title: Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia.
abstract: Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)-a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.
authors.affiliation: Department of Neurology, Gosford Hospital, Gosford 2250, Australia. y.hwang@ucl.ac.uk.|Institute of Neurology, University College London, London WC1N 3BG, UK. y.hwang@ucl.ac.uk.
authors.forename: Yun Tae
authors.initials: YT
authors.lastname: Hwang
authors.affiliation: Genetics of Learning Disability Service, Hunger Genetics, Waratah 2298, Australia. Tracy.Dudding@hnehealth.nsw.gov.au.|Grow Up Well Priority Research Centre, University of Newcastle, Waratah 2308, Australia. Tracy.Dudding@hnehealth.nsw.gov.au.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dudding
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. solange.aliagavera@mcri.edu.au.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne 3010, Australia. solange.aliagavera@mcri.edu.au.|Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago 7830490, Chile. solange.aliagavera@mcri.edu.au.
authors.forename: Solange Mabel
authors.initials: SM
authors.lastname: Aliaga
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. marta.arpone@mcri.edu.au.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne 3010, Australia. marta.arpone@mcri.edu.au.
authors.forename: Marta
authors.initials: M
authors.lastname: Arpone
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. david.francis@vcgs.org.au.
authors.forename: David
authors.initials: D
authors.lastname: Francis
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. xin.li@mcri.edu.au.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Cyto-molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. howard.slater@vcgs.org.au.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne 3010, Australia. howard.slater@vcgs.org.au.
authors.forename: Howard Robert
authors.initials: HR
authors.lastname: Slater
authors.affiliation: Genetics of Learning Disability Service, Hunger Genetics, Waratah 2298, Australia. Carolyn.Rogers@hnehealth.nsw.gov.au.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Psychology Service, Royal Children's Hospital, Melbourne 3052, Australia. Lesley.Bretherton@rch.org.au.|Melbourne School of Psychological Sciences, University of Melbourne, Melbourne 3052, Australia. Lesley.Bretherton@rch.org.au.|Child Neuropsychology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne 3052, Australia. Lesley.Bretherton@rch.org.au.
authors.forename: Lesley
authors.initials: L
authors.lastname: Bretherton
authors.affiliation: Molecular Genetics Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal children's Hospital, Melbourne 3052, Australia. dusart.desiree@mcri.edu.au.
authors.forename: Desirée
authors.initials: D
authors.lastname: du Sart
authors.affiliation: Faculty of Medicine, University of Newcastle, Newcastle 2303, Australia. morkeu@gmail.com.|Westmead Millennium Institute, University of Sydney, Westmead 2145, Australia. morkeu@gmail.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Heard
authors.affiliation: Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago 7830490, Chile. david.godler@mcri.edu.au.
authors.forename: David Eugeny
authors.initials: DE
authors.lastname: Godler
keywords: AmplideX; FMR1; FXTAS; RNA toxicity; Southern blot; ataxia; fragile X syndrome; methylation; mosaicism; tremor