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Introduction Fragile X syndrome (fragile X syndrome, FXS) is an incompletely explicit X-linked dominant hereditary disease, which is caused by a brittle fracture point of the short arm Xq27.3 of the patient's X chromosome. name. FXS is a familial mental disorder with clinical manifestations of mental retardation, special face, giant testis, big ears, language and behavioral abnormalities. Etiology (1) Causes of the disease The occurrence of brittle sites at the end of the X chromosome may be related to deoxythymidine-phosphate deficiency during DNA anabolism, while the fragile site is a DNA-rich segment when deoxythymidine-phosphate When reduced, the deoxythymidine triphosphate is reduced so that this segment does not fold tightly during mitosis, and even cracks or breaks appear to exhibit brittleness. Previous studies on fragile X chromosomes have mostly focused on cytogenetic levels. With the deepening of molecular biology research and the discovery of some special genetic laws in the disease, many important advances have been made in the study of the classification of fragile parts, the special inheritance of fragile X chromosomes and their production mechanisms. Some new concepts and theories have led people to understand the disease from a new level and perspective. Fragile parts classification: 1 hereditary brittle parts (h-fra), also known as rare brittle parts; 2 structural brittle parts (c-fra), also known as common brittle parts. The genetic characteristics of the fragile X chromosome: In the past, its typical genetic pattern was X-linked recessive inheritance. In recent years, its genetic pattern is very complicated, and it has a special genetic law that is completely different from the general genetic disease: 1 is through males without abnormal phenotype Carriers, also known as the explicit (NP) transmission, have no abnormalities in their fragile X daughters; 2 in the fra(X) family, the mentally retarded male patients account for about 20%, the isolation rate is 0.4; 3 phenotypic abnormal brittleness Among the sons of X females, the isolation rate was 0.5; the fragility X of 4 phenotypic women came from their mothers, not from the father; 5 about 35% of female carriers showed mental retardation; 6NP male fragile X mothers general phenotype All were normal, and the risk of phenotypic abnormality in patients with NP males was lower; 7 almost all mothers with fragile X syndrome had brittle X; 8 had different degrees of appearance in siblings. Several hypotheses about the production mechanism: 1 movable factor insertion hypothesis; 2 poly-purine/polypyrimidine sequential amplification hypothesis; 3 pyrimidine-rich DNA sequence recombination and amplification hypothesis; 4 pre-instability mutation hypothesis; Chromosome repression gene effect hypothesis. Jacobs et al believe that the genes for male and female germplasm cytoplasm can have the same mutation frequency and are transmitted downwards. Patients with fragile X chromosome may be passed down to the parent after two stages of genetic engineering mutations, but the phenotype of the parent is normal and fra(X) is often not detected in the peripheral blood. When his or her germ cells are mutated again and passed to a child or a woman, a fra(X)-positive patient or a female carrier is produced. Sutherland has pointed out whether there are abnormal gene products or lack of certain products in patients with fragile X chromosome. There is currently no basis. In short, the real mechanism of the occurrence of brittle sites has yet to be further studied. (B) the pathogenesis of fragile X chromosome patients in the Xq27.3 zone with fragile sites (FRAXA) is its typical cytogenetic features. In 1993, the cDNA of the fragile X chromosome coding gene was cloned, and it was found that the n copy number in the (CGG)n structure was amplified from normal 6 to 52 to ≥230, which is the molecular basis of the onset of fragile X chromosome, abnormal amplification (CGG). The n structure is located in exon 1 of the translation region of the FMR-I gene. It has been known that carriers of missense mutations and deletion mutations of the FMRI gene also exhibit the same clinical symptoms of dynamic mutation of the FMRI gene, thereby showing that patients with clinical syndrome of fragile X chromosome have a high degree of genetic heterogeneity, thereby enabling these patients and their The genetic diagnosis of family members is further complicated. 1. Cytogenetics X chromosome long arm 27.3 carries a folate-sensitive site associated with the fragile X chromosome, which can be shown as a brittle site after special treatment. A chromosome with a fragile site is called a fragile chromosome. So far, the fragile sites of 26 chromosomes have been found, and only the fragile site of the X27-X28 region of the X chromosome (FRAXA) is associated with hereditary diseases, while other fragile sites unrelated to the disease are called common fragile sites. The mechanism by which the fragile site is produced is not fully understood and is currently thought to be involved in the anabolic process of DNA. It has been found that treatment in the absence of folic acid or with higher doses of 5-fluorouracil (5-FU) can result in inhibition of the synthesis of the thymidine nucleoside, which may result in cracks or breaks at specific sites. 2. Structure, transcription and translation of the FMR-I gene The fragile X chromosome gene is called fragile X mental retardation-I (FMR-I), which is located in the Xq27.3 region and spans across the genome. 38kb, consisting of 17 exons and 16 introns. The FMR-I gene has an mRNA of 4.4 kb and encodes a brittle intelligent lagging protein (FMRP) consisting of 596 amino acids with a molecular weight of approximately 69-70 kDa, which is an RNA-binding protein expressed in various tissues in vivo. The FMR-I gene has a small exon (51-196 bp), but the intron is larger, with an average size of 2.2 kb, and the intron 1 is about 9.9 kb. There are a variety of transcriptional splicing forms in the gene involving exon 10, 12, 14, 15 and 17 of the 3' end of the FMR-I gene, where the involvement of exons 12 and 14 usually results in the loss of the entire exon. However, the partial sequences of the 5' ends of the three exons were only lost in the exons 10, 15 and 17, because there is a concatenated conserved signal on the 5' end of the three exons, after transcription. If the splicing occurs at this position, the partial sequence at the 5' end of the three exons is lost. 3. Dynamic mutation of FMR-I gene The FMR-I gene has a CGG trinucleotide repeat region at the 5' end. In normal individuals, the number of CGG structural repeats is polymorphic, ranging from 6 to 52 times, with an average of 30. In the Chinese population, (CGG) 28 is the most common. In FXS patients, CGG copy number is generally >200 times, and more than 1000 times. The