TY  - CHAP
M1  - Book, Section
TI  - Niemann-Pick Disease Types A and B: Acid Sphingomyelinase Deficiencies
A1  - Schuchman, Edward H.
A1  - Desnick, Robert J.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.174
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Types  A  and  B  Niemann-Pick  disease  (NPD)  are  lysosomal  storage  disorders  that  result  from  the  deficient  activity  of  acid  sphingomyelinase  (ASM;  EC  3.1.4.12)  and  the  accumulation  of  sphingomyelin.  Type  A  NPD  is  a  fatal  disorder  of  infancy  characterized  by  failure  to  thrive,  hepatosplenomegaly,  and  a  rapidly  progressive  neurodegenerative  course  that  leads  to  death  by  2  to  3  years  of  age.  In  contrast,  type  B  NPD  is  a  phenotypically  variable  disorder  that  is  usually  diagnosed  in  childhood  by  the  presence  of  hepatosplenomegaly.  Most  type  B  patients  have  little  or  no  neurologic  involvement  and  survive  into  adulthood.  In  more  severely  affected  type  B  patients,  progressive  pulmonary  infiltration  causes  the  major  disease  complications.The  pathologic  hallmark  of  types  A  and  B  NPD  is  the  histochemically  characteristic  lipid-laden  foam  cell,  often  referred  to  as  the  “Niemann-Pick  cell.”  These  histiocytic  cells  result  from  the  accumulation  of  sphingomyelin  and  other  lipids  in  the  monocyte-macrophage  system,  the  primary  site  of  pathology  in  this  disease.Patients  with  type  A  NPD  have  dramatically  reduced  ASM  activities  in  their  cells  and  tissues,  generally  less  than  5  percent  of  normal  depending  on  the  enzyme  source  and  assay  system  used.  Type  B  patients,  who  have  milder  disease,  have  slightly  higher  residual  ASM  activities.Types  A  and  B  NPD  are  both  inherited  as  autosomal  recessive  traits.  Somatic-cell  hybridization  and  molecular  genetic  studies  demonstrate  that  both  disorders  result  from  allelic  mutations  within  the  ASM  gene.  Type  B  NPD  is  panethnic,  whereas  Ashkenazi  Jewish  have  a  higher  incidence  of  type  A  NPD;  the  estimated  carrier  frequency  for  type  A  NPD  in  this  population  is  about  1:80.The  full-length  cDNA  and  genomic  sequences  encoding  human  and  murine  ASM  have  been  isolated  and  characterized.  The  human  ASM  gene  has  been  mapped  to  the  chromosomal  region  11p15.1-p15.4.  Although  the  ASM  mRNA  is  alternatively  spliced,  there  is  only  one  functional  transcript  that  encodes  a  629-residue  polypeptide  that  is  cotranslationally  glycosylated.  Following  translation/glycosylation,  some  of  the  ASM  polypeptides  are  transported  to  lysosomes,  while  the  remainder  are  released  from  cells  in  a  form  that  requires  Zn2+  cations  for  maximal  activity.Eighteen  published  mutations  have  been  identified  in  the  ASM  gene  that  cause  types  A  and  B  NPD.  Three  mutations,  R496L,  L302P,  and  fsP330,  account  for  about  92  percent  of  the  mutant  alleles  in  Ashkenazi  Jewish  type  A  NPD  patients.  Similarly,  a  single  lesion,  ΔR608,  is  a  common  mutation  in  type  B  patients  and  encodes  sufficient  residual  activity  to  be  “neuroprotective.”The  diagnosis  of  types  A  and  B  NPD  is  readily  made  by  enzymatic  determination  of  ASM  activity  in  cell  and/or  tissue  extracts.  However,  heterozygote  detection  is  unreliable  by  enzyme  assay  and  requires  molecular  studies.  Prenatal  diagnosis  by  enzymatic  and/or  molecular  analyses  of  cultured  amniocytes  and  chorionic  villi  has  been  accomplished.Currently,  there  is  no  specific  therapy  for  type  A  or  B  NPD.  Bone  marrow  transplantation  (BMT)  studies  in  a  “knock-out”  mouse  model  of  NPD  suggest  that  this  may  be  a  successful  therapeutic  approach  for  type  B  NPD,  but  is  unlikely  to  alleviate  the  major  neurologic  complications  of  type  A  NPD.  The  ASM  cDNA  has  been  used  to  overexpress  catalytically  active  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.174
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181464885
ER  -