TY  - CHAP
M1  - Book, Section
TI  - Plasma Membrane Carnitine Transporter Defect
A1  - Stanley, Charles A.
A1  - Bennett, Michael J.
A1  - Longo, Nicola
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  - Primary  carnitine  deficiency,  also  known  as  carnitine  uptake  defect,  is  an  autosomal  recessive  disorder  caused  by  defective  activity  of  the  OCTN2  carnitine  transporter.  The  lack  of  membrane  transporters  results  in  carnitine  wasting  in  urine  with  systemic  carnitine  deficiency.  Lack  of  carnitine  impairs  mitochondrial  fatty  acid  oxidation  and  can  result  in  fasting-induced  hypoketotic  hypoglycemia  usually  associated  with  hepatic  dysfunction,  or  in  progressive  skeletal  muscle  and  cardiac  myopathy.  Some  patients  remain  asymptomatic  into  adult  life.Metabolic  decompensation  is  usually  precipitated  by  involuntary  fasting  associated  with  infection.  Cardiomyopathy  can  develop  even  without  any  trigger  and,  if  untreated,  can  result  in  death  from  cardiac  failure  or  arrhythmia.The  OCTN2  carnitine  transporter  is  encoded  by  the  SLC22A5  gene  on  chromosome  5q31.1-32.  The  gene  is  regulated  by  peroxisome  proliferator-activated  receptor  (PPAR)  α  through  a  peroxisome  proliferator  response  element.  The  mature  protein  of  557  amino  acids  is  ubiquitously  expressed  but  has  the  highest  levels  in  human  heart  placenta,  skeletal  muscle,  kidney  and  pancreas.  OCTN2  is  localized  to  the  apical  membrane  of  renal  tubular  cells,  consistent  with  its  role  in  tubular  reabsorption.OCTN2  functions  as  a  sodium-dependent  carnitine  transporter  accumulating  carnitine  within  cells  against  a  concentration  gradient,  particularly  in  high  energy-requiring  tissues.  Carnitine  is  essential  in  the  transport  of  long-chain  fatty  acids  into  the  mitochondrion  for  β-oxidation,  a  pathway  which  is  compromised  in  carnitine  deficiency  states  such  as  the  carnitine  transporter  defect.Patients  with  the  carnitine  uptake  defect  have  very  low  levels  of  total  carnitine  in  the  circulation  (usually  less  than  9  μmol/L,  normal  25-50  μmol/L).  Diagnosis  is  confirmed  by  functional  assays  in  fibroblasts  or  DNA  testing.  Newborn  screening  can  detect  low  levels  of  free  carnitine  (C0)  in  blood  spots  of  affected  children.  Cases  of  maternal  carnitine  transporter  deficiency  have  also  been  identified  based  on  low  neonatal  carnitine  levels.Treatment  of  the  carnitine  uptake  defect  is  effective  and  relies  on  high-dose  carnitine  supplementation  (100-400  mg/kg/day).  Outcomes  are  favorable,  but  treatment  needs  to  be  continued  for  life.  At  this  time,  it  is  not  clear  whether  the  apparently  asymptomatic  maternal  cases  of  the  defect  require  the  same  degree  of  therapy  as  this  is  a  recent  observation  and  insufficient  follow  up  is  available.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181438758
ER  -