underlying cause of the fragile X chromosome is caused by mutations in the FMR-I gene. Dynamic mutation refers to the instability of CGG copy number during FMR-I gene transfer, which is the molecular genetic basis of more than 95% of FXS patients. Dynamic mutations include three types: (1) Premutation of the FMR-I gene: When the n copy number of the FMR-I gene (CGG) n structure is amplified to 53-230, the carrier has a normal phenotype, but Further amplification is likely to occur during the passage, so that the number of CGG repeats of the offspring is greatly increased, and an abnormal phenotype appears. This mutation of the FMR-I gene is called a pre-mutation, and the intelligence level of the male or female FMR-I pre-mutation gene carrier is not different from that of a normal person. According to statistics, there is no difference in n copy number in male or female pre-mutant FMR-I gene (CGG) n structure, but with the gradual n-copy number in the FMR-I gene (EGG) n structure carried by women Increasing, the probability of amplification before amplification is gradually increased. While the 38% pre-mutant FMR-I gene was transferred from paternal to daughter, the n-copy number in the (CGG) structure was reduced, but this phenomenon was only seen in the transfer of 2% of the maternal pre-mutant FMR-I gene to At the time of the daughter, it was suggested that the pre-mutant FMR-I gene had a tendency to amplify the n-copy number in the (CGG)n structure during the mother-female transmission, but there was a tendency to decrease when the father-female was delivered. (2) Full mutation of FMR-I gene: When the FMR-I gene is amplified from 53 to 230 times before the pre-mutation state (CGG) to >230 times, 100% of male carriers exhibit typical fragile X synthesis. According to the sign, 53% of female carriers showed mental retardation of varying degrees of severity, which is called full mutation. Full mutations are directly related to the appearance of mental retardation. It was found that when the number of CGG structures was more than 230, the CpG island at the 5' end of the FMR-I gene began to be abnormally methylated. This methylation extended to the promoter region, resulting in transcription failure. It cannot be transcribed, and the protein products encoded by the genes are also lacking, resulting in clinical symptoms. It is worth noting that a very small number of male fully-mutant FMR-I gene carriers lack the fragility of the FRAXA site, and the molecular genetics remains to be further studied. In terms of low-intellectual clinical manifestations, almost 100% of male FMR-I full-mutation gene carriers have mental retardation, of which approximately 89% (245/274) are moderately mentally retarded, but only 21% (36/170) female FMR -I full mutation carriers showed moderate mental retardation, and up to 59% (100/170) female FMR-I full mutation carriers did not appear mentally retarded. (3) Back-mutation of the FMR-I gene: The CGG structure of the FMR-I gene in the pre-mutation or full-mutation state undergoes a certain range of reduction in the number of copies during the passage, which is called the back mutation of the FMR-I gene ( Reverse mutation). According to the state of the FMR-I gene before and after the mutation, the back mutation can be divided into three types: full mutation → premutation; full mutation → full mutation or premutation chimerism; chimeric or premutation → Normal FMR-I gene. These phenomena can occur in the process of paternal transmission, but also in the process of maternal transmission. Although less common, it increases the difficulty of predicting the dynamic mutation of FMR-I gene, leading to intra-family genetic counseling and prenatal genes. The diagnosis is further complicated. 4. The influence of gender factors on the dynamic mutation of FMR-I gene It is believed that the amplification of FMR-I gene (CGG) n structure is a multi-path multi-step amplification process, and the genetic model of fragile X chromosome often has special Regularity, that is, a male carrier with normal phenotype can pass the fragile part to his daughter, who generally has no mental retardation or other clinical symptoms, but she can pass the affected chromosome to the offspring, so that the third generation of the family will appear FXS. patient. At this time, the third generation of boys have more obvious mental retardation, and girls often have no obvious mental abnormalities, that is, the harm caused by the mother to the children is more serious than that of the father, and the boy is more affected than the girl. Said the Sheman phenomenon. In addition, it was also found that only the pre-mutant FMR-I gene was present in the sperm sample of the male all-mutant FMR-I gene carrier. Therefore, it is now believed that the full mutation of the FMR-I gene does not involve the germ cells of the male full-mutation carrier, but there is currently insufficient evidence to suggest that the female egg has not undergone a full mutation of the FMR-I gene. In addition, during the passage of female FMR-I gene mutation carriers, the expansion and size of the (CGG)n structure changes according to the sex of the offspring, that is, it has a tendency to further expand when passed to male offspring. However, when it is passed to female offspring, the degree of expansion is small, and the structure of (CGG)n is reduced. It is possible that another normal FMR-I gene carried by female X chromosome inhibits the early stage of female embryo. Further amplification of the fully mutant FMR-I gene (CGG) n structure. In conclusion, the trend of the whole mutant FMR-I gene (CGG) n structure (either amplification or reduction) and the moderate size of change are still affected by the gender of the parent and offspring. Therefore, this mutational feature of the FMR-I gene must be considered in the genetic counseling of the FMR-I gene dynamic mutation family. 5. Non-Dynamic Mutation of FMR-I Gene In addition to dynamic mutations, non-dynamic mutations such as base substitutions and deletions occur in a small number of patients. One missense mutation and eight deletion mutations have been found. These mutations cause the same clinical symptoms and dynamic mutations, but lack the FRAXA fragile site. Current reports do not show that this mutation has a hot spot. Symptoms 1. Male patients are characterized by mental retardation, large ears and large testicles. Typical clinical symptoms include: (1) Mental retardation: IQ is often less than 50, and progressively worse. (2) Special face: The birth weight is higher, and the growth rate is fast in the first few years after birth, but the body is short in adulthood, the face is long and the forehead is prominent. The head circumference is enlarged, the sputum is full, the iris color is lightened, the ear is everted, the sacral bow, the big mouth, the thick lip, and the jaw are large and prominent. Read more...

