Rett syndrome is a genetic disease characterized by impaired development of the nervous system due to the lack of inhibition of certain genes. Manifestations of this condition are progressive mental retardation in girls (with extremely rare atypical forms – and in boys), muscular hypotension, ataxia, curvature of the spine. The diagnosis of Rett syndrome is based on the data of general and neurological examination, magnetic resonance imaging, electroencephalography and molecular genetic analyses. There is no specific treatment (there are only certain developments with encouraging results in animal experiments), symptomatic therapy is used to alleviate the patient’s condition.
General information
Rett syndrome is a genetic disease of a neuropsychiatric nature that almost always develops in girls and manifests itself with a severe degree of mental retardation. This pathology was first identified back in 1954 by the Austrian neurologist A. Rett, however, as a separate nosological unit, he identified this disease only in 1966. Rett syndrome became widely known in the scientific world in 1983 after the research of B. Hagberg. This condition is quite common – its occurrence is approximately 1:10-15 thousand newborn girls, in total, several tens of thousands of cases of pathology have been described to date. The mechanism of inheritance of Rett syndrome is dominant, linked to the X chromosome, which is why it is almost always found in girls. In boys, due to the absence of a paired X chromosome, genetic damage leading to such a disease is almost always fatal. However, there are several atypical forms of Rett syndrome, characterized by a more smoothed clinical picture and therefore affecting males. In addition, in boys, such a pathology can develop in the presence of an additional X chromosome – Klinefelter syndrome.
Causes
The etiology and pathogenesis of Rett syndrome are quite complex and are caused by the interaction of various genes and their influence on the development of the human brain. The root cause of the disease is a nonsense mutation (according to some data, missense mutations also lead to similar disorders) of the MECP2 gene localized on the X chromosome, as a result of which its expression completely stops. It encodes a specific protein called methyl-CpG-binding protein 2, which is involved in the regulation of transcription of certain DNA sites. This protein contains two domains, one of which promotes its attachment to the methylated regions of chromosomes (which are located near the genes regulating the development of the brain), and the second acts as a transcription repressor. The reason for Rett syndrome is precisely the absence of inhibition of certain genes, which leads to a violation of the formation of nervous tissue.
At the same time, Rett syndrome cannot be considered as a neurodegenerative disease, since it does not cause destruction of neurons or neuroglia. Histological studies of the brain tissues of patients reveal a violation of the ultrastructure of nerve cells – a decrease in size, a change in the number of dendrites, difficult formation of nerve tissues. The volume of neuroglia in Rett syndrome is reduced, as a result, at the macroscopic level, the size of the brain also decreases by 20-30% compared to the age norm. One of the reasons for the above processes is the lack of inhibition of the release of the GAD67 enzyme (inhibition of the gene of this enzyme is carried out by methyl-CpG-binding protein 2), which, in turn, leads to an increase in the concentration of inhibitory transmitters from the GABA group. As a result, patients with Rett syndrome have a significant prevalence of inhibition processes in the brain, which affects not only the physiology of the central nervous system, but also its morphological structure.
Geneticists have found that the complete absence of the normal MECP2 gene in the genome in the vast majority of cases is a fatal condition and often leads to stillbirth. This condition occurs in boys (due to the presence of only one X chromosome) or in homozygous girls, which is extremely rare. Because of this, there is an absolute prevalence of female patients in the sexual distribution of Rett syndrome. Mutations of the MECP2 gene in most cases are spontaneous or germinative – presumably, 70% of cases of this disease are caused by a genetic defect of the X chromosome in the germ cells of the father. Defects in this gene also lead to other pathologies of the central nervous system – the Singing variant, Luba syndrome (X-linked mental retardation in boys), congenital encephalopathy. Some researchers attribute these conditions to atypical forms of Rett syndrome.
Rett syndrome symptoms
In newborn girls, Rett syndrome does not manifest itself at first, the first 6-12 months of the child’s development occurs at the usual pace without any deviations. In the future, the progression of the disease is characterized by a certain stage. The first stage of Rett syndrome, which most often occurs at the age of 6 months to 2.5 years, is characterized by the appearance of muscle hypotension in the child, slowing down psychomotor development, followed by lagging behind peers, loss of interest in games and people around them. Pediatricians note slower than normal growth of feet and hands in length and slowing of the growth of the circumference of the head. Sometimes, in addition to neurological manifestations, there may be a violation of the liver, heart, gastrointestinal tract.
The second stage of Rett syndrome is characterized by more pronounced clinical manifestations. It develops for 1-2 years after the appearance of the first symptoms of the disease, while the child first experiences anxiety, sleep disorders. Then, quite quickly, in just a few weeks, patients with Rett syndrome lose almost all the skills acquired up to that time – speech is lost, the ability to walk disappears. Also, this stage of pathology development is characterized by respiratory disorders – periods of apnea for 1-2 minutes can be interspersed with attacks of rapid and deep respiratory movements (hyperventilation). Respiratory disorders in Rett syndrome differ in the presence only when the patient is awake and absence during sleep. Numerous neurological disorders often occur: ataxia, epileptic seizures, often repeated stereotypical movements.
The third stage of Rett syndrome is called pseudostationary, since there are few signs of disease progression in it. It usually lasts from 4 to 15 years, the condition of patients is stable, but convulsive seizures, deep mental retardation, hyperkinesis are observed. In most cases of Rett syndrome, this stage ends at puberty. The fourth stage of Rett syndrome is characterized by a decrease in the frequency of epileptic seizures until their disappearance with the progression of motor disorders. Most patients completely lose mobility, muscle atrophy occurs, vascular disorders in the lower extremities, which can lead to the development of trophic ulcers. Due to the weakness of the muscular corset of the back with Rett syndrome, scoliosis or other forms of curvature of the spine occur.
Diagnostics
The diagnosis of Rett syndrome is based on the study of the patient’s anamnesis, his current status, magnetic resonance imaging and encephalography, molecular genetic analyses. The study of hereditary history, as a rule, does not make much sense due to the sporadic nature of mutations of the MECP2 gene. Typical for Rett syndrome are the normal development of a child up to 6-12 months, the occurrence of muscle hypotension and anxiety in early childhood, the appearance of ataxia and frequent epileptic seizures in the future, the rapid loss of acquired skills. In the future, severe mental retardation, muscle weakness (up to atrophy), curvature of the spine, convulsive seizures are registered in patients.
Examination of patients with Rett syndrome reveals a lag in growth and its stop, a sharp decrease in the circumference of the head, lack of speech (echolalia is characteristic at the initial stages of pathology). Magnetic resonance imaging of the brain reveals a decrease in the size of the organ, fuzzy differentiation of gray and white matter, basal ganglia, a decrease in the folding of the cerebral cortex. The electroencephalogram confirms a decrease in the background activity of the brain and a sharply weakened reaction to external stimuli.
The most accurate diagnostic information is provided by the methods of modern genetics – the search for deletions in the locus of the MECP2 gene or direct sequencing of its sequence to determine mutations. Such confirmation of Rett syndrome is also possible in the framework of prenatal diagnosis of genetic diseases. An auxiliary role in establishing this condition can be played by examination of internal organs (for example, by ultrasound methods) – in 20-30% of patients, underdevelopment of the liver or spleen is detected.
Treatment
There is currently no specific treatment for Rett syndrome. There are encouraging data from some research laboratories whose employees managed to “turn on” the MECP2 gene in mice and thereby achieve the disappearance of symptoms of the disease. In the field of practical medicine, only symptomatic therapy is still available, but it also involves a number of difficulties – in particular, epileptic seizures with this disease are difficult to eliminate with anticonvulsants. Also, nootropic drugs are used to treat Rett syndrome, sleep disorders are corrected with sleeping pills from the barbiturate group or melatonin.
Prognosis and prevention
The prognosis of Rett syndrome is unfavorable, since this disease steadily leads to severe mental retardation, as well as to a number of motor and neurological disorders. Patients with this pathology, with appropriate care and symptomatic treatment, are able to live up to 40-50 years, but their risk of sudden death is quite high. The presence of malformations of internal organs significantly worsens the prognosis of Rett syndrome and reduces the life expectancy of patients, which occurs in about a third of cases. The main cause of death is respiratory or multiple organ failure and sudden death, adult patients also have a high risk of stroke. Prevention of Rett syndrome is possible only in the form of prenatal diagnosis of this disease by genetic methods. In the presence of a defective form of the MECP2 gene in a boy, a violation of the formation of the brain and internal organs can be noticed during preventive ultrasound examinations during pregnancy.