Fragile X-Associated Neuropsychiatric Disorders (FXAND) in Young Fragile X Premutation Carriers

Abstract

Background: The fragile X premutation carrier state (PM) (55–200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 ± 3.4) with a mean full-scale IQ of 90.9 ± 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17/52 males and 3/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p < 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…However, these findings are constrained by clinic-based or small sample sizes. To ascertain the accurate prevalence of ASD in PM carriers, larger population cohort studies are essential, given the limited scope of current research utilizing clinic-based or small-sample approaches [ 37 , 39 , 41 , 42 , 56 ]. Although no studies have systematically studied the prevalence of ASD in adult PM carriers, evidence points towards elevated rates of the broad autism phenotype (BAP) in the PM.…”

“…These findings have led to further studies of problems that occur in carriers before the onset of FXTAS and of disorders that can occur even in childhood in a subgroup of carriers. Although most carriers have normal intellectual abilities and are without neuropsychological issues, studies have shown that a subgroup of carriers have psychiatric problems in childhood, including anxiety [ 36 ], attention deficit hyperactivity disorder (ADHD) [ 37 , 38 ], social deficits [ 39 ], and even autism spectrum disorder (ASD) [ 37 , 40 , 41 , 42 ]. For carriers who experience seizures, there is a higher incidence of ASD or intellectual disabilities (ID) compared to carriers without seizures [ 43 ], and 20% of carriers with ID and ASD have a second genetic hit, as detected with whole-exome sequencing (WES) or microarray studies [ 44 ].…”

Activation Ratio Correlates with IQ in Female Carriers of the FMR1 Premutation

“…Specifically, our results suggest that AR-Sb would be useful in assessing the risk of specific psychiatric conditions, including depression, sleep disorders, ADHD, ASD, and anxiety symptoms, including social avoidance, interpersonal sensitivity, shyness, eye contact avoidance, social phobia, panic disorders, etc., which are common in PM carriers [ 2 , 53 ]. In addition, co-occurring FXAND-related conditions in carriers of PM alleles are also very common, with a higher prevalence of depression and anxiety [ 2 , 54 ]. Depression is more frequently reported in young carriers than in a matched control group [ 55 ], as well as in female than in male carriers of PM alleles [ 2 , 56 , 57 ], and is directly related to the number of CGG repeats [ 58 , 59 ].…”

Insight and Recommendations for Fragile X Premutation Associated Conditions from the 5th International Conference on <em>FMR1</em> Premutation

“…However, these findings are constrained by clinic-based or small sample sizes. To ascertain the accurate prevalence of ASD in PM carriers, larger population cohort studies are essential, given the limited scope of current research utilizing clinic-based or smallsample approaches [37,39,41,42,56]. Although no studies have systematically studied the prevalence of ASD in adult PM carriers, evidence points towards elevated rates of the broad autism phenotype (BAP) in the PM.…”