RT Book, Section
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.
SR Print(0)
ID 1181464885
T1 Niemann-Pick Disease Types A and B: Acid Sphingomyelinase Deficiencies
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=1181464885
RD 2024/04/24
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  ...