TY  - CHAP
M1  - Book, Section
TI  - X-Linked Adrenoleukodystrophy
A1  - Moser, Hugo W.
A1  - Smith, Kirby D.
A1  - Watkins, Paul A.
A1  - Powers, James
A1  - Moser, Ann B.
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  term  adrenoleukodystrophy  (ALD)  is  used  to  describe  two  genetically  determined  disorders  that  cause  varying  degrees  of  malfunction  of  the  adrenal  cortex  and  nervous  system  myelin,  and  are  characterized  by  abnormally  high  levels  of  very  long  chain  fatty  acids  (VLCFA)  in  tissues  and  body  fluids.Two  types  of  ALD  must  be  distinguished.  One  type  is  X-linked  (MIM  300100),  with  the  biochemical  abnormality  apparently  confined  to  very  long  chain  fatty  acid  metabolism,  and  normal  peroxisome  structure.  The  second  type  has  an  autosomal  recessive  mode  of  inheritance,  is  referred  to  as  neonatal  adrenoleukodystrophy  (MIM  202370),  and  resembles  the  Zellweger  cerebrohepatorenal  syndrome  (MIM  214100)  in  that  the  number  and  size  of  peroxisomes  are  diminished  and  the  function  of  at  least  five  peroxisomal  enzymes  is  impaired.  This  chapter  is  concerned  with  X-linked  ALD  (X-ALD).  Neonatal  ALD  is  discussed  in  X-Linked  Adrenoleukodystrophy.The  incidence  of  males  with  X-ALD  is  estimated  to  lie  between  1:20,000  and  1:50,000  of  the  total  population,  and  appears  to  be  the  same  in  most  ethnic  groups.  There  are  several  distinct  phenotypes.  Approximately  35  percent  of  patients  have  the  childhood  cerebral  form.  Affected  boys  develop  normally  until  4  to  8  years  of  age,  and  then  suffer  dementia  and  a  progressive  neurologic  deficit  that  leads  to  a  vegetative  state.  More  than  90  percent  of  these  have  adrenal  insufficiency.  In  approximately  35  to  40  percent  of  patients,  the  disorder  presents  in  young  adulthood  as  a  slowly  progressive  paraparesis  with  sphincter  disturbances  that  involves  the  long  tracts  in  the  spinal  cord  mainly  and  is  referred  to  as  adrenomyeloneuropathy  (AMN).  Adrenal  insufficiency  is  present  in  two-thirds  of  these  patients.  Less  common  phenotypes  include  adrenal  insufficiency  without  nervous  system  involvement,  progressive  cerebral  dysfunction  in  adults,  a  syndrome  that  resembles  olivopontocerebellar  degeneration,  and  persons  who  are  asymptomatic.  The  various  phenotypes  commonly  occur  within  the  same  kindred.  Twenty  percent  of  female  heterozygotes  develop  overt  neurologic  disturbances  that  resemble  those  of  adrenomyeloneuropathy.  Up  to  50  percent  of  heterozygotes  have  mild  neurologic  abnormalities,  but  overt  adrenal  insufficiency  is  rare.Tissues  and  body  fluids  of  patients  with  X-ALD  contain  abnormally  high  levels  of  unbranched  saturated  very  long  chain  fatty  acids,  particularly  hexacosanoate  (C26:0).  This  excess  is  most  striking  in  the  cholesterol  ester  and  ganglioside  fractions  of  affected  brain  white  matter  and  adrenal  cortex,  but  is  present  to  varying  degrees  in  virtually  all  tissues  and  body  fluids.The  very  long  chain  fatty  acid  accumulation  is  associated  with  an  impaired  capacity  for  their  degradation,  a  reaction  that  normally  takes  place  in  the  peroxisome.  The  defect  results  in  an  impaired  capacity  to  form  the  coenzyme-A  derivative  of  very  long  chain  fatty  acids  in  the  peroxisome,  a  reaction  which  is  catalyzed  by  very  long  chain  acyl-CoA  synthetases  (VLCS).The  gene  for  X-ALD  has  been  mapped  to  Xq28.  It  codes  for  a  peroxisomal  membrane  protein  with  homology  to  the  ATP-binding  cassette  (ABC)  transporter  superfamily  of  proteins.  The  X-ALD  protein  (ALDP)  is  closely  related  to  three  other  peroxisomal  membrane  ABC  proteins.  One  of  these,  ALDRP,  has  66  percent  homology  to  the  protein  product  of  the  ALD  gene  (ALDP)  and  may  have  some  overlapping  function.  Mutations  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181452847
ER  -