and  24  mutations  in  the  GNPTG  gene  have  been  identified  to  date.  Almost  all  patients  with  ML-II  have  nonsense,  frameshift,  or  splice  site  alterations  in  GNPTAB  (ML-II  alpha/beta),  whereas  ML-III  alpha/beta  patients  carry  missense  mutations  or  at  least  one  hypomorph  allele  resulting  in  residual  phosphotransferase  activity.  The  majority  of  the  ML-III  gamma  patients  have  splicing,  deletions  or  insertions  or  nonsense  mutations  in  the  GNPTG  gene.While  all  cells  and  tissues  of  affected  individuals  are  deficient  in  phosphotransferase  activity,  not  all  cells  are  deficient  in  lysosomal  enzyme  content.  This  indicates  that  some  cell  types  have  mannose  6-phosphate-independent  pathways  that  function  in  the  transport  of  lysosomal  enzymes.  The  nature  of  the  alternate  pathways  in  these  cell  types  is  incompletely  understood.Diagnosis  of  ML-II  and  ML-III  can  be  made  biochemically  by  estimation  of  plasma  lysosomal  enzyme  levels.  The  characteristic  pattern  of  enzyme  deficiencies  in  fibroblasts  also  can  be  used,  as  can  the  ratio  of  extracellular  to  intracellular  enzyme  activities.  The  phosphotransferase  activity  also  can  be  measured.  Sequencing  of  the  GNPTAB  and  GNPTG  coding  regions  detects  disease-causing  mutations  in  over  95%  of  patients.  In  general,  ML-II  and  ML-III  can  be  distinguished  on  clinical  criteria  and  on  progression  of  the  disease.  Prenatal  diagnosis  of  at-risk  pregnancies  is  dependent  on  prior  identification  of  disease-causing  mutations  in  the  family.  Carrier  detection  is  also  possible.There  is  no  definitive  treatment.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - ommbid.mhmedical.com/content.aspx?aid=1181463931
ER  -