Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype

Am J Med Genet A. 2007 Aug 15;143A(16):1827-34. doi: 10.1002/ajmg.a.31853.


Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, susceptibility to cancer, genomic instability, and sensitivity to ionizing radiation. A-T is caused by mutations that eliminate or inactivate the nuclear protein kinase ATM, the chief activator of the cellular response to double strand breaks (DSBs) in the DNA. Mild A-T is usually caused by ATM mutations that leave residual amounts of active ATM. We studied two siblings with mild A-T, as defined by clinical examination and a quantitative A-T neurological index. Surprisingly, no ATM was detected in the patients' cells, and sequence analysis revealed that they were homozygous for a truncating ATM mutation (5653delA) that is expected to lead to the classical, severe neurological presentation. Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A-T: all the tested parameters of the DSB response were severely defective as in typical A-T. This analysis shows that the severity of the neurological component of A-T is determined not only by ATM mutations but also by other influences yet to be found.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia / diagnosis*
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • Brain / pathology
  • Cell Cycle Proteins / genetics*
  • Child
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Models, Genetic
  • Mutation
  • Pedigree
  • Phenotype
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases