Ретт-синдром: варианты, генетика и клинические проявления.

Genetic brain disorder

Stage I, called early onset, typically begins between 6 and 18 months of age. the main groups are:
Congenital variant (Rolando variant): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth. The typical gaze of Rett syndrome patients is usually absent;
Zappella variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed. The Zappella variant is a milder form of Rett syndrome;
Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients have epilepsy before 5 months of age. The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillberg, 1993), the "Rett Complex" terminology has been introduced.

Genetically, Rett syndrome (RTT) is often caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome is initially diagnosed by clinical observation, and is commonly associated with a genetic defect in the MECP2 gene.

In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child, 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.

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 O'Brien, 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."

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. 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). This connection is involved in the tight modulation of motor strategies computed by a cortico basal ganglia thalamo cortical loop. 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. Dysregulation of the nigrostriatal pathway is causative from Parkinson disease (PD) in humans. Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates. The common features of PD and PD animal models are motor impairments (hypotonia, bradykinesia, hypokinesia). RTT pathology, in some aspects, overlaps the motor phenotype observed in PD patients. 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. In accordance with the motor spectrum of the RTT phenotype, Mecp2 null mice show motor abnormalities from postnatal day 30 that worsen until death. These models offer a crucial substrate to elucidate the molecular and neuroanatomical correlates of MeCP2 deficiency. Recently (2008), it was shown that the conditional deletion of Mecp2 in catecholaminergic neurons (by crossing of Th Cre mice with loxP flanked Mecp2 ones) recapitulates a motor symptomatology; it was further documented that brain levels of Th in mice lacking MeCP2 in catecholaminergic neurons only are reduced, participating to the motor phenotype. However, the most studied model for the evaluation of therapeutics is the Mecp2 null mouse (totally devoid of MeCP2). In this context, a reduction in the number and soma size of Th expressing neurons is present from 5 weeks of age and is accompanied by a decrease of Th immunoreactivity in the caudate putamen, the principal target of dopaminergic neurons arising from the SNpc. 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. The amount of fully activated Th (Serine40 phosphorylated isoform) in neurons that remain in the SNpc is mildly affected at 5 weeks but severely impaired by 9 weeks.

As reviewed by Sharifi and Yasui, MECP2 protein, encoded by the MECP2 gene binds to DNA with a high affinity for CpG methylated DNA sites and affects transcription. MECP2 can bind to 5mc (5 methylcytosine) and 5hmc (5 hydroxymethylcytosine) with similar affinity, and these dinucleotides account for the majority of MECP2 binding sites in the mammalian genome. MECP2 is involved in higher order chromatin organization and appears necessary for compacting chromosomes. MECP2 binding to DNA influences mRNA splicing events. MECP2 also appears to function in DNA repair processes. MECP2 /+ deficient female mice have elevated rates of cell death when exposed to DNA damaging agents and are prone to early senescence.

Currently there is no cure for Rett syndrome. While medicinal interventions to mitigate breathing challenges in children with Rett Syndrome (RTT) are still being developed, children with RTT may be prescribed rebreathing techniques (e. g., rebreathing masks), oxygen delivery, or non invasive ventilation as preventative or rescue breathing treatments. High oxidative stress levels in individuals with RTT have exacerbated effects on their cardiorespiratory health and functionality, 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. Prescribed treatment methods may vary depending on the breathing characteristic phenotype expressed by the child. Physicians have identified three major RTT breathing phenotypes; forceful breathers, feeble breathers, and apneustic breathers. For forceful breathers, for example, rebreathing masks may be used while the child is awake. In September 2022, the FDA accepted a new drug application for trofinetide and granted it priority review. In March 2023 the drug received FDA approval for treatment of Rett Syndrome.

Andreas Rett, a pediatrician in Vienna Austria, first described the condition in 1966. As his writings were in German, they did not become widely known in the English speaking world.

In August 2021, a novel by British author Victoria Scott, Patience, was published by Head of Zeus. The novel featured a character with Rett syndrome and explored recent developments in gene therapy.