Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1-to 3-year-old boys with FXS (n = 41) and compared these findings to age-and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability. The condition is caused by expansion of the CGG repeat in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene, resulting in hypermethylation, transcriptional silencing, and reduction or loss of the gene product, the fragile X mental retardation protein (FMRP) (1). Loss of FMRP disrupts dendritic maturation, synaptic plasticity, and cerebral development (2). Although much is understood about the typical pattern of cerebral abnormality in adults and older children with FXS, relatively little is known about the evolving nature of these abnormalities in early childhood. One of the most consistent observations in FXS is enlargement of the caudate nucleus, which has been noted in children as young as 18 months (3), relative to both typically developing children and those with idiopathic developmental delay (4). Increased caudate size also shows a negative correlation with FMRP, indicating a genetic dose-response relationship (4, 5). Another consistent finding is reduced size of the cerebellar vermis, which has been observed in FXS across a wide range of ages (4-7). Vermis size has been shown to be positively correlated with FMRP (5), although in our recent study w...

Using voxel-based (VBA) and region-of-interest (ROI) diffusion tensor imaging (DTI) analyses, we examined white matter (WM) organization in 7 children with dyslexia and 6 age-matched controls. Both methods demonstrated reduced fractional anisotropy (FA) in the left superior longitudinal fasciculus (SLF) and abnormal orientation in the right SLF in dyslexics. Application of this complementary dual DTI approach to dyslexia, which included novel analyses of fiber orientation, demonstrates its usefulness for analyzing mild and complex WM abnormalities.

The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys.

The present study extends our previous work characterizing the behavioral features of autisticspectrum disorder (ASD) in Down syndrome (DS) using the Aberrant Behavior Checklist (ABC) and Autism Behavior Checklist (AutBehav). We examined which specific behaviors distinguished the behavioral phenotype of DS þ ASD from other aberrant behavior disorders in DS, by determining the relative contribution of ABC and AutBehav subscales and items to the diagnosis of ASD. A total of 127 subjects (aged 2-24 years; mean age: 8.4 years; $70% male), comprising: a cohort of 64 children and adolescents with DS and comorbid ASD (DS þ ASD), 19 with DS and stereotypic movement disorder (DS þ SMD), 18 with DS and disruptive behaviors (DS þ DB), and 26 with DS and no co-morbid behavior disorders (DS þ none) were examined using the aforementioned measures of aberrant behavior. We found that subjects with DS þ ASD showed the most severe aberrant behavior, especially stereotypy compared to DS þ none and lethargy/social withdrawal and relating problems compared to DS þ SMD. Specifically, relatively simple stereotypic behavior differentiated DS þ ASD from DS þ DB, whereas odd/bizarre stereotypic and anxious behavior characterized DS þ ASD relative to DS þ SMD and DS þ none. Additionally, in a subset of subjects with DS þ ASD and anxiety, social withdrawal was particularly pronounced. Overall, our findings indicate that a diagnosis of DS þ ASD represents a distinctive set of aberrant behaviors marked by characteristic odd/bizarre stereotypic behavior, anxiety, and social withdrawal. ß

We conducted semiautomated, atlas-based analyses of regional brain volume changes on MRIs of children and adolescents with Down syndrome (DS) (N=15), DS with comorbid autism spectrum disorder (ASD) (N=15), and age-matched or sex-matched typically developing controls (N=22). Selective volumetric changes were correlated with neurobehavioral measures to determine their functional significance. DS involved selective reduction of frontal and parietal gray matter volumes, beyond the global microencephaly typically observed in this condition. DS with comorbid ASD involved relative hyperplasia of white matter in the cerebellum and brainstem compared with DS only. Cerebellar white matter volumes were positively correlated with severity of stereotypies, a distinctive feature of ASD in DS.