TY  - CHAP
M1  - Book, Section
TI  - Channelopathies: Episodic Disorders of the Nervous System
A1  - Jen, Joanna C.
A1  - Ptáček, Louis
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.239
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Ion  channels  are  membrane  proteins  that  allow  rapid,  passive,  but  selective  passage  of  ions.  The  dynamic  interaction  of  ion  channels  is  critical  for  the  regulation  of  membrane  excitability  and  the  function  of  excitable  cells,  such  as  nerve  and  muscle.  Indeed,  modern  molecular  techniques  have  led  to  the  successful  identification  of  mutations  in  genes  encoding  both  voltage-gated  and  ligand-gated  ion  channels  in  numerous  human  neuromuscular  disorders,  collectively  termed  channelopathies.  Channelopathies  include  periodic  paralysis,  episodic  ataxia,  congenital  myasthenic  syndromes,  hereditary  hyperekplexia,  rare  epilepsies,  cardiac  arrhythmias,  and  migraine  syndromes  that  share  similarities  in  their  episodic  nature,  precipitating  factors,  therapeutic  responses,  and  long-term  degenerative  features.  Understanding  the  phenotypic  expression  of  these  rare,  monogenic  channelopathies  may  shed  light  on  similar  mechanisms  in  the  more  common,  likely  polygenic  and  multifactorial,  paroxysmal  neurologic  disorders,  such  as  migraine  and  epilepsy.  See  Table  248-1  for  MIM  and  GenBank  numbers.Familial  periodic  paralyses  are  the  prototypical  channelopathies.  These  are  autosomal  dominant  disorders  characterized  by  episodes  of  weakness  or  by  paralysis  precipitated  by  stress  or  fatigue,  with  residual  myopathy.  Some  patients  respond  well  to  acetazolamide,  a  carbonic  anhydrase  inhibitor.  Hyperkalemic  periodic  paralysis,  so  named  because  an  oral  potassium  load  can  precipitate  an  attack,  is  associated  with  muscle  sodium  channel  mutations.  Paramyotonia  congenita,  characterized  by  myotonia  paradoxically  worsened  by  repeated  muscle  action,  is  also  associated  with  muscle  sodium  channel  mutations.  Hypokalemic  periodic  paralysis,  characterized  by  episodic  weakness  without  myotonia  precipitated  by  lowering  of  serum  potassium,  is  associated  with  muscle  calcium  channel  mutations.  Myotonia  congenita,  with  prominent  muscle  hyperexcitability  inherited  dominantly  or  recessively,  is  another  group  of  muscle  disorders  associated  with  ion  channel  mutations,  specifically  muscle  chloride  channels.Episodic  ataxia  is  an  autosomal  dominant  disorder  characterized  by  attacks  of  gait  imbalance  and  clumsiness  precipitated  by  stress  and  fatigue  and  often  dramatically  responsive  to  acetazolamide.  While  most  patients  have  no  interictal  neurologic  deficits,  some  may  experience  a  slow  decline  in  baseline  function  with  evidence  of  cerebellar  atrophy.  Episodic  ataxia  type  1  (with  myokymia)  is  associated  with  mutations  in  a  potassium  channel  gene  widely  expressed  in  the  nervous  system.  Episodic  ataxia  type  2  (with  interictal  nystagmus)  is  associated  with  mutations  in  a  calcium  channel  gene  prominently  expressed  in  the  cerebellum  and  the  neuromuscular  junction.  Other  mutations  in  the  same  calcium  channel  gene  may  cause  hemiplegic  migraine  or  severe  progressive  ataxia  in  addition  to  attacks  of  imbalance.Congenital  myasthenic  syndromes  are  nonimmune  mediated  disorders  of  neuromuscular  transmission  characterized  by  weakness,  fatigability,  and  progressive  muscle  atrophy.  Mutations  in  the  α,  β,  or  ϵ  subunit  of  the  nicotinic  acetylcholine  receptor  channel  resulting  in  abnormal  channel  kinetics  or  assembly  appear  to  be  the  cause  in  many  cases  of  congenital  myasthenic  syndromes.  Slow  channel  congenital  myasthenic  syndrome  is  an  autosomal  dominant  disorder  caused  by  mutations  that  prolong  nicotinic  acetylcholine  receptor  channel  opening,  which  contributes  to  inappropriate  endplate  depolarization  and  potential  excitotoxicity.  Heteroallelic  mutations  in  the  ϵ  subunit  gene  cause  congenital  myasthenic  syndromes  through  two  different  mechanisms:  lack  of  ϵ  subunit  leading  to  deficiency  of  acetylcholine  receptor  channels  (with  partial  phenotypic  rescue  by  the  expression  of  the  fetal  γ  subunit),  or  altered  agonist  binding  and  channel  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.239
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181475062
ER  -