Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Abstract

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...

Basal Forebrain Involvement in Low-Functioning Autistic Children: A Voxel-Based Morphometry Study

“…Abnormalities in the basal forebrain were reported in other syndromes with DD, such as Down syndrome, 40 Rett syndrome, 41 and fragile X syndrome, 42 but not in children with idiopathic DD. 42 The autistic phenotype we examined cannot be merely summarized in the term autistic behavior plus intellectual disability, because it comprises a syndromic constellation of symptoms, in which there are both signs of autism and of cognitive malfunctioning.…”

“…42 The autistic phenotype we examined cannot be merely summarized in the term autistic behavior plus intellectual disability, because it comprises a syndromic constellation of symptoms, in which there are both signs of autism and of cognitive malfunctioning. Involvement of the basal forebrain, however, might be an indicator of DD rather than autism itself.…”

El síndrome X frágil: identificación del fenotipo y propuestas educativas

“…Cuando los padres detectan estas primeras dificultades acuden al especialista buscando respuestas a sus sospechas. Si en ese momento, se realizan pruebas de neuroimagen, en niños de 1 a 3 años, no se observan alteraciones neuroanatómicas que años más tarde si se constatan, lo que parece indicar que son cambios evolutivos asociados a la falta de proteína fmrp1 (Hoeft et al, 2010). Encontrar síntomas significativos antes del año es infrecuente en personas sin antecedentes familiares de discapacidad intelectual.…”

Fragile X Syndrome as a Multilevel Model for Understanding Behaviorally Defined Disorders

“…Much of the early research on the FXS brain was done on older children and adults, but recently structural imaging studies have targeted very young children with the syndrome (Haas et al, 2009;Hoeft et al, 2008Hoeft et al, , 2010Hoeft et al, , 2011. This should in time make possible the much earlier diagnosis of FXS, identifying in infants precocious neural markers of atypical brain development.…”