There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year. Stage II
Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage which is called mouthing. The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements continue while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage. Stage III
Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features.
Parents are generally genotypically normal, without a MECP2 mutation.In cases of the sporadic form of RTT, the mutated MECP2 is thought to derive almost exclusively from a de novo mutation on the male copy of the X chromosome. It is not yet known what causes the sperm to mutate, and such mutations are rare. Germline mutations
It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MeCP2. In these cases, inheritance follows an X-linked dominant pattern and is seen almost exclusively in females, as most males die in utero or shortly after birth. MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of RTT, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). As stated by Aine Merwick, Margaret OBrien, and Norman Delanty in an article on gene disorders titled Complex single gene disorders and epilepsy, "Rett syndrome affects one in every 12,500 female live births by age 12 years." Mechanism
Pontine noradrenergic deficits
Brain levels of norepinephrine are lower in people with Rett syndrome (reviewed in). The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus. These changes include hyperexcitability and decreased functioning of its noradrenergic innervation.