Genetically Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations.
Sporadic mutations
Rett syndrome is usually caused (95% or more) by a ''de novo'' mutation in the child, and not inherited from either parent. Parents are generally genotypically normal, without a MECP2 mutation.
In sporadic cases of Rett syndrome, it is thought that the mutated MECP2 is usually derived from 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. MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, 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). Rett syndrome affects one in every 12,500 female live births by age 12 years.
Locus coeruleus and MECP2
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 ceruleus, 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. Thus, a non-mutant ''MECP2'' gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.
There have, however, been several cases of 46,XY Karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age. The incidence of Rett syndrome in males is unknown, partly due to low survival of male fetuses with the Rett syndrome associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.
The severity of Rett syndrome in females can vary depending on the type and position of the mutation of MECP2 and the pattern of X-chromosome inactivation. It is generally assumed that 50% of a female's cells use the maternal X chromosome while the other 50% uses the paternal X chromosome (see X-inactivation). However, if most cells in the brain activate the X chromosome with the functional ''MECP2'' allele, the individual will have very mild Rett syndrome; likewise, if most neurons activate the X chromosome with the mutated ''MECP2'' allele, the individual will have very severe Rett syndrome just as males with ''MECP2'' mutations do (as they only have one X chromosome).
Further Reading
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