Introduction Methylmalonic acidosis (methylmaloni cacidemia), also known as methylmalonic aciduria, is an autosomal recessive inheritance. The main clinical manifestations are early onset, severe intermittent ketoacidosis, increased methyl and malonate in blood and urine, often accompanied by central nervous system symptoms. Causes (1) Causes of the disease The disease is autosomal recessive. L-methylmalonic acid cannot be converted to succinic acid and accumulated in blood due to methylmalonyl-CoA mutase (vitamin B12 non-reactive type) or coenzyme adenosine cobalt ammonium deficiency (vitamin B12 reactive type) Caused. (B) the pathogenesis of hereditary methylmalonic acidemia has a variety of biochemical defects. Complete mutase deficiency (mut0) and partial deficiency (mut-) due to defects in two mutase apoenzymes; synthesis of two adenosine cobalamin (AdoCbl) Defects, namely mitochondrial cobamide reductase (cblA) deficiency and mitochondrial cobalamin adenosyltransferase (cblB) deficiency; and 3 abnormalities due to cytosolic and lysosomal cobalamin metabolism Defects in the synthesis of adenosine cobalamin and methylcobalamin (MeCbl) (cblC, cblD, cblF). The patients had only methylmalonic acidemia with genetic defects mut0, mut-, cblA and cblB, and the clinical manifestations were similar. Defects such as cblC, cblD, and cblF produce methylmalonic acidemia and homocystinuria. Symptoms Methylmalonic acidemia has a variety of biochemical defects, but the clinical manifestations are similar. It is early onset and usually occurs in neonates or early infancy. Common sleepiness, growth dysplasia, recurrent vomiting, dehydration, respiratory distress and low muscle tone. Some have intelligence behind, liver and coma. Symptoms of mut0 were early, and 80% were in the first week after birth. Serum cobalamin concentration is normal, metabolic acidosis, 80% have ketone blood or ketonuria, 70% have hyperammonemia. Half of the patients had leukopenia, thrombocytopenia, and anemia. Some cases have hypoglycemia. There is a large amount of methylmalonic acid in the urine or blood of the patient. Mild, late-onset or so-called "benign" cases have lower levels of methylmalonic acid. Ingestion of propionic acid and methylmalonic acid precursor proteins or amino acids can increase the accumulation of methylmalonic acid, or even cause ketosis or acidosis. Hereditary methylmalonic acidemia with homocystinuria, defects are cblC, cblD, cblF. The clinical manifestations of cblC deficiency were highly variable, but all of them were mainly neurological symptoms. Early onset symptoms appear 2 months after birth, manifested as poor growth, feeding difficulties or lethargy. Late onset symptoms can occur in 4 to 14 years of age, including burnout, cramps and tonic, or dementia, myelopathy. Most cases have abnormal blood system, such as giant red blood cells and giant red blood cell anemia, polymorphonuclear leukocyte nuclear lobulation and thrombocytopenia. Serum cobalamin and folic acid concentrations were normal. The defects of cblD generally occur later, manifested as behavioral abnormalities, intelligent backwardness and neuromuscular lesions, and no abnormalities in the blood system. Patients with cblF deficiency developed stomatitis, hypotonia and facial deformities 2 weeks after birth, and some had abnormal blood cell morphology. Some cases have hypomethioninemia and cystathioninuria. Diagnostic diagnosis using GC-MS for blood and urine organic acid analysis can diagnose this disease. The determination of various genetic defects depends on the enzymatic analysis of cultured cells. Identification should be noted to rule out ketoacidosis, cobalamin deficiency, and homocysteine in other causes of neonatal period. Complications and dysplasia, vomiting can cause dehydration acidosis, respiratory distress and mental retardation or dementia, myelopathy. Liver and coma. Hyperammonemia, hypoglycemia, paralysis and tonicity can occur. Abnormal blood system such as megaloblastic anemia and platelets, leukopenia, etc. Therapeutic Western medicine treatment is effective. Limit protein intake and reduce amino acid intake of methylmalonate precursors as soon as possible. L-carnitine and oral antibiotics may be effective. Some cases are effective for supplementing large doses of vitamin B12, that is, B12-dependent methylmalonic acidemia, which can be given first to B1 1 to 5 mg/d for 1 week. If the effect is effective, the maintenance dose can be given for a long time. The dose is generally 1 mg per week, adjusted according to clinical and biochemical reactions. The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary. Prevention is the most important prevention of most hereditary metabolic diseases without effective treatment. Antenatal diagnosis of hereditary metabolic disease is one of the effective measures to prevent the occurrence of genetic diseases. It is the practical application of human genetics knowledge and an important measure for eugenics. The prenatal diagnosis of hereditary metabolic diseases is a combination of biochemical genetics, molecular genetics and clinical practice, and has a strong practical application value. Since the early 1960s, the prenatal diagnosis has been developed with transabdominal amniocentesis. Prenatal diagnosis techniques have developed rapidly. Following the fetal microscopy of fetal blood specimens and the transcervical and transabdominal wall, it has been developed in recent years. Non-invasive prenatal diagnostic techniques. Enrichment and isolation of fetal nucleated red blood cells from the peripheral blood of pregnant women, the cells derived from the fetus can be subjected to interphase nuclear fluorescence in situ hybridization (FISH) for abnormal chromosome number detection, or DNA extracted for PCR amplification and then subjected to linkage analysis or Direct detection of mutations for prenatal genetic diagnosis. Amniocentesis can be performed through the abdominal wall 17 to 20 weeks of pregnancy. Amniocytes are epithelial cells that are shed by the fetus and can be used for enzyme activity assay or genetic analysis after culture. The fetal loss rate caused by this method is 0.5%. It is still an important means of prenatal diagnosis. The villi are from the embryonic trophoblast and can be taken through the abdominal wall 10 to 12 weeks of gestation. Can be used for enzyme activity determination or genetic analysis. The advantage is that the amniocentesis is 2 months earlier than the amniocentesis, and it is not necessary to culture, and the prenatal diagnosis result can be obtained earlier. Once the fetus is sick, the pregnant woman can choose artificial abortion in time, the subsequent operation is easier to carry out, and the psychological burden of the pregnant woman can be relieved as soon as possible. According to the detection method, it can be divided into metabolite measurement, enzyme activity measurement and gene analysis. 1. Determination of metabolites can be analyzed by amniotic fluid, such as phosphocreatine kinase (CK), alpha-fetoprotein (AFP), mucopolysaccharide in amniotic fluid can be used to diagnose mucopolysaccharidosis, including dermatan sulfate (DS), sulfuric acid Heparin (HS), keratan sulfate (KS), chondroitin sulfate (CS). The methods used are one-way or two-dimensional cellulose acetate membrane electrophoresis, dimethyl methylene blue-Tris method and the like. Methylmalonic aciduria in organic acidemia can be measured by gas chromatography-mass spectrometry (GS/MS) for methylmalonic acid in amniotic fluid. This disease can be used in amniotic fluid or mid-pregnancy gestational urinary methylmalonic acid concentration or enzyme activity in cultured amniotic fluid cells for prenatal diagnosis and termination of pregnancy if necessary. 2. Determination of enzyme activity Most of the genetic metabolic diseases are caused by enzyme defects. Therefore, prenatal diagnosis can be performed by using cultured amniotic cells or fluff using enzyme activity assays. First, the amniocytes should be harvested and cultured for 1 million hours to re-test enzyme activity, or directly measure the enzyme activity in the villi. However, some enzymes are not expressed in amniotic fluid cells or villi. For example, phenylalanine hydroxylase is only expressed in liver cells, and prenatal diagnosis of phenylketonuria can only be performed by DNA analysis. Lysosomal storage disease is a group of diseases that have the most prenatal diagnosis by enzyme activity assay. A prenatal diagnosis should have a normal specimen (amniotic fluid or villus) as a control. It would be better to have a positive specimen that was retained in the past as a positive control. A disease in which the gene has been isolated or localized can be used for prenatal genetic diagnosis. 3. Genetic diagnosis Different types of mutations have different diagnostic pathways, such as direct detection, polymorphism linkage analysis. A prerequisite for prenatal diagnosis is to make an accurate diagnosis of the proband. It is only possible for the mother to check for an enzyme or a genetic test at the time of prenatal diagnosis. Due to the serious condition of lysosomal storage disease, most diseases have no effective treatment and the prognosis is poor. The birth of a child brings a heavy economic and spiritual burden to society and the family. There is no effective treatment for this disease, but most of them can clearly determine whether the fetus is sick before delivery, and some can also make prenatal diagnosis in the early pregnancy, which has the meaning of "prevention" in eugenics. Because it can prevent the birth of a baby based on a clear prenatal diagnosis, it is not only the only viable eugenics, but also reduces the burden on families and society and improves the quality of the population.

