Rett Syndrome

Rett syndrome is an X-linked neurological disorder that is a leading cause of mental retardation among females. The progression of the disease consists of normal neonatal development followed by a regression period during which neurodevelopmental signs such as mental retardation and decline of motor abilities start to appear. The developmental progress of Rett patients is within normal range for the first 5–6 months of life. Between 6 and 18 months, development begins to slow or arrest and this stagnation period is followed by a period of regression occurring between 1 and 3 years of age. Common symptoms of the regression period include loss of hand use, decline in verbal and non-verbal communication skills and irregular breathing patterns. From age three to around age ten, the symptoms of the patient stabilize. However, movement and breathing difficulties persist through this phase. The symptoms worsen following this stage and the patient usually loses the ability to walk and suffers from severe breathing problems. With extensive care, patients may survive into adulthood, although they are severely mentally retarded Since Rett syndrome is an X-linked dominant disorder, it is mainly observed in females. Males with Rett syndrome rarely survive past two years of age. Mutations in the MECP2 gene are associated with approximately 80% of the female Rett syndrome patients. MECP2, or methyl-CpG-binding protein 2, is located on the q arm of the Xchromosome at position 28 and encodes a ubiquitous protein that is thought to act as a transcriptional repressor and silencer. MECP2 is expressed in all tissues and is thought to help regulate the methylation of DNA and mediate transcriptional repression. The methylation will occur at CpG sites which is involved in long-term silencing of genes in order for development and the repression of certain viral genomes. It is thought that both histone deacetylation, which is the way in which transcriptional repression is relieved, as well as DNA methylation are both linked by MECP2. MECP2 expression occurs during neuronal maturation and therefore its mutation can disrupt normal synaptic formation. The expression of the mutated MECP2 gene in females is complicated because of the phenomenon of X-chromosome inactivation. Because males only possess one X chromosome, the inactivation of one X chromosome occurs in females in order to equalize the amounts of X-linked gene products produced by females and males. Different cells can exhibit different patterns of X-chromosome inactivation. Thus the severity of Rett syndrome symptoms depends on the proportion of cells that have inactivated the normal X chromosome. These are the cells that end up expressing the mutated MECP2 gene. Since the X-inactivation pattern of one individual may differ from another, a spectrum of Rett phenotypes exists for female patients. This spectrum was studied in detail by Huppke et al, who compared the development of 120 female Rett syndrome patients and found a broad range of symptoms. Those with the most severe symptoms never showed a period of normal development—they were never able to sit, walk, speak and completely lost hand function towards the end of their lives. However, some Rett patients only showed minor neurological symptoms and were able to count numbers, sing songs and ride bicycles. Exactly how MECP2 mutation causes deviation from normal brain development remains an enigma. Many theories and models have attempted to explain this enigma. A