title: Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation.
abstract: The fragile X syndrome is a mutation-driven developmental disorder caused by a repetition over 200 times of the CGG trinucleotide situated in the 5'-untranslated region of the fragile X mental retardation 1 gene (FMR1). The interval between 55 and 199 CGG repeats, which is over the normal range but below full mutation, is named fragile X premutation. Recent studies have focused on the asymptomatic state of fragile X premutation carriers and their potentially relevant preclinical features. However, the underlying neurological mechanisms leading to altered functions in fragile X premutation carriers are still poorly understood. In this study, we wanted to test the hypothesis that asymptomatic women who carry the fragile X premutation present GABAergic and cerebellar abnormalities compared with healthy women without the premutation. We performed noninvasive brain stimulation protocols on both asymptomatic fragile X premutation carriers and controls comprising of measures of GABAA- and GABAB-mediated intracortical inhibition, afferent inhibition, and cerebello-motor functional interactions. Premutation carriers presented an absence of cerebellar inhibition over primary motor cortex as well as a reduced GABAA-mediated intracortical and afferent inhibition compared with healthy nonpremutated controls. These alterations are most probably dependent on a dysfunctional GABAergic mechanism associated with the fragile X premutation condition as previously found in CGG-repeat animal models. Furthermore, the lack of cerebello-motor inhibition could be related to the cerebellar structural abnormalities previously found in carriers of the premutation.
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiolgía Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Seville, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Conde
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Palomar
authors.forename: María José
authors.initials: MJ
authors.lastname: Lama
authors.forename: Raquel
authors.initials: R
authors.lastname: Martínez
authors.forename: Fátima
authors.initials: F
authors.lastname: Carrillo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pintado
authors.forename: Pablo
authors.initials: P
authors.lastname: Mir
mesh_terms: D000328:Adult; D000344:Afferent Pathways / Q000503:physiopathology; D058070:Asymptomatic Diseases; D016022:Case-Control Studies; D002531:Cerebellum / Q000503:physiopathology*; D019054:Evoked Potentials, Motor; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009154:Mutation; D009433:Neural Inhibition; D050781:Transcranial Magnetic Stimulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D005680:gamma-Aminobutyric Acid; C497683:FMR1 protein, human