TY  - CHAP
M1  - Book, Section
TI  - The Neuronal Ceroid Lipofuscinoses
A1  - Hofmann, Sandra L.
A1  - Peltonen, Leena
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  - The  neuronal  ceroid  lipofuscinoses  (NCL)  are  a  group  of  progressive  hereditary  neurodegenerative  disorders  of  children  that  are  distinguished  from  other  neurodegenerative  diseases  by  the  accumulation  of  autofluorescent  material  (“aging  pigment”)  in  the  brain  and  other  tissues.  The  major  clinical  features  include  seizures,  psychomotor  deterioration,  blindness,  and  premature  death.  Distinct  subgroups  of  NCL  have  been  recognized  that  differ  in  the  age  of  onset  of  symptoms  and  the  appearance  of  the  storage  material  by  electron  microscopy.  Three  major  groups—infantile  (INCL),  classical  late  infantile  (LINCL),  and  juvenile  (JNCL,  also  referred  to  as  Batten  disease)—are  caused  by  autosomal  recessive  mutations  in  the  CLN1,  CLN2,  and  CLN3  genes,  respectively.  A  small  number  of  adult-onset  NCL  cases  (tentatively  designated  CLN4),  variant  late-infantile  forms  (CLN5,  CLN6,  and  tentatively,  CLN7),  and  a  progressive  myoclonic  epilepsy  (CLN8)  are  also  recognized  as  NCL  disorders.  The  protein  products  of  the  CLN1  (palmitoyl-protein  thioesterase)  and  CLN2  (pepinase)  genes  are  soluble  lysosomal  enzymes,  whereas  the  CLN3  protein  (battenin)  is  a  lysosomal  membrane  protein,  as  is  (tentatively)  the  CLN5  protein.  The  identification  of  mutations  in  genes  encoding  lysosomal  proteins  in  several  forms  of  NCL  has  led  to  the  recognition  of  the  lipofuscinoses  as  true  lysosomal  storage  disorders.All  of  the  NCLs  show  accumulation  of  autofluorescent  storage  material  in  multiple  tissues  by  light  microscopy.  In  the  brain,  ballooning  of  neurons  by  storage  material,  macrophage  reaction,  and  cortical  astrocytic  gliosis  may  be  striking.  The  cerebral  cortex  is  disproportionately  affected.  The  appearance  of  the  storage  material  under  the  electron  microscope  is  highly  characteristic  for  each  of  the  major  NCL  types:  granular  osmiophilic  deposits  (GROD)  in  INCL,  curvilinear  profiles  in  classical  LINCL,  and  fingerprint  profiles  in  juvenile  neuronal  ceroid  lipofuscinosis  (JNCL).  Variant  forms  of  LINCL  usually  show  a  mixture  of  curvilinear  and  fingerprint  profiles.  Adult  onset  (Kufs)  disease  shows  fingerprint  profiles  in  most  cases,  but  GROD  in  others.  Although  the  lysosomal  storage  is  present  in  peripheral  tissues,  tissue  destruction  and  cell  loss  are  nearly  entirely  restricted  to  the  central  nervous  system.In  contrast  to  other  lysosomal  storage  disorders,  classical  biochemical  characterization  of  NCL  storage  material  has  not  provided  insights  sufficient  to  uncover  the  underlying  biochemical  defects.  This  is  probably  due  to  the  heterogeneous  nature  of  the  storage  material.  Subunit  c  of  mitochondrial  ATP  synthase  is  a  major  storage  protein  identified  in  late  infantile,  juvenile,  and  adult  forms  of  NCL,  and  sphingolipid  activator  proteins  accumulate  to  a  striking  degree  in  INCL.  The  relationship  between  the  nature  of  the  storage  material  and  the  identified  molecular  defect  still  remains  unclear.Infantile  NCL  is  caused  by  a  deficiency  in  a  lysosomal  thioesterase  activity  (palmitoyl-protein  thioesterase  [PPT])  that  removes  fatty  acids  attached  in  thioester  linkage  to  cysteine  residues  in  proteins.  Accumulation  of  small  fatty  acyl-cysteine-containing  compounds  has  been  demonstrated  in  cultured  cells  from  INCL  patients  by  metabolic  labeling  studies.  Classical  LINCL  is  caused  by  deficiency  of  a  lysosomal  protease,  pepinase.  It  is  one  of  the  rare  lysosomal  storage  diseases  caused  by  a  deficiency  of  a  lysosomal  protease.  Proteins  defective  in  JNCL,  and  a  Finnish  variant  late  infantile  NCL,  have  also  been  identified.  The  protein  defective  in  JNCL  (battenin)  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181467266
ER  -