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From the Departments of Pediatric Neurology (M.M.M.V., M.A.A.P.W.), Pediatrics (M.M.M.V., C.M.R.W.), Neurology (W.F.A., H.P.H.K.), Human Genetics (D.F.C.M.S.), and Internal Medicine (M.v.D.), Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen; Department of Pathology and the DNA-Diagnostic Laboratory of the Family Cancer Clinic (F.B.L.H., L.J.v.V.) and Experimental Therapy (A.B., L.J.v.V.), The Netherlands Cancer Institute, Amsterdam; Department of Neurology (J.A.P.H.), Máxima Medical Centre, Veldhoven; Department of Neurology (E.R.B.), University Medical Centre Groningen, University of Groningen; Department of Neurology (M.A.v.R.), Leiden University Medical Centre; Department of Clinical Genetics (D.M.K., R.A.O.), Erasmus Medical Centre, Rotterdam, The Netherlands; Cancer Research UK (J.I.L., A.M.R.T.), Institute for Cancer Studies, Birmingham University, UK; and Department of Neurology (M.A.J.T., A.M.I.D.), Academic Medical Centre University of Amsterdam, The Netherlands.
* To whom correspondence should be addressed. E-mail: M.Willemsen{at}cukz.umcn.nl.
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 
-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 + 5>A and c.496 + 5>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5>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 -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.
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  R. J. Saunders-Pullman and R. Gatti Ataxia-telangiectasia: Without ataxia or telangiectasia? Neurology, August 11, 2009; 73(6): 414 - 415. [Full Text] [PDF]
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