Introduction
Gaucher disease(Gauchers disease, GD) is the most common type of lysosomal storage disease (LSD), which is an autosomal recessive disorder that causes abnormal glucocerebroside to accumulate in reticuloendothelial cells. . French Pierree Gaucher first reported in 1882 that 50 years later Aghion reported that Gaucher disease is due to accumulation of glucocerebroside (GC) in mononuclear-macrophages of the liver, spleen, bone and central nervous system. Caused. Brady et al. discovered in 1964 that the accumulation of glucocerebroside was caused by the deficiency of β-glucosidase-gluce brosidase (GBA), which is the diagnosis and treatment of Gaucher disease. Provide a theoretical basis.
Cause
(1) Causes of the disease
GD is an autosomal recessive hereditary disease. It is due to the deficiency of β-glucosidase-glucocerebrosidase-induced accumulation of glucocerebroside in mononuclear macrophages of the liver, spleen, bone and central nervous system. The fundamental drawback of this disease is the lack of glucocerebrosidase activity, which breaks down glucosinolates into glucose and ceramides. Often in childhood, but many also occur in infancy and adulthood. Typical pathological features are extensive reticulocyte proliferation, cells filled with glucocerebroside and fibroblasts, cell deformation, one or several The nucleus deviates from the center of the cell, which can be found in the liver, spleen, lymph nodes and bone marrow.
(two) pathogenesis
A lysosome is an organelle, an ultrastructure inside a cell, a single-coated vesicle with a layer of lipoprotein membrane on the outside. It is a cell processing and recycling system. The internal liquid is acidic and contains more than 60 kinds of acidic hydrolase, which can degrade various biological macromolecules such as nucleic acids, proteins, lipids, mucopolysaccharides and glycogen. The various biomacromolecules that make up the cells are in dynamic equilibrium, constantly decomposed and continuously re-synthesized. Biomacromolecules that are ingested by endocytosis also need to be broken down into different components before they can be utilized. The decomposition of these macromolecules is carried out in lysosomes.
Each of the enzymes in the lysosome has its own coding gene. Defects in each enzyme directly cause a particular biomacromolecule to fail to degrade normally and accumulate in the lysosome. The common result is that the lysosomes are swollen, the cells become bloated, the cell function is seriously affected, and eventually the disease is called lysosomal storage disease (LSD).
Glucocerebrosidase is a soluble glycolipid and is one of the components of cells and is widely present in the body. Normal people per gram of spleen tissue (wet weight) contain GC 60 ~ 280μg, and GD patients can be as high as 3 ~ 40.5mg. Under physiological conditions, glucosinolates derived from tissue cells of aging and death are phagocytosed by mononuclear macrophages, and then hydrolyzed by plasmin in the lysosome to form glucose and ceramide. The reaction formula is as follows: :
GC H20ceramide glucose
The GC accumulated in brain tissue is mainly derived from ganglioside, and can also be derived from various tissues such as liver, kidney and muscle. Due to GBA gene mutation, GBA in the absence of GBA production or production in vivo is inactive, resulting in GC can not be effectively hydrolyzed in mononuclear macrophages, a large number of GC in the liver, spleen, bone, bone marrow, lung and brain tissue mononuclear macrophages The cells accumulate and form typical Gaucher cells.
The disease gene for Gaucher disease is located on chromosome 1. It has now been found that many different GBA point mutations are associated with pathogenesis. The gene encoding GC is located on autosome 1q21, and the gene is 7 kb in length and contains 8 exons. There is a highly homologous pseudogene at 16 kb downstream of this gene. GD patients can be found in missense mutations, splicing mutations, metastatic mutations, gene deletions, gene and pseudogene fusion. The most common mutations are missed, resulting in a decrease in the catalytic function and stability of the GC. Different human genotypes vary in variation. For example, N370S is the most common in the Ashkenzi Jewish population. It is only found in type I patients, and homozygous is mild. There is no such variant in the Asian population. L444P can be found to be homozygous in patients with type I, II and III, often with neurological symptoms. There are more than 100 genetic mutations identified in GD patients. Ten genotypes of Chinese GD have been reported, of which 5 are type I G46E/L444P, F37V/L444P, N188S/L444P, Y205S/L444P and R48W/R120W; 2 cases of type II were F213I/L444P; 3 cases of type III were N409H/N409H, G202R/N409H and L444P/L444P, of which L444P genotype was the most common, occupying 40% of alleles and appearing in each type of GD in. F37V and Y205C are unique new mutations in Chinese.
symptom
Any age can be ill from birth to age 80, but it is more common in children and children, and more than 7 years old. Can be divided into three types:
1. Adult type (type I) is the most common type of disease and is also common in lipid storage diseases. More common in the Jews (Ashkenazi-Jewish nation), but among all ethnic groups. In the United States, it is estimated that there are fewer than 5,000 children per year. You can get sick at any age, often go to the spleen for medical treatment. Progress can be fast or slow, slow progress, especially spleen, sometimes spleen infarction or spleen rupture and acute abdomen symptoms. The liver is progressively enlarged, but not as swollen as the spleen. For a long time, the skin and mucous membranes are tea yellow, often misdiagnosed as jaundice, and the exposed parts such as the neck, hands and calves are the most obvious, brownish yellow. There are often cleft palate cracks on the conjunctiva of the eyeball. The bottom is at the edge of the cornea. The tip points to the inner and outer ridges. It is yellowish white at first and then turns brownish yellow. Pulmonary fatigue can affect the gas exchange and cause symptoms. Patients with advanced limbs may have bone pain and even pathological fractures. The lower end of the femur is the most common, and may also involve the femoral neck and spinal bone. When there is hypersplenism, there may be bleeding tendency due to thrombocytopenia. Pediatric patients are often affected by height and weight.
2. Infant type (type II) The child can have large liver and spleen after birth. It is obvious after 3 to 6 months. It has difficulty in sucking, swallowing, and poor growth and development. The symptoms of the nervous system are prominent, the neck is straight, the head is reclined, the muscle tension is increased, the horn arch is reversed, the tendon reflex is hyperthyroidism, and finally it becomes soft palate, and there is no reaction. When the cranial nerve is involved, there may be symptoms such as internal oblique and facial paralysis. Easy to concomitant infection. Due to the short course of the disease, more deaths than infancy, the liver and spleen enlargement is not as obvious as the adult type, no skin pigmentation, and bone changes are not significant.
3. Juvenile type (type III) often occurs from the age of 2 to adolescence, splenomegaly often found in physical examination, usually moderately enlarged. The disease progresses slowly, and the central nervous system symptoms gradually appear, such as: myoclonic convulsions, uncoordinated movements, insanity, and finally bedridden. The liver is often slightly enlarged, but it can also be progressively enlarged and severely impaired liver function.
According to the liver, splenomegaly or central nervous system symptoms, bone marrow examination, typical Goce cells, serum acid phosphatase increased can make a preliminary diagnosis. Further diagnosis should be done to determine the GC activity of leukocytes or skin fibroblasts. It is worth noting that sometimes a pseudo gaucher's cell, which is similar to Gaucher cells, is seen in the bone marrow. It can occur in chronic myeloid leukemia, thalassemia, multiple myeloma, Hodgkin. Lymphoma, plasmacytoid lymphoma and chronic myelogenous leukemia. It differs from the Gaucher cells in that there is no typical tube-like structure in the cytoplasm. GC enzyme activity can be determined in differential diagnosis.
Electroencephalography can detect early infiltration of the nervous system, and there are a wide range of abnormal waveforms before the onset of neurological symptoms. Type III patients are difficult to differentiate from type I before neurological symptoms appear. EEG examination can predict whether patients may have neurological symptoms in the future.
Prenatal diagnosis: The mother of the patient may take the prenatal diagnosis of the villus or amniotic fluid cells after the pregnancy, and if the genotype of the patient has been determined, the prenatal genetic diagnosis may also be performed.
Typical cells can be found in specimens of bone marrow, spleen puncture or liver biopsy. Cell culture without cerebroside esterase activity can be clearly diagnosed. Gaucher disease can be prenatally diagnosed by amniocentesis or villus sampling. DNA technology can diagnose specific Gaucher disease alleles, genes encoding glucuronide Located at the Iq21 position of the human chromosome.
diagnosis
The disease should be identified with the following diseases.
1. Niemann-Pick disease (sphingomyelin storage disease) is found in infants, and the liver and spleen are also swollen, but the liver is larger than the spleen; the central nervous system symptoms are not as significant as Gaucher disease. The main identification point is the cherry red spot on the macula. The special cells seen in the bone marrow are significantly different from Gaucher disease, and the acid phosphatase reaction is negative, which can be identified by combining other histochemical staining.
2. Some metabolic diseases such as GM1 ganglioside storage disease in lipid storage disease, fucosidosis storage disease and mucopolysaccharidosis type IH (Hurler syndrome), have hepatomegaly and spleen Large and nervous system performance, but GM1 ganglioside storage disease is 50%, there are red spots on the macula, and there are foam cells in the bone marrow. All three have ugly face, large tongue, and hypertrophy. X-ray films are often multiple. Sexual bone dysplasia changes, fucoside storage disease has skin thickening and difficulty breathing.
3. Diseases with hepatosplenomegaly such as leukemia, Hodgkin's disease, Hand-Schüller-Christian disease, and severe globin-producing anemia in blood diseases are generally not difficult to identify. Han-Xu-Ke disease has bone defects and/or exophthalmos and/or diabetes insipidus in addition to liver and splenomegaly. In addition, it should be differentiated from kala-azar and schistosomiasis.
4. Diseases with Gaucher cells. Gaucher cells can be found inChronic myeloid leukemia, heavy globin-producing anemia,Chronic lymphocyte leukemiaIn these patients, β-glucocerebrosidase is normal, but due to too many white blood cells, such as the daily conversion rate of sphingolipids in chronic myeloid leukemia is 5 to 10 times normal; when heavy globin is abnormally anemia The sphingolipid conversion rate of red blood cells also increases, surpassing the catabolic ability of the tissue macrophage system, and the deposition of glucocerebroside occurs to form Gaucher cells. Gossip cells can also be present in AIDS and mycobacterial infections and Hodgkin's disease. Identification depends on clinical, auxiliary examination and determination of β-glucocerebrosidase.
5. Spleen lymphoma/leukemia: Microscopically consistent lymphoma cells/leukemia cell infiltration in the spleen, immunophenotype showed clonal growth of heterotypic cells. For unexplained hepatosplenomegaly and mild anemia or with progressive developmental retardation, mental retardation, pathological fractures should be thought of the possibility of the disease, bone marrow puncture smear, resection of the pathological section of the specimen to find Gaucher cells, help The diagnosis of the disease depends on the culture of white blood cells and skin fibroblasts. The isotope-labeled glucosides are used as substrates, and the β-glucosidase activity is measured. The glucosidase activity is <20% (the carrier is 60% or less). ), while serum acid phosphatase activity is high.
complication
1. The main complication is life-threatening spleen infarction or spleen rupture The normal structure of the spleen is destroyed and fibrosis; the liver has varying degrees of fibrosis.
2. Combined with pathological fractures, common in the lower femur fracture, can also be seen in the femoral neck and spinal fractures.
3. Neuronal degeneration in the cranial nerve nucleus, basal ganglia, thalamus, cerebellum and pyramidal tract in the brain.
treatment
(a) treatment
1. General therapy pay attention to nutrition and prevent secondary infection.
2. Symptomatic treatment of anemia or bleeding can be component blood transfusion, spleen or hypersplenism symptoms can be considered to cut the spleen, but after total splenectomy can reduce abdominal burden, reduce anemia and bleeding tendency, improve development, even It can heal and heal itself, but it can accelerate the liver and bone destruction. Therefore, surgery should be delayed as much as possible. If necessary, partial splenectomy should be considered. Osteocorticotropic hormone can be used for bone pain.
3. Enzyme therapy In recent years, β-glucocerebrosidase has been used in the treatment of this disease in recent years, and a certain effect has been achieved. After 1 year of adult treatment, the general condition improved, the liver and spleen decreased significantly, the growth and development accelerated, the hemoglobin increased, the platelets also increased slowly, and the lung function was also improved. Bone lesions are old, but it is found that there is hypocalcemia in the early stage of treatment without increased urinary calcium. It is speculated that bone disease may take a long time to improve. After the baby type is applied, the liver and spleen can be reduced, but the brain symptoms can not be improved. At present, the application dose and method are not uniform. The preliminary application results are considered to be 2.3U/kg, 3 times a week, intravenous drip, and the curative effect is 60U/kg, which is similar to the effect every 2 weeks. This suggests that the high-dose method once every two weeks is very uneconomical, and the former method can reduce the extremely expensive drug costs. Infant type doses are generally considered to be large, 70 to 120 U/kg per month, 2 or 3 times per week. There are two sources of this enzyme: one is from the placental name alglucerase (alglucerase) or β-glucocerepinase (ceredase), and the other is a recombinant product, named imiglucerase or cerezyme, each of which is double-blind Comparison, the effect is similar.
Intravenous input of glucosamine esterase extracted from the placenta can improve the clinical symptoms of type I patients. The more common method is to enter each intravenously for more than 1~2 hours, once every 2 weeks (dose varies from person to person, initial The dose is 60u/kg each. The treatment plan (dose, input frequency and input rate) needs further study, and the dose is slightly less than the 60u/kg recommended by the FDA every 2 weeks.
4. Bone marrow transplantation allogeneic bone marrow transplantation can increase enzyme activity, liver and spleen shrink, and Gaucher cells decrease, but the risk and efficacy of surgery must be carefully considered.
5. Gene therapy It has been tried to insert a normal gene of β-glucocerebrosidase into its own stem cells and perform self-transplantation.
(two) prognosis
Type I GD progresses slowly, and can survive for a long time after splenectomy. The intelligence is normal, but growth and development are backward. GBA replacement therapy has a significant effect and the best prognosis. After type I GD splenectomy, GC accumulation in the liver and bone marrow is accelerated, so it can die early in the lung and liver dysfunction, infection bleeding.
Type II GD died of secondary infection within 1 year after onset, and a few survived for more than 2 years.
Type III GD is more likely to suffer from complications due to heavier symptoms of the nervous system. Due to the application of GBA, the prognosis has been greatly improved.
prevention
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. After the disease is identified in the child's genotype, the mother's re-pregnancy can be used for prenatal genetic diagnosis or heterozygous examination.
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.
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. In particular, prenatal genetic diagnosis, in addition to deletion and direct detection of genetic defects by PCR / ASO method, other linkage analysis methods are based on clinical diagnosis. The reason is that some genetic diseases have genetic heterogeneity, and the same disease phenotype can be caused by mutations in multiple loci, such as muscular dystrophy, more commonly DMD/BMD, but other genetic mutations can lead to muscular dystrophy. . If the clinical diagnosis is inaccurate, the genetic diagnosis of B disease with the polymorphic site of A disease is bound to be led astray, leading to a diagnosis error. Secondly, to avoid sample contamination, the contamination of maternal DNA in fetal materials can not be ignored. Bloody amniotic fluid is often one of the root causes of diagnosis errors. Severe bloody amniotic fluid must be removed from the white blood cells of pregnant women. After collecting the villi, be sure to check and select under the inverted microscope to remove the endometrial tissue.
It is clear in the prenatal period whether the fetus is sick or not, 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.
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