TY  - CHAP
M1  - Book, Section
TI  - Galactosialidosis
A1  - d’Azzo, Alessandra
A1  - Andria, Generoso
A1  - Bonten, Erik
A1  - Annunziata, Ida
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.183
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Galactosialidosis  (GS)  is  a  lysosomal  storage  disease  (LSD)  belonging  to  the  subgroup  of  the  glycoproteinoses.  The  disease  is  associated  with  combined  deficiency  of  β-galactosidase  (β-GAL)  and  neuraminidase  1  (NEU1),  which  is  secondary  to  a  primary  defect  of  the  serine  carboxypeptidase/protective  protein  cathepsin  A  (PPCA),  and  is  transmitted  as  an  autosomal  recessive  trait.All  patients  have  clinical  manifestations  typical  of  a  lysosomal  storage  disease,  including  coarse  facies,  cherry-red  spots,  vertebral  changes,  foam  cells  in  the  bone  marrow,  and  vacuolated  lymphocytes  in  peripheral  blood.  Three  phenotypic  subtypes  are  recognized.  The  early  infantile  form  is  associated  with  fetal  hydrops,  edema,  ascites,  visceromegaly,  skeletal  dysplasia,  and  early  death.  Hepatosplenomegaly,  growth  retardation,  cardiac  involvement,  and  rare  occurrence  of  important  neurologic  signs  characterize  the  late  infantile  type.  The  majority  of  reported  patients  have  the  juvenile/adult  form  and  are  mainly  of  Japanese  origin.  Myoclonus,  ataxia,  angiokeratoma,  cognitive  disability,  neurologic  deterioration,  absence  of  visceromegaly,  and  long  survival  are  quite  characteristic  of  this  subtype.Sialyloligosaccharides  and  glycopeptides  accumulate  in  patients’  lysosomes  and  are  excreted  in  their  body  fluids,  hence  the  classification  of  the  disease  as  a  glycoproteinosis.  Ultrastructural  analysis  of  central,  peripheral,  and  autonomic  nervous  systems,  retina,  liver,  kidney,  skin,  and  lymphocytes  shows  numerous  membrane-bound  vacuoles  and,  in  some  tissues,  membranous  cytoplasmic  bodies.The  autosomal  gene  encoding  human  PPCA  is  localized  on  chromosome  20q13.1.  Both  PPCA  cDNA  and  genomic  sequences  are  routinely  used  to  analyze  the  disease-causing  mutations  in  patients  with  different  clinical  phenotypes.  Mainly  single-base  substitutions  or  splice-junction  defects  have  been  identified  to  date.  Correlation  of  genotype  with  disease  severity  has  emerged  from  structure-function  studies  of  the  mutant  enzyme.Mammalian  PPCA  is  a  multifunctional  enzyme  with  distinct  protective  and  catalytic  activities.  It  associates  with  β-GAL  and  NEU1  in  an  early  biosynthetic  compartment,  which  allows  the  2  glycosidases  to  be  correctly  compartmentalized  in  lysosomes  and  become  catalytically  active  and  stable.  PPCA  is  synthesized  as  a  zymogen  of  54  kDa  that  is  processed  at  acidic  pH  into  a  32/20-kDa,  2-chain,  mature  enzyme.  It  is  active  at  both  acidic  and  neutral  pH  and  functions  as  cathepsin  A/deamidase/esterase  on  a  subset  of  neuropeptides,  including  substance  P,  oxytocin,  and  endothelin  I.  Cathepsin  A  activity  has  been  found  to  be  deficient  in  every  patient  with  GS  who  has  been  tested.The  3-dimensional  structure  of  the  PPCA  precursor  has  been  solved  by  a  combination  of  molecular  replacement  and  twofold  density  averaging.  The  structure  revealed  an  unusual  inactivation  mechanism  of  the  zymogen  that  explains  how  removal  of  the  2-kDa  peptide  triggers  activation.  A  number  of  amino  acid  substitutions  found  in  defective  PPCA  from  different  GS  patients  have  been  modeled  in  the  3-dimensional  structure.  There  appears  to  be  a  significant  correlation  between  the  effect  of  each  mutation  on  the  integrity  of  protein  structure  and  the  general  severity  of  the  clinical  phenotype.The  disease  can  be  suspected  in  patients  with  clinical  features  of  a  lysosomal  storage  disease  showing  sialyloligosacchariduria  on  thin-layer  chromatography.  The  demonstration  of  a  combined  deficiency  of  β-GAL  and  NEU1  in  lymphocytes  or  cultured  skin  fibroblasts  is  the  preferred  method  of  biochemical  diagnosis.  Assaying  only  the  cathepsin  A  activity  of  PPCA  might  give  a  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.183
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181466794
ER  -