TY  - CHAP
M1  - Book, Section
TI  - Cystinosis: A Disorder of Lysosomal Membrane Transport
A1  - Gahl, William A.
A1  - Thoene, Jess G.
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  - Cystinosis  is  a  rare  inherited  autosomal  recessive  lysosomal  storage  disorder  caused  by  defective  carrier-mediated  transport  of  the  amino  acid  cystine  across  the  lysosomal  membrane.  The  major  clinical  manifestation  of  cystinosis  is  renal  failure  in  patients  at  approximately  9-10  years  of  age.  The  cystinosis  gene  has  been  isolated,  and  several  different  mutations  have  been  identified.In  cystinosis,  free,  nonprotein  cystine  accumulates  to  10-1000  times  normal  levels  and  forms  crystals  within  the  lysosomes  of  most  tissues,  which  are  damaged  at  different  rates.  The  diagnosis  is  made  by  demonstrating  an  elevated  cystine  content  in  polymorphonuclear  leukocytes  or  cultured  fibroblasts  or  by  slit-lamp  examination  showing  corneal  crystals,  which  are  generally  present  in  patients  older  than  1  year  of  age.  Cystinosis  can  be  diagnosed  in  utero  by  cystine  measurements  in  amniocytes  or  chorionic  villi  or  at  birth  by  cystine  measurements  of  the  placenta.Children  with  cystinosis  are  normal  at  birth  but  develop  signs  of  renal  tubular  Fanconi  syndrome,  usually  between  6  and  12  months  of  age.  Symptoms  include  dehydration,  acidosis,  vomiting,  electrolyte  imbalances,  hypophosphatemic  rickets,  and  failure  to  grow.  Weight  is  proportional  to  height,  and  head  circumference  and  intelligence  are  not  affected.  Other  manifestations  of  cystinosis  include  photophobia,  hypothyroidism,  and  decreased  ability  to  sweat.  Renal  glomerular  damage  progresses  inexorably,  requiring  dialysis  or  transplantation  at  6  to  12  years  of  age.Cystine  storage  does  not  occur  in  the  donor  kidney,  but  continued  accumulation  in  the  host  tissue  can  result  in  retinal  blindness,  corneal  erosions,  diabetes  mellitus,  a  distal  myopathy,  swallowing  difficulties,  decreased  pulmonary  function,  pancreatic  insufficiency,  primary  hypogonadism  in  males,  and  neurologic  deterioration  in  a  significant  number  of  postrenal  transplant  patients  aged  13-50  years.The  cystinosis  gene,  CTNS,  is  located  on  chromosome  17p13,  has  12  exons  spanning  23kb  of  genomic  DNA,  and  codes  for  a  367-amino-acid  protein  called  cystinosin,  with  7  transmembrane  domains  and  8  potential  glycosylation  sites.  Approximately  40  percent  of  cystinosis  patients  from  northern  Europe  are  homozygous  for  a  57-kb  deletion  that  disrupts  CTNS.  Sixty  percent  of  nearly  500  alleles  of  an  American-based  cystinosis  population  contain  the  57-kb  deletion.  One  hundred  and  eight  other  mutations  have  been  identified  to  date.Therapy  for  cystinosis  includes  replacement  of  renal  losses  due  to  Fanconi  syndrome;  provision  of  thyroxine,  insulin,  pancreatic  enzymes,  and  testosterone  for  deficient  patients;  and  symptomatic  care  of  ophthalmic  complaints.  Chronic  cystine-depleting  therapy  with  the  aminothiol  cysteamine  significantly  lowers  leukocyte  and  parenchymal  cystine  levels,  improves  growth,  and  obviates  the  need  for  thyroid  hormone  replacement.  More  importantly,  oral  cysteamine  therapy  preserves  renal  function  and,  if  initiated  in  the  first  2  years  of  life,  can  allow  for  a  net  increase  in  the  glomerular  filtration  rate.  Long-term  oral  cysteamine  therapy  also  prevents  most  of  the  late  nonrenal  complications  of  cystinosis.  Side  effects  of  oral  cysteamine  include  nausea  and  vomiting.  Cysteamine  eyedrops  can  dissolve  corneal  crystals  in  young  children  and  remove  the  haziness  from  the  corneas  of  older  patients.The  clinical  course  and  severity  of  cystine  accumulation  in  cystinosis  vary  in  different  kindreds,  from  ocular  cystinosis  in  adults  with  corneal  crystals  but  no  renal  disease,  to  intermediate  cystinosis  in  adolescents  with  late-onset  renal  deterioration,  and  finally  to  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/23
UR  - ommbid.mhmedical.com/content.aspx?aid=1181473990
ER  -