TY  - CHAP
M1  - Book, Section
TI  - Niemann-Pick Disease Type C: A Lipid Trafficking Disorder
A1  - Patterson, Marc C.
A1  - Vanier, Marie T.
A1  - Suzuki, Kinuko
A1  - Morris, Jill A.
A1  - Carstea, Eugene
A1  - Neufeld, Edward B.
A1  - Blanchette-Mackie, Joan E.
A1  - Pentchev, Peter G.
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  - Niemann-Pick  disease  type  C  (NP-C)  is  an  autosomal  recessive  lipidosis  with  protean  clinical  manifestations,  distinguished  biochemically  by  a  unique  error  in  cellular  trafficking  of  exogenous  cholesterol  that  is  associated  with  lysosomal  accumulation  of  unesterified  cholesterol.  A  majority  of  patients  with  this  phenotype  are  linked  genetically  to  chromosome  18,  the  locus  of  Niemann-Pick  disease  type  1  gene  (NPC1).  NPC1  is  a  novel  gene  whose  predicted  protein  product  contains  between  13  and  16  transmembrane  domains,  and  a  sterol-sensing  domain  with  homologies  to  Patched,  HMG-CoA  reductase,  and  sterol  regulatory  element  binding  protein  [SREBP]  cleavage-activating  protein  (SCAP).  A  region  designated  the  NPC  domain,  conserved  in  yeast,  nematode,  and  mouse,  contains  a  leucine  zipper.  NP-C  is  distinct  at  clinical,  biochemical,  and  molecular  levels  from  the  primary  sphingomyelin  lipidoses  (Niemann-Pick  disease  types  A  [NP-A]  and  Niemann-Pick  disease  types  B  [NP-B],  respectively]),  with  which  it  has  traditionally  been  grouped.  Niemann-Pick  disease  type  D  (NP-D)  is  allelic  with  NP-C,  and  should  be  regarded  as  a  variant  phenotype  associated  with  a  genetic  isolate,  rather  than  a  distinct  entity.  A  small  group  of  patients  belong  to  a  second  genetic  complementation  group  that  does  not  link  to  chromosome  18.  These  individuals  are  believed  to  have  mutations  in  a  gene  provisionally  designated  Niemann-Pick  disease  type  2  gene  (NPC2).The  clinical  manifestations  of  NP-C  are  heterogeneous.  Most  patients  with  NP-C  have  progressive  neurologic  disease,  although  hepatic  damage  is  prominent  in  certain  cases,  and  may  be  lethal  in  some.  Variable  hepatosplenomegaly,  vertical  supranuclear  ophthalmoplegia,  progressive  ataxia,  dystonia,  and  dementia  characterize  the  “classic”  phenotype.  These  children  present  in  childhood,  and  die  in  the  second  or  third  decade.  Other  phenotypes  include  presentations  with  fetal  ascites,  fatal  neonatal  liver  disease,  early  infantile  onset  with  hypotonia  and  delayed  motor  development,  and  adult  variants  in  which  psychiatric  illness  and  dementia  predominate.NP-C  is  panethnic.  Genetic  isolates  have  been  described  in  Nova  Scotia  (formerly  Niemann-Pick  disease  type  D)  and  southern  Colorado.  Complementation  studies  have  demonstrated  two  distinct  groups.  About  95  percent  of  patients  link  to  chromosome  18q11,  and  thus  to  NPC1;  the  remainder  are  believed  to  have  mutations  in  a  second  gene,  provisionally  designated  NPC2.NP-C  has  an  estimated  prevalence  of  approximately  1:150,000,  making  it  a  more  common  phenotype  than  NP-A  and  NP-B  combined.  It  is  likely  that  the  true  prevalence  of  the  disease  has  been  underestimated  because  of  confusing  terminology,  the  lack  of  a  definitive  diagnostic  test  prior  to  the  discovery  of  the  abnormalities  of  cellular  cholesterol  processing,  and  failure  to  recognize  the  clinical  phenotypes.Foam  cells  or  sea-blue  histiocytes  are  found  in  many  tissues.  Such  cells  are  not  specific  for  NP-C  and  may  be  absent,  particularly  in  cases  lacking  visceromegaly.  Characteristic  inclusions  (polymorphous  cytoplasmic  bodies)  may  be  identified  in  skin  and  conjunctival  biopsies.  Neuronal  storage  with  cytoplasmic  ballooning  and  a  variety  of  inclusions  is  present  throughout  the  nervous  system.  Neurofibrillary  tangles,  meganeurites,  and  axonal  spheroids  are  also  seen.In  most  cases  of  NP-C,  the  primary  molecular  defect  lies  in  NPC1.  Unesterified  cholesterol,  sphingomyelin,  phospholipids,  and  glycolipids  are  stored  in  excess  in  the  liver  and  spleen.  Glycolipids  are  elevated  in  the  brain,  the  principal  target  of  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181465066
ER  -