RT Book, Section
A1 Beitel, Lenore K.
A1 Pinsky, Leonard
A1 Elhaji, Youssef A.
A1 Trifiro, Mark A.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181453633
T1 Spinobulbar Muscular Atrophy
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=1181453633
RD 2024/04/19
AB X-linked  spinobulbar  muscular  atrophy  (SBMA,  Kennedy  disease,  OMIM  no.  313200)  is  an  adult-onset  motor  neuronopathy  that  typically  causes  slowly  progressive,  symmetric  wasting  and  weakness,  initially  of  the  proximal  muscles  of  the  hip  and  shoulder.  Muscle  cramps,  hand  tremors,  and  fasciculations  are  often  associated.  Eventually,  motor  nuclei  of  the  brain  stem  become  involved,  leading  to  speech  and  swallowing  difficulties.  Male  hypogonadism,  usually  represented  by  gynecomastia  and  testicular  atrophy  and  attributable  to  mild  androgen  insensitivity,  is  not  infrequent.  Variable  expressivity  is  prominent.SBMA  is  the  archetype  and  prototype  of  the  class  of  Mendelian,  adult-onset  neuronodegenerative  diseases  caused  by  proteins  with  expanded  polyglutamine  (polyGln)  tracts.  It  is  archetypical  for  two  reasons:  (a)  it  was  the  first  member  of  the  class  to  be  identified  when  it  was  discovered  that  exon  1  of  the  androgen  receptor  gene  (AR)  in  SBMA  patients  had  an  expanded  (CAG)  n  tract,  and  (b)  it  was  the  first  member  of  the  class  in  which  the  normal  functions  of  the  culpable  protein  were  well  known.  Since  subjects  with  complete  androgen  insensitivity,  including  those  with  complete  AR  deletions,  do  not  develop  SBMA,  this  knowledge  mandated  the  logic  that  the  polyCAG-expanded  AR  or  the  polyGln-expanded  AR  protein  is  somehow  motor  neuronotoxic  by  a  gain,  not  a  loss,  of  function.SBMA  is  prototypical  of  the  class  for  several  reasons:  (a)  it  is  now  clear  that  the  polyGln-expanded  AR  protein,  and  probably  the  expanded  polyGln  tracts  themselves,  with  certain  flanking  segments  of  the  various  parental  proteins,  are  the  essential  pathogenetic  agents  in  this  class  of  neuronodegenerative  disease,  (b)  the  preferential  death  of  certain  motor  neurons  in  SBMA  exemplifies  the  fact  that  selective  death  of  certain  neuronal  populations  is  responsible  for  the  clinical  diversity  among  the  known  diseases  in  the  class,  (c)  there  is  extremely  variable  clinical  expressivity  (age  of  onset,  rate  and  pattern  of  progression)  of  SBMA,  and  compared  with  other  members  of  the  class,  relatively  little  of  this  variability  is  attributable  to  different  degrees  of  polyGln  expansion  generated  by  meiotic  or  mitotic  instability  of  (CAG)  n  -repeat  size,  and  (d)  SBMA  illustrates  that  expansion  to  beyond  approximately  38  repeats  endows  a  polyGln  tract  with  a  threshold  property  (or  more  than  one)  that  is  selectively  lethal  to  certain  neurons.  The  biochemical,  histopathologic,  and  neurophysiologic  features  of  SBMA  are,  unremarkably,  those  secondary  to  motor  denervation.  Endocrine  laboratory  evidence  of  mild  androgen  insensitivity  (normal  or  elevated  serum  testosterone  and  luteinizing  hormone  levels)  may  or  may  not  be  found.The  mild  androgen  insensitivity  component  of  SBMA  is  clearly  due  to  a  loss  of  function  by  the  polyGln-expanded  AR  protein.  The  loss  may  be  attributable  to  one  or  more  of  the  following:  decreased  steady-state  levels  of  AR,  decreased  androgen-binding  affinity  of  the  mutant  AR,  or  decreased  transcriptional  regulatory  competence  of  the  mutant  AR.  These  factors  may  contribute  to  different  extents  in  various  androgen  target  cells.  Since  androgens  are  both  motor  neuronotropic  and  motor  neuronotrophic,  it  is  possible  that  the  polyGln-expanded  AR  protein  loses  a  function  that  is  necessary,  but  not  sufficient,  for  the  motor  neuronopathy  of  SBMA  generally  or  for  death  of  certain  motor  ...