Latent Class Analysis Identifies Distinctive Behavioral Subtypes in Children with Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is associated with a characteristic profile of physical and neurobehavioral abnormalities. These phenotypical features are highly variable among affected individuals, which leads to difficulties in developing and evaluating treatments as well as in determining accurate prognosis. The current investigation employed data from FORWARD, a clinic-based natural history study of FXS, to identify subtypes by applying latent class analysis (LCA).A pediatric cross-sectional sample of 1,072 males and 338 females was subjected to LCA to identify neurobehavioral classes (groups).Input consisted of multiple categorical and continuous cognitive and behavioral variables, including co-occurring behavioral conditions, sleep and sensory problems, measures of autistic behavior (SCQ, SRS-2), and scores on the Aberrant Behavior Checklist revised for FXS (ABCFX). Clinically relevant class solutions were further delineated by identifying predictors using stepwise logistic regressions and pairwise comparisons. Following this, classes were characterized in terms of key demographic, genetic, and clinical parameters.LCA fit parameters supported 2-to 6-class models, which showed good correspondence between patterns of co-occurring conditions and scores on standardized measures. The 5-class solution yielded the most clinically meaningful characterization of groups with unique cognitive and behavioral profiles. The "Mild" class (31%) included patients with attention problems and anxiety but few other major behavioral challenges as reflected by scale scores. Most individuals in the "Severe" class (9%) exhibited multiple co-occurring conditions and high mean scale scores on behavioral measures. Three "Moderate" classes were identified: a "Moderate Behavior" class (32%), a "Social Impairment" class (7%), and a "Disruptive Behavior" class (20%). All classes displayed distinctive SRS-2, SCQ, and ABCFX profiles, which reflected their degree of non-overlap as estimated by pairwise effect sizes. Groups differed with regard to sex, intellectual disability, autism spectrum disorder diagnosis, and medication use.

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

“…In the area of clinical trials, it may eventually become necessary to stratify patients based on the severity of their condition, and this clinical research would also call for more detailed laboratory studies. 47,48 We anticipate that Patient A will remain fully independent but numerous issues regarding genetic counseling for FXS, mental health and overall wellness still need to be addressed. His daughters would carry the gene for this condition at least in the PM state.…”

“…In addition, several laboratories were contacted before we found one that would test the patient's protein and mRNA level using a blood sample. In the area of clinical trials, it may eventually become necessary to stratify patients based on the severity of their condition, and this clinical research would also call for more detailed laboratory studies 47,48 …”

“…In the area of clinical trials, it may eventually become necessary to stratify patients based on the severity of their condition, and this clinical research would also call for more detailed laboratory studies. 47 , 48 …”

Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome

“…Within the CNS, FMRP regulates synaptic plasticity, neural development, and cognitive function, primarily by regulating the translation, transport, and stability of many mRNAs [ 10 ]. The loss of FMRP results in intellectual disability and, often, attention-deficit/hyperactivity disorder (ADHD), anxiety, autism, and other neurological and behavioral symptoms [ 11 , 12 , 13 ]. Predictably, decreasing FMRP levels are associated with increasing severity of FXS [ 14 ], lowered IQ [ 15 ], and other neurological disorders including bipolar disorder, depression, and schizophrenia [ 16 , 17 , 18 ].…”

Sensory Symptoms and Signs of Hyperarousal in Individuals with Fragile X Syndrome: Findings from the FORWARD Registry and Database Multisite Study

“…The FXS phenotype includes a wide range of physical and neurological abnormalities, such as cranial dysmorphia, strabismus, otitis media, joint hypermobility, and seizures (Hersh et al, 2011;Kidd et al, 2014). The behavioral phenotype includes mild to severe attention-deficit/hyperactivity disorder (ADHD), anxiety, aggressive behaviors, and autistic features or ASD (Bailey et al, 2008;Boyle & Kaufmann, 2010;Kaufmann et al, 2017Kaufmann et al, , 2022. Closely linked to these behavioral problems are sensory symptoms (SS) and hyperarousal (HA).…”