Family impact of FXTAS diagnosis: Genetic counseling for at-risk relatives

Introduction. - Fragile X associated Tremor/Ataxia Syndrome (FXTAS) is related to premutation expansions of the FMR1 gene, including 55 to 200 CGG repeats, whereas full expansions, over 200 repeats, cause Fragile X mental retardation. FXTAS is observed in about one-third of men with premutation, generally in their 1950s and over, and less commonly in women. It is characterized by action tremor, ataxia, cognitive, parkinsonism, behavioral difficulties, autonomic dysfunction and peripheral neuropathy. Brain magnetic resonance imaging (MRI) often shows symmetric increases in T2-weighted signal intensity in the middle cerebellar peduncles. The diagnosis of FXTAS in a patient raises important family issues. Case report. - A 47-year-old male patient complained of an abnormal hearing sensation and dizziness for several months. Neurological examination was normal. Brain MRI showed the common signal intensity in middle cerebellar peduncles and bilateral punctual increases in T2-weighted signal intensity in the cerebral white matter. Genetic analysis showed 87 CGG repeats, in favor of a possible FXTAS. At the time of diagnosis, fragile X syndrome was subsequently suspected and confirmed in his 10-month-old grandson. Discussion. - Due to X-linked inheritance and to the specific related mutational mechanism, the diagnosis of FXTAS in a patient raises major issues for relatives over several generations, including males and females, who should be considered as obligate or potential premutation carriers. Premutated females are not only at risk of transmitting a full mutation to their children but also of developing Fragile X related premature ovarian failure (FXPOI) that may influence their choices in family planning. Conclusion. - The diagnosis of FXATS in a patient should induce delivery of extensive information and genetic counseling for potential carrier relatives. (C) 2013 Published by Elsevier Masson SAS.