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A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA
  1. S Saviozzi1,
  2. A Saluto1,
  3. A M R Taylor2,
  4. J I L Last2,
  5. F Trebini3,
  6. M C Paradiso4,
  7. E Grosso4,
  8. A Funaro1,
  9. G Ponzio1,4,
  10. N Migone1,4,
  11. A Brusco1
  1. 1Dipartimento di Genetica, Biologia e Biochimica, Torino, Italy
  2. 2CRC Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK
  3. 3Divisione di Neurologia, Ospedale Mauriziano Umberto I, Torino, Italy
  4. 4Unità Operativa di Genetica Medica, Azienda Ospedaliera San Giovanni Battista, Torino, Italy
  1. Correspondence to:
 Dr A Brusco, Dipartimento di Genetica, Biologia e Biochimica, via Santena 19, 10126 Torino, Italy;
 a.brusco{at}cios.to.cnr.it

https://doi.org/10.1136/jmg.39.1.57

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    A taxia-telangiectasia (A-T) is a multisystem autosomal recessive disorder, with an estimated frequency of 1/40 000-1/100 000 live births.1 The ataxia-telangiectasia mutated gene (ATM), located on chromosome 11q22-23,2 encodes a nuclear 370 kDa phosphoprotein, homologous to a family of phosphatidylinositol kinase related proteins involved in DNA damage response and cell cycle regulation.3–6 Classical A-T patients show progressive cerebellar degeneration with onset in childhood, oculocutaneous telangiectasia, variable immunodeficiency, recurrent sinopulmonary infections, and high levels of serum α-fetoprotein, chromosomal instability, and predisposition to lymphoid malignancies. The majority of patients are compound heterozygotes for two truncating ATM mutations with no detectable ATM protein. The A-T phenotype, therefore, is most commonly the result of null alleles, although missense mutations can also destabilise the protein, with similar consequences.7–9

    Milder cases, designated A-T variants, are a heterogeneous group characterised by a combination of one or more of the following: later onset of clinical signs, slower progression, extended life span when compared to most classical A-T patients, and decreased levels of chromosomal instability and cellular radiosensitivity.10–12 In these patients telangiectasia and/or immunodeficiency can be absent while secondary features of A-T, such as peripheral neuropathy, dysarthria, chorea and/or dystonia, are present. Cancer and recurrent sinopulmonary infections may also be absent or reduced. The genotype of A-T variants is mostly compound heterozygous for a severe mutation together with a mild or leaky mutation, which is expected to express some ATM protein with residual function.13–15

    A normal level of ATM protein in A-T variants can also be suggestive of mutations in other genes such as hMRE11, mutated in an A-T-like disorder with a classical A-T phenotype without telangiectasia.16–17 Other syndromes, such as Nijmegen breakage syndrome (NBS), include some A-T signs combined with a typical facies, sinopulmonary infections, …

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