RT Book, Section
A1 Hudson, Lynn D.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181479237
T1 Pelizaeus-Merzbacher Disease and the Allelic Disorder X-linked Spastic Paraplegia Type 2
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=1181479237
RD 2024/04/19
AB Pelizaeus-Merzbacher  disease  (PMD)  (MIM  312080),  together  with  the  allelic  disorder  spastic  paraplegia  type  2  (SPG2)  (MIM  312920),  which  also  maps  to  Xq22,  are  leukodystrophies  of  widely  varying  severity.  PMD  is  characterized  chiefly  by  impaired  motor  development  that  presents  within  the  first  year  and  progresses  throughout  life:  nystagmus,  ataxia,  spasticity,  and  mental  retardation  are  usually  encountered.  SPG2  patients  display  spasticity  of  the  lower  limbs.  In  patients  with  the  complicated  form  of  SPG2,  cerebellar  ataxia,  sensory  loss,  nystagmus,  and  optic  atrophy  may  also  be  present.A  loss  of  myelin  is  evident  by  MRI  or  histopathology  in  both  PMD  and  SPG2,  and  a  loss  of  oligodendrocytes  is  obvious  in  the  severe  connatal  form  of  PMD.  Abnormal  central  nervous  system  conduction  velocities,  as  analyzed  by  evoked  potentials,  reflect  the  myelin  defect.Mutations  in  the  X-linked  PLP  gene  (GenBank  M27110),  which  encodes  the  major  central  nervous  system  myelin  protein  (PLP)  and  its  alternatively  spliced  isoform  an  isoform  of  proteolipid  protein  with  a  MW  of  20  kDa  (DM20),  are  responsible  for  the  pathogenesis  of  PMD  and  SPG2.  Females  are  affected  only  infrequently  in  PMD,  but  in  the  relatively  mild  SPG2  the  PLP  mutation  can  act  semidominantly.Animal  models  exist  that  have  the  identical  mutation  found  in  the  human  form  of  the  disease:  the  jimpymsd  mouse  for  the  connatal  form  of  PMD  and  the  jimpyrsh  mouse  for  the  complicated  form  of  SPG2.PLP  is  a  gene  subject  to  dosage  control,  as  overexpression  of  PLP  is  the  most  common  type  of  mutation  in  PMD.  Transgenic  mice  carrying  multiple  copies  of  PLP  mimic  the  phenotype  of  PLP  duplications  found  in  the  classical  form  of  PMD.At  a  cellular  level,  the  extent  of  pathophysiology  in  PMD/SPG2  can  be  correlated  with  the  type  of  mutation  in  the  PLP  gene.  In  the  most  severe  mutations  (the  connatal  form  of  PMD),  nascent  PLP  and  DM20  accumulate  in  the  rough  endoplasmic  reticulum  of  oligodendrocytes  and  trigger  apoptosis.  Less  severe  mutations  spare  DM20,  which  can  traffic  to  the  sites  of  myelin  assembly  and  participate  in  myelin  sheath  formation.  Abnormal  PLP  and  DM20  proteins  generate  phenotypes  that  span  the  PMD/SPG2  spectrum,  while  either  too  much  or  too  little  of  these  lipoproteins  leads  to  intermediate  phenotypes,  such  as  the  classical  form  of  PMD  or  the  complicated  form  of  SPG2.