Rett Syndrome

Rett syndrome (RS) has a prevalence of 1 in 10,000. Although first accepted as a distinct clinical entity only in 1983, progress in understanding the pathophysiology of RS has been spectacular. The phenotype of RS falls within the autism spectrum. Unlike autism, however, the symptoms of RS typically emerge only after a period of normal development, and they affect females almost exclusively. One of the most common first symptoms is the loss of purposeful hand movements, which are often replaced by incessant hand-wringing. Other symptoms and signs soon emerge. An arrest of language development and profound cognitive delays are seen in the majority. Play and motor skills are lost in more than half the cases. Regression most commonly occurs between 12 and 18 months of age, but it can be noted as early as 6 months or as late as 36 months (Charman et al., 2002). Growth retardation, microcephaly, ataxia, gait disturbance, and seizures are also common (Hagberg, 2002). The EEG in RS children is invariably abnormal, showing focal, multifocal, or generalized epileptiform abnormalities and rhythmic slow-wave (theta) activity, primarily in frontocentral regions (Glaze, 2002).

Genetics. The genetic deficit for RS has been narrowed to a region of the X chromosome (Xq27.3-Xqter). Being a dominant gene, the mutation for RS is thought to be lethal to males before birth. Females who have a spare X chromosome are spared death during fetal development and later life because one of the two X chromosomes in each of the postmitotic cells is randomly inactivated, leaving a significant subset of cells with normally functioning X chromosomes (Armstrong, 2002). All known mutations thus far associated with RS in this region have been shown to affect the MeCP2 gene, which encodes methyl-CpG binding protein 2, a ubiquitous deoxyribonucleic acid (DNA)-binding protein. MeCP2 has high affinity for binding to methylated CpG dinucleotides. When the MeCP2 protein binds to these dinucleotides within the promotor region of a gene, a complex is formed that contains the CpG dinucleotide, the

MeCP2 protein, a co-repressor (Sin3A), and certain enzymes (histone deacetylases). This complex then deacetylates histones associated with the chromatin, making the chromatin more compact and thereby repressing transcription of downstream genes (Van den Veyver and Zoghbi, 2002).

More than 200 mutations to the MeCP2 gene have been reported. Nonsense, missense, or frameshift mutations are detected in more than 80 percent of affected girls. More than 60 percent of the mutations cause recurrent cytosine-to-thymine substitutions in a codon for arginine (CGA) at one of 8 different mutation hot spots containing CpG dinucleotides. In 10 percent of cases, recurrent multinucleotide deletions have been noted in the C-terminal region of the gene (Van den Veyver and Zoghbi, 2002). MeCP2 is normally abundantly present in most neurons and in many body tissues, especially lung and spleen, and it tends to be expressed increasingly as cells mature. Most of the known mutations of the MeCP2 gene are predicted to produce total or partial loss of function of the MeCP2 protein.

The normal developmental function of the MeCP2 gene seems to be to assist maturational programs in many body tissues by silencing numerous other genes that are expressed earlier in development (Shahbazian et al., 2002b). The failure of this global transcriptional repressor may allow biochemical processes active early in development to proceed with little regulation. This failure of gene "silencing" is thought in most cases to trigger the emergence of RS symptoms. The phenotypic variability in RS symptoms is presumably related to the many alternative ways in which the gene can be spliced, which would produce variable patterns and degrees of disruption in normal brain development. The degree of X-chromosome inactivation within the brain is also thought to be a major determinant of the clinical phenotype and disease severity (Van den Veyver and Zoghbi, 2002).

An alternative theory relating the MeCP2 mutation and the timing of emergence of symptoms is that compounds expressed early in brain development are not repressed as they normally would be. These compounds may actually be toxic when present in excess, and it takes time for them to accumulate postnatally. When their concentration reaches a certain threshold, they might damage neurons and disrupt normal brain function. It is at this time that the symptoms of RS would then emerge, after a period of relatively normal brain development and the attainment of normal early maturational milestones. The recent development of an MeCP2 knockout mouse that has neurological symptoms similar to those of RS should be helpful for evaluating the merits of these competing, though not necessarily mutually exclusive theories, and it may offer promise for developing genetically based therapeutic interventions (Shahbazian et al., 2002a).

Neurobiological Substrate. Consistent with the hypothesized role of MeCP2 in repressing the expression of early developmental genes, histology of cortex from individuals with RS suggests the presence of a developmental immaturity (Belichenko et al., 1994; Cornford et al., 1994), including reductions of neurotransmitter metabolites and nerve growth factor (Lekman et al., 1989; Lipani et al., 2000). Histological immaturity is similarly seen in many body tissues of individuals who have RS (Armstrong, 2002).

The regions of the brain that are most dysfunctional and responsible for the generation of symptoms in RS are unknown. Imaging studies have reported higher levels of choline and lower levels of N-acetylaspartate (NAA, a putative marker of neuronal viability) in RS (Horska et al., 2000; Khong et al., 2002). Regional glucose metabolism, assessed with positron emission tomography (PET), shows reduced occipital cortical and increased cerebellar activity (Villemagne et al., 2002). Benzodiazepine (BZ) receptor binding as measured with SPECT seems reduced in front temporal cortices (Yamashita et al., 1998).

Taken together, extant imaging studies suggest the presence of neuronal pathology and reduced metabolism primarily in frontal cortices, although additional disturbances have been reported in parietal, temporal, and cerebellar tissues. These heteromodal association cortices are involved in higher level cognitive processes that develop later than primary sensory, sensory association, and motor cortices. Such deficits are consistent with the theories of maturational arrest and toxicity caused by deficient production of MeCP2 protein early in development.

How To Win Your War Against Anxiety Disorders

How To Win Your War Against Anxiety Disorders

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