title: Novel SETX variants in a patient with ataxia, neuropathy, and oculomotor apraxia are associated with normal sensitivity to oxidative DNA damaging agents.
abstract: BACKGROUND
  Homozygous and compound heterozygous mutations in SETX are associated with AOA2 disease, a recessive form of ataxia with oculomotor apraxia and neuropathy with onset of ataxia between the first and second decade of life. The majority of the AOA2 mutated cell lines tested show hypersensitivity to oxidative DNA damaging agents, with one exception.
  
  
  RESULTS
  We describe a patient presenting with early-onset progressive ataxia, oculomotor apraxia, axonal sensory-motor neuropathy, optic atrophy, delayed psychomotor development, and a behavior disorder. The patient carries two novel missense variants in the SETX gene. Based on the hypothesis that the patient's clinical phenotype may represent an atypical form of the AOA2 disease, we tested the patient-derived cell line for hypersensitivity to oxidative DNA damaging agents, with negative results.
  
  
  CONCLUSIONS
  The lack of hypersensitivity we observed may be explained either by considering the atypical clinical picture of the patient analyzed or, alternatively, by hypothesizing that the variants detected are not the cause of the observed phenotype. Consistent with the first hypothesis of an atypical AOA2 form and based on the multiple functions of senataxin reported so far, it is likely that different sets of SETX mutations/variants may have variable functional effects that still need to be functionally characterized. The possibility that the severe and complicated clinical picture presented by the patient described here represents a clinical entity differing from the known recessive ataxias should be considered as well.
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vantaggiato
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Cantoni
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guidarelli
authors.affiliation: Scientific Institute IRCCS E. Medea, Neuropsychiatry and Neurorehabilitation Unit, Bosisio Parini, Lecco, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Romaniello
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Citterio
authors.affiliation: Scientific Institute IRCCS E.Medea, Neuroimaging Unit, Bosisio Parini, Lecco, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Arrigoni
authors.affiliation: Radiology and Pediatric Neuroradiology, Buzzi Hospital, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Doneda
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Castelli
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Airoldi
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy; Dino Ferrari Centre, IRCCS Ca' Granda, Ospedale Maggiore Policlinico Foundation, Department of Physiopathology and Transplantation, University of Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Scientific Institute IRCCS E. Medea, Neuropsychiatry and Neurorehabilitation Unit, Bosisio Parini, Lecco, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Borgatti
authors.affiliation: Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy. Electronic address: mariateresa.bassi@bp.lnf.it.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D020240:Apraxia, Ideomotor / Q000150:complications / Q000235:genetics*; D002452:Cell Count; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D004249:DNA Damage / Q000187:drug effects; D004265:DNA Helicases; D005260:Female; D006801:Humans; D064251:Multifunctional Enzymes; D020125:Mutation, Missense; D009901:Optic Nerve Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016877:Oxidants / Q000633:toxicity; D020365:RNA Helicases / Q000235:genetics*
chemical_list: D064251:Multifunctional Enzymes; D016877:Oxidants; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
keywords: AOA2; DNA damage; Hypersensitivity; SETX