RT Book, Section
A1 Zimran, Ari
A1 Elstein, Deborah
A2 Kaushansky, Kenneth
A2 Lichtman, Marshall A.
A2 Prchal, Josef T.
A2 Levi, Marcel M.
A2 Press, Oliver W.
A2 Burns, Linda J.
A2 Caligiuri, Michael
SR Print(0)
ID 1121096821
T1 Gaucher Disease and Related Lysosomal Storage Diseases
T2 Williams Hematology, 9e
YR 2015
FD 2015
PB McGraw-Hill Education
PP New York, NY
SN 9780071833004
LK hemonc.mhmedical.com/content.aspx?aid=1121096821
RD 2024/04/16
AB SUMMARYGaucher  disease  and  Niemann-Pick  disease  are  the  two  lipid  storage  disorders  that  are  most  likely  to  be  encountered  by  the  hematologist  because  both  may  cause  hepatosplenomegaly  and  cytopenias.Gaucher  disease  is  a  common  autosomal  recessive  lipid  storage  disorder,  with  an  increased  prevalence  among  Ashkenazi  Jews,  in  whom  the  estimated  birth  occurrence  is  1  in  850.  Deficiency  of  the  enzyme  β-glucocerebrosidase  results  in  accumulation  of  the  sphingolipid  glucocerebroside  in  the  cells  of  the  macrophage-monocyte  system.  Patients  with  the  most  prevalent  form,  type  1,  have  no  primary  neuronopathic  symptoms,  whereas  there  is  involvement  of  the  central  nervous  system  in  type  2  and  type  3.  Diagnosis  of  Gaucher  disease  depends  on  demonstration  of  decreased  enzymatic  activity  of  β-glucocerebrosidase  combined  with  identification  of  mutations  in  the  β-glucocerebrosidase  gene  at  the  DNA  level,  usually  with  elevation  of  biomarkers,  such  as  chitotriosidase  as  ancillary  confirmation  and  means  of  followup.  Disease  manifestations  include  hepatosplenomegaly,  thrombocytopenia,  anemia,  osteopenia/osteoporosis  with  pathologic  fractures  and  osteonecrosis,  and,  less  commonly,  pulmonary  infiltration.  Many  patients,  especially  those  homozygous  for  the  common  N370S  mutation,  are  putatively  protected  against  neurologic  involvement,  albeit  there  is  evidence  of  a  genetic  risk  factor  for  Parkinson  disease.  Generally,  many  patients  with  type  1  may  be  asymptomatic  or  so  mildly  affected  that  they  may  not  present  until  their  fifth  or  sixth  decade  and  do  not  require  disease-specific  therapy,  whereas  for  those  with  more  severe  signs  and  symptoms,  enzyme  replacement  therapy  (currently  three  infusible  enzymes)  is  available.  Substrate  reduction  therapy  is  an  oral  modality  but  is  associated  with  a  more  problematic  safety  profile.  Pharmacological  chaperones  and  oral  enzyme  are  being  tested.Niemann-Pick  disease  is  a  heterogeneous  group  of  autosomal  recessive  disorders.  Type  A  and  type  B  result  from  deficiency  of  the  enzyme  sphingomyelinase,  whereas  type  C  results  from  mutations  in  the  NPC1  or  NPC2  gene,  which  appears  to  be  involved  in  cholesterol  trafficking  and  resulting  in  accumulation  of  cholesterol  as  well  as  sphingomyelin.  Type  A  is  a  lethal  infantile  form  with  marked  progressive  neurologic  involvement.  Type  B  is  a  later-onset  form  with  no  neurologic  involvement  but  hepatosplenomegaly  in  many  patients.  Patients  with  type  C  disease  manifest  progressive  neurologic  involvement  and  hepatosplenomegaly,  but  may  survive  into  adulthood.  The  marrow  of  these  patients  contains  typical  foam  cells  with  small  droplets  in  the  cytoplasm  and  sea-blue  histiocytes.  Substrate  reduction  therapy  was  approved  for  patients  with  type  C  disease  in  2008  in  Europe;  pharmacologic  chaperone  therapy  is  being  attempted.Fabry  disease,  Wolman/cholesteryl  ester  storage  disease  (CESD),  and  GM1-gangliosidoses  are  other  lipid  storage  diseases  characterized  by  hepatosplenomegaly;  GM2-gangliosidosis  by  hepatomegaly  only.  CESD  patients  may  result  in  anemia  and  have  sea-blue  histiocytes.  They  are  usually  not  cared  for  by  hematologists  and  will  not  be  discussed  in  this  chapter.