In the original publication of this article [1], the author name Leonard Abbeduto was misspelled as Leonardkk Abbeduto. The original article has been corrected.

Purpose: Emerging evidence indicates that women who carry an FMR1 premutation can experience complex health profiles beyond the two well-established premutation-associated disorders: fragile X–associated primary ovarian insufficiency (FXPOI, affects ~20–30% carriers) and fragile X–associated tremor–ataxia syndrome (FXTAS, affects ~6–15% carriers). Methods: To better understand premutation-associated health profiles, we collected self-reported medical histories on 355 carrier women. Results: Twenty-two health conditions were reported by at least 10% of women. Anxiety, depression, and headaches were reported by more than 30%. The number of comorbid conditions was significantly associated with body mass index (BMI) and history of smoking, but not age. Survival analysis indicated that women with FXPOI had an earlier age at onset for anxiety and osteoporosis than women without FXPOI. Cluster analysis identified eight clusters of women who reported similar patterns of comorbid conditions. The majority of carriers (63%) fell into three categories primarily defined by the presence of only a few conditions. Interestingly, a single cluster defined women with symptoms of FXTAS, and none of these women had FXPOI. Conclusion: Although some women with a premutation experience complex health outcomes, most carriers report only minimal comorbid conditions. Further, women with symptoms of FXTAS appear to be distinct from women with symptoms of FXPOI.

Background: The evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status. Methods: Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ < 70). ELS procedures for collecting samples in conversation and narration were followed and analyzed separately. Five measures were derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers): number of C-units per minute (talkativeness), number of different word roots (vocabulary), C-unit length in morphemes (syntax), percentage of C-units containing dysfluency (utterance planning), and percentage of C-units that were fully or partly unintelligible (articulatory quality). ELS procedures were administered twice at 4-week intervals for each participant. Standardized tests and informant reports were administered and provided measures for evaluating construct validity of ELS measures. Results: We found low rates of noncompliance, suggesting the task can be completed meaningfully by most individuals with FXS, although noncompliance was higher for younger, lower IQ, and more autistic participants. Minimal practice effects and strong test-retest reliability over the 4-week interval were observed for the full sample and across the range of ages, IQs, and autism symptom severity. Evidence of convergent construct validity was observed for the measures of vocabulary, syntax, and unintelligibility for the full sample and across the range of IQ and autism symptom severity, but not for participants under age 12. Conversation and narration yielded largely similar results in all analyses. Conclusions: The findings suggest that the ELS procedures are feasible and yield measures with adequate psychometric properties for a majority of 6 to 23 years with FXS who have ID. The procedures work equally well regardless of level of ID or degree of ASD severity. The procedures, however, are more challenging and have somewhat less adequate psychometric properties for individuals with FXS under age 12.

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.

Objective: Approximately 20% of women with a premutation in the FMR1 gene experience primary ovarian insufficiency (POI). We explored diagnostic patterns, frequency of appropriate hormone replacement, obstetric outcomes, fertility treatment, reproductive decisions, and counseling of women with fragile X-associated POI (FXPOI). Methods: Semistructured interviews with 79 women with FXPOI were conducted by a single interviewer. FMR1 cytosine-guanine-guanine repeat size was determined from a blood, saliva, or buccal sample. Results: The median age of POI onset for women in our study was 33 years. Seventy-two percent of the women had an FMR1 cytosine-guanine-guanine repeat length of 80 to 100. Mean length of time from symptom onset to POI diagnosis was 1.12 years, longer in women with a younger age of POI onset and shorter in women who knew they were carriers. After diagnosis, 52% of women never took hormone therapy, started it years after POI diagnosis, or stopped it before 45 years of age. Forty-nine percent of the women had infertility, but 75% had had at least one genetically related child. Obstetric outcomes were similar to the general population. Forty-six percent of women had a diagnosis of low bone mineral density or osteoporosis, and an additional 19% had never had a bone density assessment. Conclusions: Women with FXPOI are at significant risk for delayed POI diagnosis and undertreatment with hormone therapy. Although approximately 50% of women had infertility, most were able to conceive at least one child and had no elevated risk of adverse obstetric outcomes.

