RT Book, Section
A1 Gatti, Richard A.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181414123
T1 Ataxia-Telangiectasia
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=1181414123
RD 2024/04/19
AB The  diagnosis  of  ataxia-telangiectasia  (A-T)  is  based  primarily  on  clinical  examination  and  should  include  progressive  cerebellar  ataxia  with  onset  between  1  and  3  years  of  age.  Ocular  apraxia  is  a  reliable  diagnostic  criterion  after  3  years  of  age.  Telangiectasias  often  are  manifested  several  years  after  the  onset  of  ataxia;  the  degree  of  telangiectasia  is  quite  variable  from  family  to  family.  Serum  α-fetoprotein  (AFP)  is  elevated  in  95  percent  of  patients.  Magnetic  resonance  imaging  shows  a  dystrophic  cerebellum.  Karyotyping,  if  successful,  reveals  characteristic  translocations  involving  chromosomes  14q11-12,  14q32,  7q35,  and  7p14.  Immunodeficiency  and  cancer,  usually  lymphoid,  are  observed  in  many  A-T  patients.  Most  patients  have  no  measurable  ATM  (A-T  mutated)  protein  in  lysates  of  their  cells  or  cell  lines,  while  a  few  have  small  amounts.Because  A-T  patients  are  radiosensitive,  conventional  doses  of  radiation  therapy  are  contraindicated.  In  all  young  patients  with  lymphoid  malignancies,  an  underlying  diagnosis  of  A-T  should  be  considered  before  one  calculates  doses  of  radiation  or  radiomimetic  drugs.The  incidence  of  A-T  is  estimated  at  1  per  40,000  live  births  in  the  United  States.  The  carrier  frequency  was  estimated  at  1  percent;  recent  molecular  studies  support  this  early  estimate.  In  some  assays,  carriers  are  indistinguishable  from  normal  individuals.  Despite  this,  female  carriers  are  reported  to  be  at  a  fivefold  increased  risk  of  breast  cancer.  Carriers  may  account  for  5  percent  of  all  cancer  patients  in  the  United  States.  Carriers  are  intermediate  in  their  in  vitro  responses  to  ionizing  radiation-induced  DNA  damage.  Whether  they  are  clinically  more  radiosensitive  than  normals  is  not  known.  Conventional  wisdom  suggests  that  exposure  of  A-T  carriers  to  ionizing  radiation  should  be  minimized.  However,  mammograms  are  recommended,  and  the  same  age-dependent  schedule  as  for  noncarriers  should  be  followed.  Thus  far,  attempts  to  demonstrate  an  increased  frequency  of  ATM  mutations  in  breast  cancer  patients  have  not  corroborated  earlier  epidemiologic  observations.  Given  the  lack  of  convincing  data  on  cancer  risks  for  A-T  carriers,  it  is  prudent  to  advise  carriers  only  that  the  possibility  of  an  increased  cancer  risk  is  still  under  investigation.The  ATM  gene  and  gene  product(s)  are  very  large:  3056  amino  acids,  350  kDa,  a  13-kb  transcript  (and  smaller,  alternatively  spliced  products),  and  66  exons  that  cover  150  kb  of  genomic  DNA.  ATM  is  expressed  in  all  organs  tested.  ATM  belongs  to  a  large-molecular-weight  family  of  protein  kinases.  Delayed  or  reduced  expression  of  p53  in  radiation-damaged  A-T  cells  suggests  that  ATM  interacts  with  proteins  upstream  of  p53  in  sensing  double-strand  break  DNA  damage.  The  ATM  gene  product  also  plays  a  role  in  gametogenesis,  as  part  of  the  synaptonemal  complex.Seventy  percent  of  ATM  mutations  result  in  a  shortened  (truncated)  protein.  These  mutations  are  found  over  the  entire  gene  and  are  best  detected  by  mRNA-based  techniques  that  first  translate  the  mRNA  to  cDNA  by  RT-PCR  before  screening  for  mutations.  The  favored  RT-PCR-based  methods  are  PTT,  REF,  SSCP,  and  direct  sequencing.  Rapid  assays  that  are  DNA-based  are  being  developed  for  the  more  common  mutations,  and  for  mutations  that  are  common  to  particular  ethnic  populations,  such  as  the  Amish,  Moroccan  Jews,  Sardinians,  Italians,  British,  ...