Fragile X

Fragile X, a relatively common form of mental retardation caused by a single mutation in the long arm of the X chromosome, occurs once in every 2000 to 4000 live births. Approximately 20 percent of such children exhibit autistic symptoms. Conversely, 8 percent of males and 6 percent of females diagnosed with autism carry the fragile X abnormality. The mutation alters brain development and produces a distinctive physical, cognitive, and neuropsychiatric phenotype. Clinical symptoms are insufficient to make the fragile X diagnosis. Instead, specific genetic abnormality must be evident using molecular diagnostic techniques (Hagerman, 1999).

Because it is an X-linked disorder, fragile X affects males and females differently. In boys, fragile X is associated with variable presentations of mental retardation, difficulties with visuospatial and memory functioning, gaze avoidance, stereotypic behaviors, hyperactivity, and abnormal speech patterns, including echolalia, high-pitched speech, poor articulation, and dysfluency. Aggression and self-injurious behaviors are prominent in some individuals. Persons with fragile X commonly have a characteristic appearance that includes an elongated face, a large protruding jaw, large ears, enlarged testicles, and accentuated secondary sexual characteristics. In girls who are heterozygous for the fragile X full mutation, the syndrome is associated with a normal physical appearance, variable cognitive functioning that ranges from normal to mildly mentally retarded, and difficulties with mathematics, attention, social communication, and the regulation of anxiety (Reiss et al., 2000a). Because carrier females on average have milder symptoms, they are more likely to reproduce and transmit the fragile X gene (Nelson, 1995; Oostra and Halley, 1995).

Genetics. Some proportion of human cells, when grown in the absence of folic acid, display a break point on one of the X chromosomes. Fragile X co-segregates with this "fragile" site. Progression of disease severity over generations, referred to as anticipation, was noted before the gene was identified. In 1991, the molecular basis for anticipation was discerned when the FMR-1 gene (i.e., the "first fragile X, mental retardation" gene) was identified. The mutation consists of the transgenerational expansion of a so-called DNA triplet repeat, a sequence of three successive bases [specifically, cytosine-guanine-guanine (CGG), a sequence encoding the amino acid arginine] repeated many times (O'Donnell and Warren, 2002). It is situated within a segment of the long arm of the X-chromosome, at Xq27.3.

Healthy individuals have between 6 and 50 repeats of these bases in their FMR-1 gene. In affected individuals, the number of repeats typically ranges from 200 to 1000. Repeats numbering between 50 and 200, termed premutations, are typically present in the mothers of affected probands and yield milder symptoms. Individuals with permutations have a high risk for expanding the number of repeats in subsequent generations.

The CGG trinucleotide repeat of FMR-1 is located in the promoter region of this gene. All regions rich in C+G nucleotides ("CpG islands") are prone to methylation, and therefore a greater expansion of the triplet repeat is accompanied by greater methy-lation of the promoter region, which increasingly represses expression of the FMR-1 gene product, a protein termed fragile X mental retardation protein (FMRP). In addition to this primary cause of fragile X, a minority of children have microdeletions of the FMR-1 gene. Thus, different mutations in different parts of the FMR-1 gene can produce the same clinical phenotype, a phenomenon termed allelic heterogeneity.

Neurobiological Substrate. FMRP is a binding protein for ribonucleic acid (RNA) that associates with polyribosomes in the cytosol to form a large messenger ribonucleoprotein (mRNP) complex (Feng et al., 1997). FMRP is thought to modulate the translation of the RNA ligands that this mRNP polyribosomal complex processes. FMRP is located at the synapse, where it apparently modulates synaptic plasticity (Weiler et al., 1997). The brains of individuals with fragile X as well as FMR-1 knockout mice have abnormal morphology of dendritic spines (Comery et al., 1997). Repression of the FMRP production in fragile X is thought to disrupt synapse formation and plasticity, cellular processes important for development of normal learning and memory. FMRP is widely distributed throughout the mammalian brain (Hinds et al., 1993), and in humans, the FMR-1 gene is expressed most abundantly during early development in neurons of the hippocampus, nucleus basalis, and cerebellum (Abitbol et al., 1993), brain areas that subserve learning and memory.

This pattern of normal expression of FMRP prompted initial neuroimaging studies of individuals with fragile X to focus on these regions (Reiss et al., 1991a, b, 1994, 1995). MRI studies have found diminished sizes of lobules VI and VII of the cerebellar vermis and enlarged fourth ventricles in fragile X males but not other developmentally delayed individuals. Females with fragile X had similar, albeit smaller, reductions in the same brain areas (Reiss et al., 1991b). This suggests the presence of an "intermediate gene dosage effect" of the FMR-1 mutation in heterozygote females. In girls, cerebellum volumes correlated inversely with ratings of social communication and stereotypic behaviors (Mazzocco et al., 1997), and with IQ and measures of executive functioning (Mostofsky et al., 1998). Volumes of the hippocampus, a structure important in learning and memory, have been reported to be larger in individuals with fragile X (Reiss et al., 1994), although this finding has not been replicated (Jakala et al., 1997). These studies suggest that the abnormal expression of FMRP observed in animal studies contributes to disturbances of brain development in fragile X and its associated cognitive and behavioral deficits.

Functional MRI studies have tried to elucidate the consequences of the FMR-1 mutation for human brain function. Reduced activity in frontal-subcortical circuits, important for the regulation of impulses and attention, has been reported in individuals with fragile X (Hjalgrim et al., 1999), and FMRP levels in females with fragile X have been reported to correlate significantly with the magnitude of brain activation in the frontal and parietal cortices during a working memory task (Menon et al., 2000). These findings suggest that deficient production of FMRP may contribute to the hyperactivity, inattention, and perseveration that are important features of the fragile X clinical phenotype.



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