title: Fragile X-associated tremor/ataxia phenotype in a male carrier of unmethylated full mutation in the FMR1 gene.
abstract: The Fragile X syndrome is caused by a CGG repeat expansion >200 in the promoter of the Fragile X mental retardation 1 (FMR1) gene termed full mutation (FM). These alleles are silenced through methylation of the FMR1 promoter, leading to deficit of the FMR1 protein (FMRP), and neurodevelopmental changes. However, occasional FM individuals have a complete lack of methylation, and those typically have only minor deficit of FMRP levels compared with normal controls and their intelligence may be in the normal range. FM alleles are generated through expansion of the CGG repeat from the premutation (PM) range of 55-200 repeats, linked to the late onset Fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder has been attributed to a 'toxicity' of the FMR1 mRNA, which is significantly elevated in male carriers of PM alleles and of unmethylated FM alleles. This is the first report of a 65-year-old male with an unmethylated FM allele and history of alcohol abuse, who developed symptoms of FXTAS. We postulate that, although the elevation of FMR1 transcripts associated with unmethylated FM alleles have a potential to cause FXTAS, in some cases this disorder may occur through an additional effect of exposure to neurotoxicants including alcohol.
authors.affiliation: School of Psychological Science, La Trobe University, Melbourne, VIC 3086, Australia. d.loesch@latrobe.edu.au
authors.forename: D Z
authors.initials: DZ
authors.lastname: Loesch
authors.forename: S
authors.initials: S
authors.lastname: Sherwell
authors.forename: G
authors.initials: G
authors.lastname: Kinsella
authors.forename: F
authors.initials: F
authors.lastname: Tassone
authors.forename: A
authors.initials: A
authors.lastname: Taylor
authors.forename: D
authors.initials: D
authors.lastname: Amor
authors.forename: S
authors.initials: S
authors.lastname: Sung
authors.forename: A
authors.initials: A
authors.lastname: Evans
mesh_terms: D000368:Aged; D000437:Alcoholism / Q000150:complications / Q000235:genetics*; D001259:Ataxia / Q000209:etiology / Q000235:genetics*; D019175:DNA Methylation; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000209:etiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D014202:Tremor / Q000209:etiology / Q000235:genetics*; D018911:Trinucleotide Repeats
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human