Objective Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The primary features of FXTAS are late-onset intention tremor and gait ataxia. Previous reports have shown global deficits in neuropsychological measures among males with FXTAS, particularly those related to executive functioning. The purpose of this study was to investigate the neuropsychological profile among older males with the premutation who are at risk for FXTAS. Method Premutation carriers, 66 with motor symptoms and 23 without, and 18 non-carrier siblings were recruited from pedigrees diagnosed with fragile X syndrome, all over age 50. Subjects were examined with a neurological test battery to identify symptoms of FXTAS and a neuropsychological test battery to investigate cognitive and behavioral profiles. Linear regression and ANCOVA were used to determine the effect of the premutation on outcome measures adjusting for age and education. Results We identified a significant decrease in scores of general intelligence and a marginally significant decrease in scores of logical memory among premutation carrier males with motor symptoms compared to the non-carrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. Discussion Similar to other reports, we found that the FMR1 premutation is associated with deficits in general intelligence and memory among older males with symptoms of FXTAS. However, our results differed in that we found no evidence of premutation-associated executive dysfunction. We provide possible explanations for this difference.

The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype–phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype–phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p<0.05. All FMR1 premutation carriers were men of mean age 65±7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869–878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6±6) compared to the other groups (p<0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p<0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor-and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.

Introduction We investigated olfactory defects in fragile X-associated tremor/ataxia syndrome (FXTAS), a finding reported on in other neurodegenerative disorders with clinical features that overlap those of FXTAS. Methods We measured olfactory identification capacity in 41 FMR1 premutation carriers and 42 controls using the University of Pennsylvania Smell Identification Test (UPSIT). Carriers received neurologic evaluations using motor rating scales for tremor, ataxia, and parkinsonism. Cognitive function was measured using the Montreal Cognitive Assessment test. Results Frequency of olfactory defects was higher in carriers, compared to controls (61% versus 29%; P = 0.003). There was no statistically significant group difference in severity of olfaction defects, after accounting for differences in age, and in rates of head injury and smoking. However, both the frequency (odds ratio = 3.9; 95% confidence interval: 0.81–19.1) and severity (28.6 versus 33.4; P = 0.01) of these defects were greater in cognitively impaired, compared to cognitively intact, carriers. There was no correlation between UPSIT scores and the above-mentioned motor rating scales. Conclusions FMR1 premutation carriers are susceptible to olfactory identification defects. The severity of these defects is comparable to that reported in hereditary ataxias, but less than that in PD and Alzheimer’s disease. This concurrence across neurodegenerative disorders suggests a shared system vulnerability that correlates with, but is not limited to, cognitive impairment, because it is also found in cognitively intact carriers. These results need to be corroborated in a larger prospective study of FMR1 premutation carriers that extends beyond olfactory identification to include measures of smell thresholds.

Instability of the FMR1 repeat, commonly observed in transmissions of premutation alleles (55–200 repeats), is influenced by the size of the repeat, its internal structure and the sex of the transmitting parent. We assessed these three factors in unstable transmissions of 14/3,335 normal (~5 to 44 repeats), 54/293 intermediate (45–54 repeats), and 1561/1,880 premutation alleles. While most unstable transmissions led to expansions, contractions to smaller repeats were observed in all size classes. For normal alleles, instability was more frequent in paternal transmissions and in alleles with long 3′ uninterrupted repeat lengths. For premutation alleles, contractions also occurred more often in paternal than maternal transmissions and the frequency of paternal contractions increased linearly with repeat size. All paternal premutation allele contractions were transmitted as premutation alleles, but maternal premutation allele contractions were transmitted as premutation, intermediate, or normal alleles. The eight losses of AGG interruptions in the FMR1 repeat occurred exclusively in contractions of maternal premutation alleles. We propose a refined model of FMR1 repeat progression from normal to premutation size and suggest that most normal alleles without AGG interruptions are derived from contractions of maternal premutation alleles.

We investigated the effect of AGG interruptions on fragile X repeat instability upon transmission of fragile X intermediate and small premutation alleles with 45-69 CGG repeats. The FMR1 repeat structure was determined for 375 mothers, 48 fathers, and 538 offspring (457 maternal and 81 paternal transmissions) using a novel PCR assay to determine repeat length and AGG interruptions. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3′ end were correlated with repeat instability on transmission. Maternal alleles with no AGGs conferred the greatest risk for unstable transmissions. All nine full mutation expansions were inherited from maternal alleles with no AGGs. Furthermore, the magnitude of repeat expansion was larger for alleles lacking AGG interruptions. Transmissions from paternal alleles with no AGGs also exhibited greater instability than those with one or more AGGs. Our results demonstrate that characterization of the AGG structure within the FMR1 repeat allows more accurate risk estimates of repeat instability and expansion to full mutations for intermediate and small premutation alleles.