Introduction What are the symptoms of myasthenia gravis syndrome? 1. Myasthenia gravis (1) It is estimated that only 12% to 20% of the live babies born to MG mothers have reduced muscle tone, low crying, and sucking power. Weak muscle is weak; the rest of the baby's blood AchR-Ab can be increased, but does not show muscle weakness. (2) About 78% of newborn MGs have muscle weakness and electrophysiological manifestations within a few hours to one day, and blood AchR-Ab can be increased. Since the sick child itself does not produce AchR-Ab, the muscle weakness gradually decreases until it disappears. After 18 days and rarely more than 2 months, the AchR-Ab in the blood gradually decreased and no longer relapsed. (3) The phenomenon of intrauterine fetal movement reduction during MG mother's pregnancy is rare. If the fetal muscle weakness is severe, the fetus is inactive in the uterus for a long time, and the joint is bent after birth. This condition may also occur after the mother produces it. 2. Congenital myasthenia gravis syndrome (1) Children with less fetal movement before birth, onset soon after birth or birth, neonatal period showed sag ptosis intermittent or progressive aggravation, medullary muscle weakness, facial muscle weakness, often Affect feeding. The sucking power of breastfeeding is weak, the crying is weak, and the respiratory muscle weakness occurs when crying, which are important clues to the congenital muscle weakness syndrome. There is no obvious progress in the course of the disease. The generalized muscle weakness is either with or without. It is generally not serious. It can start to improve at 6 to 7 years old, but it cannot be completely relieved. (2) Most of the onset in infancy or childhood, continuous exercise can produce muscle weakness, fluctuating eye muscle paralysis and abnormal fatigue, etc. In some cases, until 10 years old or 20 years old, there is obvious muscle weakness and fatigue. . Check that the sputum reflex is normal and there is no muscle atrophy. Patients are prone to respiratory infections, often due to fever, excitement and vomiting, causing potentially fatal muscle weakness, respiratory muscle weakness can lead to decreased ventilation, dyspnea and hypoxic brain damage. With age, the onset of crisis can be gradually reduced. 3. Congenital endplate Ach esterase deficiency This disease occurs in males, and all skeletal muscle weakness and abnormal fatigue are present at birth. Muscle biopsy was normal, and cytochemical examination by light and electron microscopy revealed a lack of Ach esterase. 4. Slow channel syndrome Infants, children or adults with onset, progressive aggravation, can have several years of intermittent. Typical muscle weakness can affect the neck, shoulder and extensor muscles, with mild to moderate ptosis, limited extraocular muscle activity, varying degrees of muscle weakness in the mandible, facial, upper limb, respiratory and trunk muscles. The lower limbs are relatively spared. Muscle atrophy and fatigue are visible in the affected muscle, and the limb reflex is seriously affected. 5. Congenital acetylcholine receptor deficiency often begins in infancy, clinical symptoms and electrophysiological characteristics are similar to myasthenia gravis. Muscle biopsy showed a decrease in the number of AchR and normal cholinesterase. Serum AchR-Ab was negative and no immune complex was seen in the endplate region. 6. Drug-induced myasthenia gravis (1) Drugs and toxins cause myasthenia gravis syndrome onset, the symptoms last for hours to days, patients can recover completely without respiratory failure, eye muscles, facial muscles, bulbar muscles and Limb muscles can be affected. The history of medication, the history of exposure to poisons, and the history of poisoning can provide an important basis for clinical diagnosis. (2) Chronic graft ver sus host disease may occur in long-term (2 to 3 years) survivors after allogeneic bone marrow transplantation. Typical myasthenia gravis is a local manifestation. (3) Myasthenia gravis caused by interferon-α: Batocchi et al (1995) reported autoimmune myasthenia gravis during treatment of interferon-α (IFN-α) in 2 patients with malignant tumors; Piccolo et al. (1996) reported One patient with chronic hepatitis C developed MG after treatment with IFN-α; Mase et al (1996) reported that a patient with hepatitis C who was susceptible to MG genetic quality developed severe MG during IFN-α2a treatment. Diagnosis can be made based on clinical manifestations of different clinical types and related laboratories and other ancillary examinations. See clinical performance and related laboratory tests, auxiliary examinations.

Introduction About the relationship between aplastic anemia and pregnancy, most scholars believe that pregnancy is not the cause of aplastic anemia, does not induce or promote the occurrence of aplastic anemia, pregnancy with aplastic anemia is often the two in pregnancy The coupling, or some patients have already developed before pregnancy, and the disease is aggravated after pregnancy. Therefore, not all patients with aplastic anemia must terminate their pregnancy. However, a large number of clinical data indicate that aplastic anemia can cause adverse effects on pregnancy; pregnancy with aplastic anemia, high incidence of hypertensive disorder complicating pregnancy and early onset, serious illness, prone to heart failure and placental abruption , prone to miscarriage, premature delivery, fetal death, fetal growth restriction. The high incidence of postpartum hemorrhage and infection rate is the main cause of maternal mortality in pregnancy with aplastic anemia. If hemoglobin is <60g/L after pregnancy, abortion should be hospitalized in the early stages of pregnancy. If you have reached the second trimester, the risk of bleeding and infection due to induction of labor is greater than that of natural childbirth, and termination of pregnancy does not reduce maternal mortality in aplastic anemia, so you can continue your pregnancy while actively supporting the therapy. However, the treatment of acute aplastic anemia is not effective, especially the severe reduction of hematopoietic cells, the occurrence of maternal and child complications, and serious threat to the mother and child, should also consider termination of pregnancy. Patients who continue to have a pregnancy should work closely with the hematologist. Develop a careful treatment plan. Detailed observation and treatment of hospitalization if necessary. Accept a strict system of perinatal care. Active prevention and treatment of pregnancy complications. After full-term pregnancy, if there is no indication of obstetrics, vaginal delivery should be done as much as possible to reduce the surgical output. It is best to carry out planned delivery; after the cervical ripening, after transfusion of whole blood or blood, hemoglobin reaches 80g/L, and platelets reach 20×. 109/L (20,000) or more, in the case of preparing enough fresh blood to promote childbirth. Try to avoid tissue damage during childbirth, carefully check and improve the suture wound. The uterine contraction agent is used in time after delivery to accelerate the exfoliation and discharge of the placenta. Effectively promote uterine contractions and reduce postpartum hemorrhage. Antibiotics are routinely used in clinical postpartum to prevent infection. In the puerperium period, the clinical manifestations of infection should be closely observed, and antibiotics should be continued, supplemented by appropriate Chinese medicine treatment to promote uterine involution. It has been argued that if cesarean section is required for obstetric indications, the uterus can be removed to avoid severe bleeding and infection after surgery. Wu Jing et al (1996) reported that in patients with pregnancy and aplastic anemia, strict perinatal care, pregnancy and childbirth and neonatal care can significantly improve the prognosis of mother and child. It is generally believed that hemoglobin >60g/L during pregnancy has little effect on the fetus. Newborns who can survive after childbirth generally have normal blood and rarely have aplastic anemia. Hemoglobin ≤ 60g / L can lead to miscarriage, premature delivery, fetal growth restriction, stillbirth and stillbirth. The prognosis of aplastic anemia is related to its type. Severe and very severe AA treatment is difficult, mortality is high, acute aplastic anemia is more than one year of onset, and intracranial hemorrhage and severe infection are the most common causes of death. 30% to 50% of patients with chronic aplastic anemia can be cured after active treatment. Although aplastic anemia is not a contraindication to pregnancy, the risk at pregnancy is much greater than during non-pregnancy. Pregnancy and childbirth in patients with aplastic anemia must be given sufficient attention and serious consideration. It is generally believed that patients with aplastic anemia should have strict contraception and should not be pregnant.

Introduction Fabry disease - (Farre disease) is a very rare X-linked genetic glycosphingolipid metabolism disease, the pathogenesis of which is due to the congenital deficiency of α-galactosidase A (α-GalA) in patients Thus, the human metabolites sphingosine trihexosylglycoside (Gb3) and ceramide hexosamine dihexosides cannot be cleaved, accumulating in the blood vessels and organs of patients, causing very severe pain in the limbs, and on the kidneys and heart. The brain, nerves and other organs cause serious damage and cause lesions, and the condition is progressively aggravated. If it is not treated effectively, it will be life-threatening. The cause of Fabry disease (Frebe disease) is a very rare X-linked genetic glycosphingolipid metabolism disease, the pathogenesis of which is due to the congenital deficiency of α-galactosidase A (α-GalA) in patients Thus, the human metabolites sphingosine trihexosylglycoside (Gb3) and ceramide hexosamine dihexosides cannot be cleaved, accumulating in the blood vessels and organs of patients, causing very severe pain in the limbs, and on the kidneys and heart. The brain, nerves and other organs cause serious damage and cause lesions, and the condition is progressively aggravated. If it is not treated effectively, it will be life-threatening. Fabry disease is a lysosomal storage disease (ICD-10-E). Due to a mutation in the gene encoding α-galactosidase (α-GAL), the patient lacks α-galactosidase, making some lipids, especially trihexosylceramide (GL3), unable to be metabolized. And accumulate in the lysosome, leading to various clinical symptoms. The disease is inherited in a X-linked recessive manner. Most of the patients are male and have severe symptoms. Women with a disease-causing gene are usually milder than men. Clinical manifestations Most of the clinical symptoms begin to appear in children or adolescents, and male symptoms are heavier. The main clinical manifestations of the disease include: (1) intermittent pain or paresthesia in the hands and feet, the degree of pain is like a burning feeling, and in normal cases, it is impossible to live and work normally. Pain can last from a few minutes to a few days, sometimes recurring. Pain usually occurs when the temperature is high or seasonal, and can be exacerbated after exercise. (2) Red or purple-black vascular keratomas (angiokeratoma) often appear in the lower abdomen, thighs, scrotum, and external genitalia. The degree of lesions often increases with age, and the patient's ears, oral mucosa, conjunctiva, and nails may also develop lesions. Ocular vertebral opacity is a characteristic manifestation of the disease. Diagnosis of the disease is often misdiagnosed as rheumatism, arthritis, growth pain or psychogenic pain, and is even considered to be a patient. Clinical diagnosis is based on pain in the extremities, skin lesions, vortex corneal opacity, and the discovery of lipid-filled cells in urine or tissue samples. Alpha-galactosidase assay can confirm the diagnosis. Enzymatic and genetic testing of individuals with a family history can screen patients and carriers early. The treatment of Fabry disease can be divided into symptomatic treatment and enzyme replacement therapy. Enzyme replacement therapy can supplement the lack of enzymes in patients, keep lipid metabolism normal, improve patients' symptoms and prevent disease progression.

Introduction Langenhans cell histiocytosis (LCH), formerly known as histiocytosis, is a group of unexplained tissue cell proliferative disorders. Tradition is divided into three clinical types, namely, Leter's syndrome, (Litterer-Siwe disease, referred to as LS disease), Han-Xue-Ke syndrome, (Hand-Schuller-Christian disease, referred to as HSC disease) and bone hobby Eosinphilic granuloma of bone (EGB). The cause is unknown. In recent years, studies have found that it is associated with immune regulation disorders in vivo. The incidence of this disease is estimated to be 1/200,000 to 1/20,000. It mainly occurs in babies and children, but also in adults and even the elderly. Many reports mention that male patients are mostly. The etiology of the cause is still unclear. Although its genetic characteristics are still unclear, it has a certain familial nature, and the incidence among siblings is much higher than that of ordinary children. It is also considered that the disease has the nature of a tumor. Symptoms Clinical manifestations The onset of this disease is different, the symptoms are diverse, LCH, skin, single or multiple bone damage, with or without diabetes insipidus is limited; liver, spleen, lung, hematopoietic system and other organs Damage, or bone and skin lesions are extensive. This patient involved multiple systems and multiple organs belonging to the extensive LCH. The lighter is an isolated painless bone lesion, and the severe one is extensive organ infiltration with fever and weight loss. (1) Skin lesions of the rash are often the primary symptoms of the diagnosis. The rash is a variety of acute infants with initial rash. The rash is mainly distributed in the trunk and scalp, behind the ear, and begins to be a maculopapular rash. It quickly oozes out (similar to eczema). Can be seborrheic dermatitis), may be associated with bleeding, and then crusted, loose, and finally left with pigmentation leukoplakia, white spots are not easy to dissipate for a long time. Each stage of rash can exist at the same time or a batch of retreats can be repeated, and there is often fever in the case of rash. Chronic rash can be scattered throughout the body, initially paleomenopausal papules or sputum nodules, when the depression subsides the central depression, some are dark brown, very similar to scab, and finally the local skin thinning slightly concave Slightly shiny or slightly desquamated. The rash can occur at the same time as other tube damage, or as the only affected manifestation, common in male infants under 1 year old. (2) Bone lesions Bone lesions are found in almost all patients with LCH. Individual bone lesions have more bone lesions, mainly manifested as osteolytic lesions. Skull lesions are most common, followed by lower extremity bones, ribs, pelvis and spine, and jaw lesions are also quite common. On the X-ray film, the bone disintegration is characterized by irregular edge. The skull damage changes from the worm-like shape to the large defect or the chisel-like change. The shape is irregular, round or elliptical, and the edge is jagged. The boundary of the initial or progressive lesion is blurred, and the common intracranial pressure is increased, the fracture of the bone is broken or the hydrocephalus of the communication may be accompanied by headache. However, during the recovery period, the bone is gradually clear at the edge, the hardening zone appears, the bone density is uneven, the bone defect gradually becomes smaller, and finally the whole repair does not leave any trace. X-ray changes of other flat bones: visible rib swelling, thickening, thin bone or cystic changes, and then bone absorption, atrophy, thinning. Vertebral destruction can become a flat vertebra, but the intervertebral space is not narrow, and angular deformities rarely occur. Spinal arch destruction is prone to spinal nerve compression, and a small number of paravertebral soft tissue swelling. Jaw disease can be expressed as both alveolar and jaw shape. (3) Lymph node lesions of lymph node LCH can be expressed in three forms. 1 simple lymph node lesions, known as lymph node primary eosinophilic granuloma; 2 is a concomitant lesion of localized or focal LCH, often involving osteolytic lesions or skin lesions; 3 as systemic diffuse LCH portion. Often involved in the isolated lymph nodes in the neck or groin, most patients have no fever, and a few have only pain in the enlarged lymph nodes. Simple lymph node involvement, the prognosis is good. (4) The inflammation of the outer ear of the ear and mastoid LCH is often the result of proliferation and infiltration of Langerhans cells in the soft tissue of the ear canal or bone tissue. Sometimes it is difficult to distinguish from diffuse bacterial ear infections. The main symptoms are empyema in the external auditory canal, swelling behind the ear and conductive deafness. CT examination can show both bone and soft tissue lesions. Mastoid lesions can include mastoiditis, chronic otitis, cholesteatoma formation, and hearing loss. (5) Under normal circumstances, there is no LC in the bone marrow, and even LCH invading multiple sites is also difficult to see LC in the bone marrow. Once the LC invades the bone marrow, the patient may have anemia, leukopenia and thrombocytopenia, but the degree of abnormal bone marrow function. It is not proportional to the amount of LC infiltration in the bone marrow. LC alone in the bone marrow is not sufficient as a basis for diagnosis of LCH. (6) The thymus thymus is one of the organs that LCH often involves. (7) Pulmonary lesions of lung LCH may be part of systemic lesions, or may exist separately, the so-called primary lung LCH. Pulmonary lesions can occur at any age, but are more common in infants during childhood, manifesting as dyspnea, hypoxia, and lung compliance. In severe cases, pneumothorax and subcutaneous emphysema may occur, and respiratory failure may occur and death may occur. Pulmonary function tests often show restrictive damage. (8) Liver system diffuse LCH often invades the liver, and the affected parts of the liver are mostly in the liver triangle. The degree of involvement can range from mild gallbladder deposition to severe hepatic hilar infiltration, hepatocyte injury and bile duct involvement, and liver performance. Abnormal function, jaundice, hypoproteinemia, ascites and prolonged prothrombin time can progress to sclerosing cholangitis, liver fibrosis and liver failure. (9) spleen diffuse LCH often has spleen and elbow swelling, accompanied by peripheral blood one or more blood cell reduction, which may be due to the expansion of the spleen volume, causing blockage of platelets and granulocytes without damage, increased by yin The stagnation of blood cells and peripheral blood cells can still reach a dynamic balance, so bleeding symptoms are not common. (10) Gastrointestinal lesions are common in systemic diffuse LCH. Symptoms are mostly related to the affected area. The small intestine and ileum are most often involved, showing vomiting, diarrhea and malabsorption, which can cause stagnation in children for a long time. (11) The involvement of the central nervous system in the central nervous system LCH is not uncommon. The most common site of involvement is the thalamus-pituitary area. Diffuse LCH can have substantial brain lesions. Most patients with neurological symptoms appear in other parts of LCH several years later, often with ataxia, dysarthria, nystagmus, hyperreflexia, rotational dyskinesia, difficulty swallowing, blurred vision and so on. Diabetes insipidus caused by the thalamus and/or pituitary granulomatosis can occur before or after the brain symptoms or with the brain symptoms, or it can be the only manifestation of the CNS. (12) Letterer-Siwe disease is the most serious type of Langerhans cell histiocytosis, accounting for about 1%. A typical case is a baby less than 2 years old, with a scaly seborrheic eczema-like rash, sometimes Presents a purplish rash that invades the scalp, ear shell, abdomen, and wrinkled areas of the neck and face. Skin damage can become a gateway to microbial invasion, leading to sepsis. Common ear overflow pus, lymphadenopathy, hepatosplenomegaly. In severe cases, hepatic dysfunction can be associated with hypoproteinemia and decreased synthesis of coagulation factors, anorexia, irritability, and weight loss. There are obvious respiratory symptoms (such as cough, shortness of breath, pneumothorax), severe anemia, and sometimes neutropenia. Thrombocytopenia is often a precursor to death. Because of these manifestations, young patients are often misdiagnosed or missed. Diagnostic diagnosis method is based on clinical, X-ray and pathological examination results, that is, the pathological examination of the lesions in the lesions can be confirmed by tissue infiltration. The key to the diagnosis of this disease is the pathological examination of the tissue infiltration of Langerhans cells. Therefore, biopsy should be done as much as possible. Identification 1. Seborrheic dermatitis: The lesions of Langerhans cell hyperplasia sometimes appear as seborrheic dermatitis, but seborrheic dermatitis in infancy does not have systemic symptoms and hepatosplenomegaly. 2. Xanthomas: Langerhans cell hyperplasia with yellow tumors should be differentiated from other diseases that may cause yellow tumor damage, the latter may have hyperlipoproteinemia and other underlying diseases, generally no obvious systemic symptoms and bone Loss, if necessary, should be examined for bone marrow, histopathology, etc. Complications Chronic otitis media and otitis externa: caused by involvement of the sacral mastoid and rocky parts; lumps in the orbital area can cause exophthalmos, optic nerve or eyeball muscles to cause vision loss or strabismus; the most common site of bone invasion is flat bone ( Such as skull, ribs, pelvis and shoulder blades). Long bones and lumbar vertebrae, the tibia is less affected. The lesion on the long bone resembles Ew-ing sarcoma, osteosarcoma and osteomyelitis. Wrist, head, knee, foot or cervical vertebrae are rare. Parents often report the early maturity of the child, which is actually due to the gingival recession and the exposure of immature dentin. The treatment of Western medicine in the low-risk group was >2 years old, and the hematopoietic system, liver, lung or spleen was not violated. The risk group is <2 years old, or with the aforementioned organs being violated. Due to the persistence of the disease, patients often cannot follow the strict design of the program, combined with treatment, so there may be multiple organ involvement symptoms (Table 137-2). Patients in the 0-II group, especially those with a single systemic disease, require almost no systemic treatment and no morbidity and no death. Some group II and most group III (ie, with multi-system disease) require systemic therapy, but are generally effective. Group IV young and multi-system patients have morbidity and mortality rates as high as 20%. Although recurrence is common, almost all patients with good outcomes can eventually discontinue treatment. In adult patients, the process of chronic disease can also be presented. Severe patients should be hospitalized and given maximum doses of antibiotics to maintain airway patency, nutritional support (including high-energy nutrition), blood products, skin care, physiotherapy and necessary medical care. Strict hygiene measures can effectively reduce hearing, skin and gum damage. Debridement can even remove severely damaged gingival tissue to limit oral lesions. A selenium-containing shampoo can be used for seborrheic dermatitis (2 times a week). If the shampoo is not effective, a small amount of corticosteroid can be used locally to control small lesions in a short period of time. Most patients with diabetes insipidus or other symptoms of hypopituitarism need to be supplemented with hormone therapy. Topical treatment (surgical and radiotherapy) Read more...

