Rett syndrome

Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6-18 months of age and almost exclusively in girls.

[5] This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first.

[5] The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing.

[21][22] Rett syndrome is initially diagnosed by clinical observation, and is commonly associated with a genetic defect in the MECP2 gene.

One piece of evidence for this is that mice with induced Rett syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults.

[26] 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.

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).

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.

[33] 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.

[34] 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.

[34] 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.

[34] 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 substantia nigra pars compacta (SNpc), the ventral tegmental area (VTA) and the retrorubral field (RRF) contain dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).

[35][36][37] The nigro-striatal pathway originates from the SNpc; its principal rostral target is the caudate-putamen (CPu), which it irradiates through the median forebrain bundle (MFB).

[38] Indeed, based on the canonical anatomofunctional model of basal ganglia, nigrostriatal dopamine is able to modulate the motor loop by acting on dopaminergic receptors located on striatal GABAergic medium spiny neurons.

[43][44][45] Several neuropathological studies on postmortem brain samples argued for an SNpc alteration, evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even, controversially, signs of apoptosis.

In parallel, a hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products.

[30] Mouse models of RTT are available; the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Katelyn McCormick laboratories.

[52] Moreover, a neurochemical analysis of dopaminergic contents in microdissected midbrain and striatal areas revealed a reduction of dopamine at five and nine weeks of age.

It is noteworthy that later on (at nine weeks), the morphological parameters remain altered but not worsened, whereas the phenotype progresses and behavioral deficits are more severe.

[52] Finally, using a chronic and oral L-Dopa treatment on MeCP2-deficient mice, authors reported an amelioration of some of the motor deficits previously identified.

[52] Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in MeCP2-deficient animals as a contributor of the neuromotor deficits.

MECP2-/+ deficient female mice have elevated rates of cell death when exposed to DNA damaging agents and are prone to early senescence.

Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight.

[5] Because of the increased risk of sudden cardiac death, when long QT syndrome is found on an annual screening EKG it is treated with an anti-arrhythmic such as a beta-blocker.

[66] Due to this, it is vital to closely monitor atypical breathing behaviors in children with RTT, making sure to effectively use lifesaving respiratory improvement devices and strategies as prescribed.

[citation needed] Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have one or more extra X chromosomes, or have somatic mosaicism.

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 location of the gene responsible for Rett syndrome
A girl with short brown hair sits in a neon orange push chair. She is on a concrete pathway in front of a building.
A girl with Rett Syndrome mouthing her hands, a common behavior with Rett Syndrome
A picture of an infant with Rett Syndrome.
Girl with Rett syndrome with stereotyped hand movements