Excuse me, what disease is RETT and how to treat it?

Rett syndrome is a nervous system disease that seriously affects children's psychomotor development. It was first reported by Andreas Rett on 1966 [1], and was first reported by the Department of Pediatrics of the First Hospital of Beijing Medical University on1987 [2,3]. In the past 30 years, thousands of cases have been reported, of which the majority are women and only 8 are men. Up to now, there are no biological indicators as the basis for diagnosis, and the diagnosis depends on clinical manifestations. The main manifestations are: onset in 6 ~ 18 months, severe psychomotor disorder, hand apraxia, rigid movements, autistic behavior and * * * ataxia. 1988 established the international diagnostic criteria for Rett syndrome, which are recognized criteria, including 9 necessary criteria, 8 supporting criteria and 7 exclusion criteria, and are divided into 4 stages [4]. In addition to typical cases (75%), there are mild cases (2 1%) and severe cases (4%). Hagberg put forward the inclusion criteria of Rett syndrome in 1994, which provided a basis for the diagnosis of atypical cases.

I. international diagnostic criteria and staging of Rett syndrome

Necessary criteria: (1) normal before and during the perinatal period; (2) The psychomotor development is normal in 6 months after birth (the longest is 18 months); (3) Normal head circumference at birth; (4) 5 months to 4 years after birth, the growth of the head slows down; (5) losing the acquired purposeful hand skills within 6 months to 30 months, and the social communication ability is declining; (6) The ability of language expression and understanding is seriously impaired, resulting in serious mental and motor retardation; (7) After the purposeful hand movements disappear, stiff hand movements appear, such as writing words, twisting hands, slapping, biting hands, washing hands and rubbing hands. (8) 1 ~ 4 years old has ataxia, gait and somatization; (9) The initial diagnosis can only be made at the age of 2 to 5.

Support criteria: (1) abnormal breathing; (2) Abnormal EEG; (3) convulsions; (4) spasm; (5) Abnormal peripheral vascular movement; (6) Scoliosis; (7) growth retardation; (8) Foot atrophy.

Exclusion criteria: (1) intrauterine growth retardation; (2) Signs of enlargement of internal organs or other cumulative diseases; (3) retinopathy or optic atrophy; (4) small head at birth; (5) Evidence of perinatal acquired brain injury; (6) Some metabolic diseases or other progressive neuropathy; (7) Neuropathy caused by severe infection or head trauma.

Clinical stages: stage ⅰ: onset time is 6 ~ 18 months after birth, lasting for several months, and development is stagnant; Head growth retardation; Not interested in playing ball and the surrounding environment; Low muscle tone. Phase Ⅱ: It begins at the age of 1 ~ 3 years, lasts for several weeks to several months, and fades quickly and is irritating; Improper application of hands; Stiff hand movements; Seizure; Autism manifestations; Lose the ability of language expression. Stage ⅲ: from 2 ~ 10 years old, lasting for several months to several years, with serious mental retrogression or obvious mental retardation; Seizure; Typical hand movements; Obvious ataxia and physical apraxia; Reflex enhancement and progressive rigidity; Awake apnea; Lose weight; Early scoliosis; Grit your teeth. Stage Ⅳ: It started at the age of 10 and lasted for several years, involving both upper and lower neurons. Progressive scoliosis, muscle disuse and rigidity; The motor function declines, and it needs to rely on wheelchair exercise; Growth retardation; Can look at people for a long time and show deep gaze; Unable to understand and use language; Bipedal atrophy; The frequency of convulsions has decreased.

Second, the research progress of nervous system pathology and biochemistry of Rett syndrome

The incidence of this disease is110000 ~15000 girls. Although most of them are sporadic cases, some cases (about 5%) have family history (all maternal family history), and the incidence of identical twins is highly consistent, so they are considered to be hereditary diseases. At present, the genetic mode and etiology of the disease are not clear, but in recent years, new progress has been made in neuropathology, neurobiochemistry and genetics.

Neuropathological and neuroradiological studies show that (1) patients have extensive brain atrophy, including the brain and cerebellum, and the number of dendrites in pyramidal cells of cerebral cortex is generally reduced, and dendrites and synapses are poorly formed [5]. (2) The volume of whole brain neurons decreased [6], there was no sign of active neurodegeneration, and the number of neurons did not decrease significantly. (3) The number of cholinergic neurons in the forebrain decreases, and the forebrain is the main area of cholinergic neurons in the cerebral cortex [7]. (4) There are different reports about the decrease of melanin in basal ganglia neurons, but there is evidence of cell death and no neurodegeneration. (5) Single photon diffraction CT showed that the type of cerebral blood flow perfusion in children with Rett syndrome aged 2-3 years was similar to that in normal infants aged 2-3 months. Pathological results show that the degree of brain abnormality is closely related to the severity of symptoms at death [8].

