Krista Charen
Emory University
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Human Reproduction | 2008
J. Rohr; Emily Graves Allen; Krista Charen; J. Giles; Weiya He; Celia E. Dominguez; Stephanie L. Sherman
BACKGROUND Women who carry the fragile X mental retardation (FMR1) premutation are at risk for fragile X-associated primary ovarian insufficiency. Past studies have shown that carriers who are still cycling have increased levels FSH compared with non-carriers. As anti-Mullerian hormone (AMH) has been shown as an excellent marker of ovarian decline, we examined AMH levels among premutation carriers to characterize their ovarian function. METHODS We determined the level of FSH and AMH in serum samples collected during early follicular phase from women who carried longer FMR1 repeat alleles (defined as >or=70 repeats, n = 40) and those with shorter repeat alleles (<70 repeats, n = 75), identified by DNA analysis. Comparisons were made stratified by age and carrier status. RESULTS For all age groups, AMH levels were significantly lower among longer repeat allele carriers compared to shorter repeat allele carriers (P = 0.002, 0.006 and 0.020 for women ages 18-30, 31-40 and 41-50 years, respectively). In contrast, increased FSH indicative of early ovarian decline was only evident for longer repeat allele carriers aged 31-40 years (P = 0.089, 0.001 and 0.261 for women ages 18-30, 31-40 and 41-50 years, respectively). CONCLUSIONS These preliminary data suggest that AMH levels indicate early ovarian decline among women with longer FMR1 repeat alleles; moreover, AMH appears to be a better marker than FSH in identifying this early decline.
Behavior Genetics | 2008
Jessica Ezzell Hunter; Emily Graves Allen; Ann Abramowitz; Michele Rusin; Mary Leslie; Gloria Novak; Debra Hamilton; Lisa Shubeck; Krista Charen; Stephanie L. Sherman
The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (~55–199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18–50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.
Genetic Epidemiology | 2008
Jessica Ezzell Hunter; Michael P. Epstein; Stuart W. Tinker; Krista Charen; Stephanie L. Sherman
The fragile X mental retardation gene (FMR1) contains a CGG repeat sequence in its 5′ untranslated region that can become unstable and expand in length from generation to generation. Alleles with expanded repeats in the range of ∼55–199, termed premutation alleles, are associated with an increased risk for fragile‐X‐associated primary ovarian insufficiency (FXPOI). However, not all women who carry the premutation develop FXPOI. To determine if additional genes could explain variability in onset and severity, we used a random‐effects Cox proportional hazards model to analyze age at menopause on 680 women from 225 families who have a history of fragile X syndrome and 321 women from 219 families from the general population. We tested for the presence of a residual additive genetic effect after adjustment for FMR1 repeat length, race, smoking, body mass index, and method of ascertainment. Results showed significant familial aggregation of age at menopause with an estimated additive genetic variance of 0.55–0.96 depending on the parameterization of FMR1 repeat size and definition of age at menopause (P‐values ranging between 0.0002 and 0.0027). This is the first study to analyze familial aggregation of FXPOI. This result is important for proper counseling of women who carry FMR1 premutation alleles and for guidance of future studies to identify additional genes that influence ovarian insufficiency. Genet. Epidemiol. 2008.
American Journal of Medical Genetics | 2012
Jessica Ezzell Hunter; Mary Leslie; Gloria Novak; Debra Hamilton; Lisa Shubeck; Krista Charen; Ann Abramowitz; Michael P. Epstein; Adriana Lori; Elisabeth B. Binder; Joseph F. Cubells; Stephanie L. Sherman
The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5′‐untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55–199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self‐report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State‐Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.
Neuropsychology (journal) | 2011
Emily Graves Allen; Jessica Ezzell Hunter; Michele Rusin; Jorge L. Juncos; Gloria Novak; Debra Hamilton; Lisa Shubeck; Krista Charen; Stephanie L. Sherman
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 noncarrier 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 noncarrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. CONCLUSIONS 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.
Menopause | 2016
H. Hipp; Krista Charen; Jessica B. Spencer; Emily Graves Allen; Stephanie L. Sherman
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.
