ABSTRACT
Auditory processing abnormalities in fragile X syndrome (FXS) may contribute to difficulties with language development, pattern identification, and contextual updating. Participants with FXS (N = 41) and controls (N = 27) underwent auditory event-related potentials during presentation of an oddball paradigm. Data was adequate for analysis for 33 participants with FXS and 27 controls (age 4-51 y, 13 females [FXS]; 4-54 y, 11 females [control]). Participants with FXS showed larger N1 and P2 amplitudes, abnormal lack of modulation of P1 and P2 amplitudes and P2 latency in response to oddball stimuli ) relative to controls: Females with FXS were more similar to controls. Participants with FXS showed a marginal speeding of the P2 latency, suggesting potentiation to oddball stimuli rather than habituation. Participants with FXS showed a heightened N1 habituation effect compared to controls. Gamma power was significantly higher for participants with FXS. Groups did not differ on mismatch negativity. Both controls and participants with FXS showed similar developmental trajectories in P1 and N1 amplitude, P2 latency, and gamma power, but not for P2 amplitude. One month retest analyses performed in 14 participants suggest strong test-retest reliability for most measures. Individuals with FXS show previously demonstrated increased response amplitude and high frequency neural activity. Despite an overall normal developmental trajectory for most measures, individuals with FXS show age-independent but gender-dependent decreases in complex processing of novel stimuli. Many markers show strong retest reliability even in children and thus are potential biomarkers for clinical trials in FXS.
Subject(s)
Attention/physiology , Auditory Perception/physiology , Brain Waves/physiology , Evoked Potentials, Auditory/physiology , Fragile X Syndrome/diagnosis , Fragile X Syndrome/physiopathology , Adolescent , Adult , Biomarkers , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sex Factors , Young AdultABSTRACT
BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disease that affects older carriers of premutation (CGG) repeat expansions of the fragile X mental retardation 1 (FMR1) gene. Clinical features include intention tremor, gait ataxia, memory loss, peripheral neuropathy, autonomic dysfunction, and parkinsonism. The presence of parkinsonism in FXTAS raises the possibility that some individuals who have Parkinson disease are actually carriers of a premutation FMR1 allele. OBJECTIVE: To screen DNA samples from a large cohort of females with Parkinson disease for an excess of expanded alleles of the FMR1 gene. DESIGN AND PATIENTS: We screened a cohort of 595 women with parkinsonism, the largest screening of a parkinsonism-associated group to date, for the presence of an FMR1 premutation allele (55-200 CGG repeats). The screening protocol uses an enhanced polymerase chain reaction method capable of flagging any FMR1 expanded CGG repeat in women as well as in men. SETTING: Diagnostic assessments were performed at an outpatient tertiary clinic (Parkinson Institute, Milan). Genotyping was conducted at the University of California, Davis. MAIN OUTCOME MEASURES: CGG repeat number and clinical/neuroimaging assessments of patients with Parkinson disease were conducted. Two premutation carriers were identified. RESULTS: Two individuals possessed an FMR1 allele in the premutation range (CGG repeats: 30 and 75; 30 and 115). This carrier frequency (2 of 595 [0.34%]) is not significantly different from estimates of the allele frequency among women in the general population (0.4%-0.8%). Clinical and radiologic features of these 2 patients were similar to those of the general Parkinson disease population; however, 1 patient (115 CGG repeats) had a family history of 2 sons with the fragile X syndrome. CONCLUSION: Screening of women within the parkinsonism clinical spectrum is unlikely to be productive in the absence of additional medical or family history suggestive of involvement of the FMR1 gene.
Subject(s)
Fragile X Mental Retardation Protein/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Parkinson Disease/genetics , Parkinson Disease/metabolism , Adult , Aged , Aged, 80 and over , Cohort Studies , DNA Mutational Analysis , Female , Fragile X Syndrome/complications , Fragile X Syndrome/genetics , Fragile X Syndrome/physiopathology , Gene Frequency/genetics , Genetic Markers/genetics , Genetic Testing , Genotype , Heterozygote , Humans , Male , Middle Aged , Parkinson Disease/physiopathologyABSTRACT
Hepatic tumors are rare childhood neoplasms with uncertain etiology. We report the cooccurrence of hepatic tumors in 2 boys with fragile X syndrome, one with hepatoblastoma and another with desmoplastic nested spindle cell tumor of liver. The pathogenesis of fragile X syndrome involves silencing of the fragile X mental retardation 1 gene and consequent loss of FMR1 protein. We speculate regarding molecular pathways that might explain the cooccurrence of the 2 conditions. Further examination of a possible functional link between hepatic neoplasia and loss of FMRP is warranted.
Subject(s)
Fragile X Syndrome/genetics , Hepatoblastoma/genetics , Liver Neoplasms/genetics , Neoplasms, Glandular and Epithelial/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Diagnosis, Differential , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/diagnosis , Fragile X Syndrome/therapy , Gene Silencing , Hepatoblastoma/diagnosis , Hepatoblastoma/therapy , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/therapy , Liver Transplantation , Male , Neoplasms, Glandular and Epithelial/diagnosis , Neoplasms, Glandular and Epithelial/therapy , Predictive Value of Tests , RNA, Messenger/genetics , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: Individuals with fragile X-associated tremor/ataxia syndrome frequently have associated features of parkinsonism, often leading to an initial diagnosis of Parkinson disease or other parkinsonism spectrum disorders. Parkinson disease populations may thus include individuals who harbor premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. OBJECTIVE: To screen DNA samples (male) from an Italian Parkinson disease clinic for an excess of premutation expansions of the FMR1 gene. DESIGN: DNA samples obtained from 903 unrelated males through consecutive clinic visits were analyzed by an enhanced polymerase chain reaction method for detecting expanded CGG repeats. SETTING: Diagnostic assessments were performed at the Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. Genotyping was conducted at the University of California Davis School of Medicine. PARTICIPANTS: A cohort of unrelated males with clinical features of parkinsonism. All but 12 males were of Italian origin, and all reported Caucasian ethnicity. MAIN OUTCOME MEASURE: CGG repeat number. RESULTS: Three premutation carriers (61, 69, and 80 CGG repeats) were identified (0.33%), which is not significantly higher than the frequency of premutation alleles in the general population. The outcome of the current study, the largest screen of individuals with parkinsonism to date, supports previous screens of smaller parkinsonism cohorts. CONCLUSION: Broad screening for premutation alleles in Parkinson disease populations is unlikely to be productive in the absence of additional clinical or family history data that suggest involvement of the FMR1 gene.