Biochemical research confirmed that the activity of choline acetyltransferase (ChAT) in neocortex, hippocampus, thalamus and basal ganglia of children with Rett syndrome decreased significantly, which was consistent with the decrease of cholinergic neurons in forebrain found by neuropathology. In addition, the study found that the level of nerve growth factor in cerebrospinal fluid decreased [9]. Nerve growth factor is necessary for the development of cholinergic neurons in forebrain. These data show that the dysfunction of cholinergic neurons may be the initial factor, which may cause some other defects, such as the dysfunction of extrapyramidal system. In addition, there are significant gender differences in the vulnerability of cholinergic neurons in the forebrain, which is related to the different distribution of estrogen receptors on these neurons [7]. If the dysfunction of cholinergic neurons is indeed the initial factor of Rett syndrome, it can explain the gender ratio difference of patients. (2) There are different reports about the changes of biogenic amines in autopsy tissues and cerebrospinal fluid. (3) The level of β -endorphin in thalamus and glutamate in cerebrospinal fluid increased [10]. In a word, clinical, biochemical and neuropathological data show that Rett syndrome is a neurodevelopmental disease, which may be the abnormality of programmed cell death in early infancy or the lack of some neurotrophic factors [1 1], and its influence is the most serious in the first few years after birth, because it is the peak of dendritic proliferation and the period of synaptic formation.

Thirdly, the genetic research progress of Rett syndrome.

The exact genetic model of Reiter's syndrome is not clear. Because Rett syndrome mainly involves women, the general view in the past was that X-linked dominant inheritance and male embryo died, and the hypothesis of non-random inactivation of X chromosome was introduced. However, recent studies do not support that the pathogenic gene of Rett syndrome is located on the X chromosome, and the study of twin X chromosome inactivation and single parent diploid provides further evidence [12]. Migeon studied three pairs of identical twins with Rett syndrome, two of which were consistent with Rett syndrome and one was not. The results show that monozygotic twins have non-random inactivation of X chromosome, but it has nothing to do with the type of Rett syndrome. In addition, the consistent phenotype of most monozygotic twins with Rett syndrome (112) has never been observed in other female twins known as X-linked mutation diseases, which is also a controversial point whether Rett syndrome is X-linked. Non-random inactivation of X chromosome has also been reported in non-X linked diseases. However, the role of X chromosome in Rett syndrome cannot be completely denied. Bühler et al. [13] put forward the hypothesis that Rett syndrome is the result of interaction between a locus on autosome and a locus on X chromosome. On the basis of the above hypothesis, Anvret et al. [14] chose the chromosome11p14-pter region for research, because this region contains important genes for the growth and development of neurons. Include tyrosine hydroxylase, brain-derived neurotrophic factor, dopamine D4 receptor and insulin-like growth factor 2. In the family studied, no sequence abnormality was found in the gene detection of this region. However, the author thinks that Rett syndrome is probably caused by the interaction between two parts. These two loci may be located on the autosome and X chromosome, or both loci may be located on the autosome.

Whether the abnormal programmed death of brain cells in early infancy can explain the neuropathological changes in patients with Rett syndrome has also been further studied. Bcl-2 plays an important role in apoptosis, so the gene located on chromosome 22 was analyzed, and no sequence abnormality was found in 6 patients.

Naidu et al. [15] think that the characteristics of maternal inheritance of Rett syndrome suggest that mitochondrial DNA, the only genetic material in its cytoplasm, should be analyzed, especially in patients with Rett syndrome, the mitochondrial structure of muscle fibers and the abnormal functions of several respiratory chain enzymes were found in muscle biopsy [16]. However, two recent studies using brain magnetic resonance spectroscopy found no mitochondrial abnormalities. It has also been reported that in substantia nigra, the mitochondrial matrix of some neurons is full of round inclusions, and the mitochondrial matrix of cortical and cerebellar neurons has electronically dense granular inclusions. Like other mitochondrial diseases, patients with Rett syndrome also have lactic acidosis, and the levels of lactic acid and pyruvate in cerebrospinal fluid are increased, which is consistent with the change of redox state [17], but some authors believe that this is caused by abnormal breathing. Naidu et al. [15] analyzed 22 tRNA genes by SSCP and Dan sequencing, and found no abnormal or obvious rearrangement of mitochondrial DNA. Hass et al. [18] detected several hot spots of mitochondrial DNA mutation (3243, 8344 and 8993 sites of mitochondrial DNA) and "* * * homologous deletion" of 4977 bp, but no abnormality was found. Lewis et al. [19] detected the genes encoding 22 tRNA in the mitochondrial DNA of children with Rett syndrome, and found that 1 children had abnormal mitochondrial DNA encoding tRNASer~tRNAAsp and tRNAThr~tRNAPro, and 2 children had abnormal mitochondrial DNA encoding tRNAGly. Later, he studied the blood samples of 2 children with Rett syndrome and the brain tissue samples of 3 children after death, and found that 1 children had a point mutation at T→C of tRNAArg 10463, which was located in a highly conserved region and was not found in normal controls. In addition to mitochondrial DNA, nuclear DNA can also cause mitochondrial abnormalities. Chromosome Xp2 1-22 contains a gene encoding mitochondrial pyruvate dehydrogenase E 1-α subunit, so it should also be listed as a candidate gene from the perspective of mitochondrial abnormality, but no abnormality has been found in the study of this region at present. Through quantitative determination, the level of pyruvate dehydrogenase in skin fibroblasts is also normal. Therefore, the analysis of mitochondrial DNA and nuclear DNA related to mitochondrial structural and functional abnormalities needs further study.