Journal of Genetic Counseling | 2012
Jeannie Visootsak; Krista Charen; Julia Rohr; Emily Graves Allen; Stephanie L. Sherman
Fragile X syndrome (FXS) is an inherited genetic condition with critical consequences to the proband and family members at all levels in the generations. Although evidence demonstrates that the rates of diagnosis for FXS are the same in all racial groups, age of diagnosis in African American children has been reported to occur later than in Caucasian children. Additionally, African American families are seriously under-represented in existing FXS research studies. As such, it is important to understand the possible disparities in the underlying factors to receiving a diagnosis in African American families with FXS. Herein, a qualitative approach was adopted to describe the overall FXS diagnosis experiences (pre-diagnosis, diagnosis, and post-diagnosis stages) of a convenience sample of 10 African American mothers. We identified three major findings among our participants: (1) FXS testing is not ordered immediately once a parent expresses concerns of developmental delays to the pediatricians, (2) the diagnosis is sometimes delivered in an insensitive manner with information often being outdated and unbalanced towards negative aspects, (3) communication issues among family members exists once the diagnosis is discovered. Although these qualitative data may not be representative of the whole group, these findings have significant implications for genetic counseling and our understanding in providing support and advocacy for African American families with FXS.
Journal of Genetic Counseling | 2016
Whitney Espinel; Krista Charen; Lillie Huddleston; Jeannie Visootsak; Stephanie L. Sherman
Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive – inductive approach to determine the prominent themes related to the participants’ experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.
Frontiers in Genetics | 2018
Emily Graves Allen; Anne Glicksman; Nicole Tortora; Krista Charen; Weiya He; Ashima S. Amin; H. Hipp; Lisa Shubeck; Sarah L. Nolin; Stephanie L. Sherman
Fragile X-associated primary ovarian insufficiency (FXPOI) occurs in about 20% of women who carry a premutation allele (55–200 CGG repeats). These women develop hypergonadotropic hypogonadism and have secondary amenorrhea before age 40. A non-linear association with repeat size and risk for FXPOI has been seen in multiple studies women with a premutation: those with a mid-range of repeats are at highest risk (∼70–100 CGG repeats). Importantly, not all carriers with 70–100 repeats experience FXPOI. We investigated whether AGG interruptions, adjusted for repeat size, impacted age at secondary amenorrhea. We have reproductive history information and AGG interruption data on 262 premutation women: 164 had an established age at amenorrhea (AAA) (for some, age at onset of FXPOI) or menopause, 16 had a surgery involving the reproductive system such as a hysterectomy, and 82 women were still cycling at the last interview. Reproductive status was determined using self-report reproductive questionnaires and interviews with a reproductive endocrinologist. For each of these 262 women, FMR1 repeat size and number of AGG interruptions were determined. We confirmed the association of repeat size with AAA or menopause among women with a premutation. As expected, both premutation repeat size and the quadratic form of repeat size (i.e., squared term) were significant in a survival analysis model predicting AAA (p < 0.0001 for both variables). When number of AGG interruptions was added to the model, this variable was not significant (p = 0.59). Finally, we used a regression model based on the 164 women with established AAA to estimate the proportion of variance in AAA explained by repeat size and its squared term. Both terms were again highly significant (p < 0.0001 for both), but together only explained 13% of the variation in AAA. The non-linear association between AAA and FMR1 repeat size has been described in several studies. We have determined that AGG interruption pattern does not contribute to this association. Because only 13% of the variation is described using repeat size, it is clear that further research of FXPOI is needed to identify other factors that affect the risk for FXPOI.
Journal of Genetic Counseling | 2017
Victoria Reines; Krista Charen; Tracie C. Rosser; Arri Eisen; Stephanie L. Sherman; Jeannie Visootsak
Research studies focusing on parents’ perspectives of pharmacological clinical trials have not kept pace with the number of emerging pharmacologic clinical trials in Down syndrome (DS) and Fragile X syndrome (FXS). Since individuals with DS or FXS have limited cognitive ability to make decisions about their participation in clinical trials, it is important to consider the parents’ perspectives and explore the ways in which decisions are made for their children. Using a semi-structured interview, we enrolled 9 parents of a child(ren) with FXS and 15 with a child with DS to analyze their views, experiences, and knowledge of pharmacological clinical trials. Although our study is preliminary in nature, it revealed that parents are generally supportive of pharmacological clinical trials, yet there may be concerns about safety and long-term implications and consideration for their child in the decision process. There is also parental misunderstanding of the objectives of pharmacological clinical trials; thus, it is important for pharmaceutical companies, study investigators, clinicians/medical professionals, and parent advocacy groups to collaborate to provide appropriate and up-to-date educational resources that fully explain the risks and benefits of clinical trials.