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.
Moreover, a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of MECP2-null male as well as in adult heterozygous (MECP2+/-) female mice. Using immunoquantitative techniques, a decrease of Th protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic MeCP2-deficient mice. However, locus coeruleus cells are not dying, but are more likely losing their fully mature phenotype, since no apoptotic neurons in the pons were detected.Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction." The restoration of normal locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome. Midbrain dopaminergic disturbances
The majority of dopamine in the mammalian brain is synthesized by nuclei located in the mesencephalon. The substantia nigra pars compacta (SNpc), the ventral tegmental area (VTA) and the retrorubral field (RRF) contains dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).The nigro-striatal pathway originates from SNpc and irradiate its principal rostral target, the Caudate-Putamen (CPu) through the median forebrain bundle (MFB).