Introduction Phenylketonuria (pku) is an inherited disorder of phenylalanine metabolism due to lack of phenylalanine hydroxylase (pah) or decreased activity. It is more common in hereditary amino acid metabolism-deficient diseases. The genetic pattern of this disease is autosomal recessive inheritance. The clinical manifestations were not uniform. The main clinical features were mental retardation, mental and neurological symptoms, eczema, skin scratch marks, pigmentation and rat odor, and abnormal EEG. If early diagnosis and early treatment are available, the aforementioned clinical manifestations may not occur, intelligence is normal, and EEG abnormalities can be restored. Causes (1) Causes of the disease With the increase of age, the amount of phenylalanine ingested for the synthesis of protein is gradually reduced. After birth, the daily intake of phenylalanine is about 0.5g, and for children and adults it is increased to 4g. The larger part is oxidized to tyrosine, a process that relies mainly on phenylalanine hydroxylase (pah), but also requires cofactor involvement. If this oxidation process is impeded, phenylalanine accumulates in the body. In this case, phenylalanine is metabolized by other means to produce phenylpyruvate harmful substances. Phenylketonuria (pku) is a hereditary disease caused by reduced or absent pah activity. Decreased pah activity also inhibits tyrosine and reduces melanin production, which is inhibited by the accumulation of oxybenzoic acid. The disease is autosomal recessive, and the mutated gene is located on the long arm of chromosome 12 (12q24.1). The small variation of the gene can cause the disease, not due to gene deletion. It is a hereditary disease caused by the marriage of two heterozygotes. The offspring of close relatives are more common, and about 40% of the children are sick. Due to the mutation of the phenylalanine hydroxylase gene, the phenylalanine hydroxylase deficiency in the liver is a basic biochemical abnormality of the disease. If the base pair of the mutation is different, the severity of the clinical manifestation varies greatly, and it can be expressed as a typical pku or mild hyperphenylalaninemia. (II) Pathogenesis Phenylalanine (pa) is an essential amino acid that participates in the formation of various protein components but cannot be synthesized in the human body. Under normal circumstances, about 50% of the ingested pa is used to synthesize proteins of various components, and the rest is changed to tyrosine by the action of phenylalanine hydroxylase, and then converted into tyrosine by other enzymes. Dopa, dopamine, adrenaline, norepinephrine and melanin. Phenylalanine hydroxylase is a complex enzyme system. In addition to the hydroxylase itself, it also includes dihydropterin reductase and coenzyme tetrahydrobiopterin. Any enzyme deficiency can cause an increase in blood phenylalanine. When pa hydroxylase is deficient, phenylalanine that is not involved in the synthesis of the first step protein is accumulated in plasma and deposited in whole body tissues including the brain. The phenylalanine in the blood is discharged beyond the renal threshold, resulting in phenylalanine amino acid urine. After the main pathway of pa (hydroxylation) is blocked, the secondary metabolic pathway of pa is compensatoryly increased, and the proportion of pa converted to phenylpyruvate, phenyllactate, n-hydroxyphenylacetic acid and phenylacetic acid is gradually increased. Normally, this metabolic bypass is carried out very little, so the content of these metabolites is extremely small; when pa hydroxylase is deficient, these metabolites reach abnormally elevated levels, accumulated in tissues, plasma and cerebrospinal fluid, and a large number. Excreted from the urine, resulting in phenylketonuria. 1. According to the difference of biochemical defects can be divided into (1) typical pku: congenital phenylalanine hydroxylase deficiency. (2) persistent hyperphenylalaninemia: found in phenylalanine hydroxylase isomerase deficiency or heterozygous phenylketonuria, blood phenylalanine increased. (3) transient mild hyperphenylalaninemia: more common in premature infants, is caused by delayed maturity of phenylalanine hydroxylase. (4) phenylalanine aminotransferase deficiency: Although the content of blood phenylalanine is increased, phenylpyruvate and hydroxyphenylacetic acid in urine may not be increased, and blood tyrosine is not increased after oral administration of a load of phenylalanine. (5) Dihydropterin reductase deficiency: complete or partial lack of enzyme activity, in addition to affecting brain development, can make basal ganglia calcification. (6) Dihydropterin synthesis defects: lack of methanol ammonia dehydratase or other various enzymes. The typical pku children have normal nervous system at birth. Because of the lack of neuroprotective measures in children with homozygotes, the nervous system is exposed to phenylalanine for a long time. If the mother is homozygous, the blood phenylalanine level is high, the child is heterozygous, the central nervous system damage can occur in the uterus, and the birth manifests as mental retardation. Ordinary pku and some mild and severe variants, the early stages of the disease can be mentally degraded without treatment. It is speculated that it may be an allelic mutant, manifested as hyperphenylalaninemia, no phenylketonuria and nervous system involvement. In addition, even a small number (about 3%) of patients who control hyperphenylalaninemia cannot prevent progression of neurological disease. 2. Molecular biology studies Normal human pah protein has a fold and has an iron binding site. The maintenance of the iron binding site structure is related to the serine at position 349 in the 3d structure associated with the active site, and the stable polymerization of the serine and pah structures at this site and the catalytic properties of pah are also important. Fusetti et al. determined the crystal structure of human pah (residues 118 to 452) and found that this enzyme and tetramer crystals appeared in each monomeric composition of the catalytic and tetramerization regions. The characteristic in the tetramerization zone is the presence of exchange arms that interact with other monomeric species, thus forming an antiparallel spiral coil, and a significant asymmetry, due to the presence of two chelating zones in the spiral that cause the spiral Caused by an alternating configuration. Some of the most common pah mutations occur at the junction of the catalytic and tetrameric regions. Mutations in different pah genes cause different degrees of pah activity to be affected, and the effects on pah structure are also different. Camez et al. revealed pah mutations using different expression systems: leu348val, ser349leu, val388met caused pah protein to have folding defects. Expression of the mutated pah protein in Escherichia coli showed thermal instability compared to wild-type pah protein, and the time course of degradation was also different. Bjorgo et al. studied pah7 missense point mutations, namely r252g/q, l255v/s, a259v/t and r270s. There is also a mutation called g272x. When these mutated pah proteins and maltase were co-expressed in Escherichia coli as fusion proteins, the ability to fold and polymerize human pah proteins into homotetramers/dimers was demonstrated to be defective, and most of the recovery was none. Active aggregation type. R252q and r252g recovered catalytically active tetramers and dimers, and r252g recovered some dimers. The aforementioned three mutations resulted in pah activity of only 20%, 44% and 4.4% of the wild type activity, respectively. When expressed in vitro by a coupled transcription-translation system, all mutant pahs recovered a mixture of non-phosphorylated and phosphorylated forms with low allospecific activity. All of the variant pah proteins expressed by these pah gene mutations are defective in oligomerization, and the sensitivity to restriction protein lysis is increased in vitro, the stability in cells is reduced, and the catalytic activity is also reduced to varying degrees. . All of the foregoing effects appear to be the result of a disordered monomeric structure. Based on the crystal structure of the human pah catalytic domain, the effect of mutation on folding and monomer oligomerization provides an analytical. These are the correlations between the structural and activity variants of pah protein caused by mutations in the liver pah gene. 99% of hyperphenylalaninemia or pku are caused by mutations in the pah gene, and only 1% are due to disorders in cofactor biosynthesis or regeneration. Mutations in the pah gene may involve exons and introns and may be missense mutations or nonsense mutations. Mutation types are a bit mutated, inserted or deleted, early stop coding, splicing and polymorphism. The mutated genotypes are homozygous, heterozygous, and complex heterozygotes. Scriver is equivalent to the 1996 review of the pah gene mutation. In 26 countries around the world, 81 researchers analyzed the chromosomes of the 3986 mutation and identified 243 different mutations. By March 1999, zekanowski et al. pointed out in the paper that there are more than 350 pah gene mutations in the world. The authors studied a regulatory region encoding the pah enzyme: a partial exon 3 mutation can cause classical pku, mild pku, and mild hyperphenylalaninemia, the latter mutations often located at positions 71-94. Amino acid residues. Wang Ning pointed out that by April 1998, the global pah gene mutation had increased to 390 species. In China, Xu Lingting et al. reported in 1996 that there are more than 20 mutations in the pah gene, accounting for about 80% of the pah mutant gene. Most scholars believe that there is a correlation between the genotype of the pah mutation and the phenotype, with the exception of a few patients. Guldberg et al. suggest that the inconsistency between the genotype and phenotype of some patients with pah mutations may be due to methods used to examine mutations or due to differences in phenotypic classification. The pah gene mutations in pku patients in different countries and regions are different, and the distribution of pah gene mutation types in northern and southern populations in China is also inconsistent. The most common mutation in the subgroup of Turkish ancestors was ivs1o-11 g→a (38% of the alleles analyzed); in the Romanian pku patients, the pah gene mutation was mostly arg408trp (47.72% of the allele), lys363fsdelg ( 13.63%) and phe225thr accounted for 6.81%, 3 mutations accounted for 70% of the mutant alleles; arg408trp mutations accounted for 54.9% in Czech pku patients. The differences in the distribution of pah gene mutation types in different regions may reflect multiple mechanisms of pah gene mutation, including founder effect, genetic drift, hypermutability, and selection. . These are the abnormalities of the pah protein caused by the structure, properties and mutations and mutations of the liver pah gene. In addition to expression in liver cells, pah proteins are also expressed in non-liver tissues, including the kidney, pancreas and brain. The primary structure of pah in the kidney is consistent with that in the liver, except that its regulation is different from pah in the liver, but in the body's phenylalanine balance, the pah of the kidney may work. In addition to the absence or reduction of liver pah activity can cause pku, there are also changes in the cofactor of pah can also be caused. The main cofactor involved in pah action is 5,6,7,8-tetrahydrobiopterin, which is hydroxylated by phenylalanine, tyrosine and tryptophan. A necessary cofactor. The gene responsible for encoding this substance is the 6-pyruvoyltetrahydropterin synthase (ptps) gene. If the enzyme gene is mutated, ptp is deficient, and pah activity can cause pku even if it is normal. Another enzyme that causes pku is dihydropterin reductase. Accordingly, the pathogenesis of pku involves at least three enzyme genes, and mutation of one gene can cause absent or reduced pah activity, thereby causing pku. 3. Pathological changes in the brain show non-specific changes, usually marked by white matter changes. There are roughly the following situations. (1) Brain maturity disorders. The fetus begins to have abnormal brain development in the late pregnancy, and the white matter and gray matter stratification of the brain are unclear. There is an ectopic gray matter in the white matter. (2) Myelin formation disorders. The myelin formation of the cortical spinal cord, cortical-ponsal-cerebellar bundle fibers is most obvious. (3) gray matter and white matter cystic degeneration; in addition, the dark matter of the brain, the pigmentation of the blue spot disappeared, and the weight of the brain was reduced. Symptom PKU is a hereditary disease, so newborns have hyperphenylalaninemia. Because they have not eaten, the concentration of blood phenylalanine and its harmful metabolites is not high, so there is no clinical manifestation at birth. If the newborn is not screened for phenylketonuria, the phenylalanine and its metabolites in the blood gradually increase with the prolonged feeding time, and the clinical symptoms gradually manifest. The main clinical manifestations are: 1. Growth retardation, in addition to somatic growth and development retardation, mainly in mental retardation. The performance is lower than the normal baby of the same age, and can appear 4 to 9 months after birth. The intelligence of the heavy-duty is less than 50, and about 14% of the children reach the level of idiots, especially the language development disorder. These manifestations suggest brain developmental disorders. Limiting neonatal intake of phenylalanine prevents intellectual developmental disorders. Mental developmental disorders in children with severe PKU are higher than those in milder blood. It can be considered that mental retardation is related to phenylalanine toxicity, but More detailed pathophysiological mechanisms remain unclear. 2. Neuropsychiatric manifestations There are cerebellar malformations due to brain atrophy, recurrent seizures, but alleviate with age. Increased muscle tone and hyperreflexia. There are often excitement, hyperactivity and abnormal behavior. 3. Skin and hair show that the skin is often dry and prone to eczema and skin scratches. Because of the inhibition of tyrosinase, the melanin synthesis is reduced, so the child's hair is light and brown. 4. Others Due to the lack of phenylalanine hydroxylase, phenylalanine produces increased phenyllactate and phenylacetic acid from another pathway, and is odorous (or murine odor) from sweat and urine. In general, clinical manifestations and types of PAH gene mutations are associated with the severity of clinical phenotypes, and cofactor deficiency is less clinically phenotypical than PAH protein abnormalities. diagnosis Read more...