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Objectives/background  Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T,  ATM  gene), ataxia with oculomotor apraxia type 1 (AOA1,  APTX  gene) and type 2 (AOA2,  SETX  gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha-fetoprotein (AFP) serum level.    Materials and methods  We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of  ATM ,  APTX  and  SETX  genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in  SETX  by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected.    Results  Thirteen patients (12 families) carried  SETX  mutations (AOA2, 57%), two were mutated in  ATM  (A-T), and three in  APTX  (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the  SETX  p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported  SETX  mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14–45 years). The patient carrying the p.K992R  SETX  polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features.    Discussion and conclusions  We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor apraxia. In our survey ~60% of juvenile-to-adult cases with cerebellar ataxia, sensorimotor neuropathy and increased AFP are due to mutations in the  SETX  gene, and a smaller percentage to  APTX  and  ATM  gene mutations.

SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein