title: Clinical spectrum of ataxia-telangiectasia in adulthood.
abstract: OBJECTIVE
  To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene.
  
  
  METHODS
  Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity.
  
  
  RESULTS
  Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations.
  
  
  CONCLUSIONS
  Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.
authors.affiliation: Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: M M M
authors.initials: MM
authors.lastname: Verhagen
authors.forename: W F
authors.initials: WF
authors.lastname: Abdo
authors.forename: M A A P
authors.initials: MA
authors.lastname: Willemsen
authors.forename: F B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: D F C M
authors.initials: DF
authors.lastname: Smeets
authors.forename: J A P
authors.initials: JA
authors.lastname: Hiel
authors.forename: E R
authors.initials: ER
authors.lastname: Brunt
authors.forename: M A
authors.initials: MA
authors.lastname: van Rijn
authors.forename: D
authors.initials: D
authors.lastname: Majoor Krakauer
authors.forename: R A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: A
authors.initials: A
authors.lastname: Broeks
authors.forename: J I
authors.initials: JI
authors.lastname: Last
authors.forename: L J
authors.initials: LJ
authors.lastname: van't Veer
authors.forename: M A J
authors.initials: MA
authors.lastname: Tijssen
authors.forename: A M I
authors.initials: AM
authors.lastname: Dubois
authors.forename: H P H
authors.initials: HP
authors.lastname: Kremer
authors.forename: C M R
authors.initials: CM
authors.lastname: Weemaes
authors.forename: A M R
authors.initials: AM
authors.lastname: Taylor
authors.forename: M
authors.initials: M
authors.lastname: van Deuren
mesh_terms: D000328:Adult; D000367:Age Factors; D001260:Ataxia Telangiectasia / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult