Gaucher disease

Introduction to Gaucher disease Gauchersdisease (GD) is the most common type of lysosomal storage disease (LSD). It is an autosomal recessive disorder that causes abnormal glucocerebroside to accumulate in reticuloendothelial cells. . French Pitt doctor Phillipe Gaucher first reported in 1882 that 50 years later Aghion reported that Gaucher disease is due to glucocerebroside (GC) accumulation in the mononuclear-macrophages of the liver, spleen, bones and central nervous system. To. Brady et al. discovered in 1964 that the accumulation of glucocerebroside was caused by the deficiency of -glucosidase-gluce brosidase (GBA), which is the diagnosis and treatment of Gaucher disease. Provide a theoretical basis. basic knowledge The proportion of illness: 0.001% Susceptible people: no specific population Mode of infection: non-infectious Complications: spleen rupture, fracture

Cause of Gaucher disease

(1) Causes of the disease

GD is an autosomal recessive hereditary disease due to the accumulation of glucocerebroside in the liver, spleen, bone and mononuclear macrophages of the central nervous system due to the lack of -glucosidase-glucocerebrosidase. The fundamental deficiency of this disease is the lack of glucocerebrosidase, which breaks down glucosinolates into glucose and ceramides, often in childhood, but many also occur in infancy and adulthood. Typical Pathology is characterized by extensive reticular cell proliferation, cells filled with glucocerebroside and fibroblasts, cell deformation, with one or several nuclei deviating from the cell center, which can be found in the liver, spleen, lymph nodes and bone marrow.

(two) pathogenesis

Lysosome is an organelle, the ultrastructure of cells. It is a single-layer coated vesicle with a layer of lipoprotein membrane. It is a cell processing and recovery system. The internal liquid is acidic. Containing more than 60 kinds of acidic hydrolase, it can degrade various biological macromolecules, such as nucleic acids, proteins, lipids, mucopolysaccharides and glycogen. The various biomolecules that make up the cells are in dynamic equilibrium, and are continuously decomposed and continuously Biomacromolecules that are re-synthesized and 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. The defect of each enzyme directly causes a specific biomacromolecule to not be normally degraded and is stored in the lysosome. The common result is lysozyme. The body then swells, the cells become bloated, the cell function is severely affected, and eventually the disease is called lysosomal storage disease (LSD).

Glucocerebrosidase is a soluble glycolipid and is one of the components of cells. It is widely present in the body. Normal humans contain 60-280 g of GC per gram of spleen tissue (wet weight), while GD patients can be as high as 340.5mg, physiologically, glucosinolates derived from senescent dead tissue cells are phagocytosed by mononuclear macrophages, and then hydrolyzed by lysosome to form glucose and ceramide by ceramide. Its reaction formula is as follows:

GC H20, ceramide 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 in the body. GBA gene mutation causes GBA in the absence of GBA production or production in vivo. The GC in mononuclear macrophages cannot be effectively hydrolyzed, and a large amount of GC accumulates in mononuclear macrophages of liver, spleen, bone, bone marrow, lung and brain tissue to form typical Gaucher cells.

The pathogenic gene of Gaucher disease is located on chromosome 1. It has been found that many different GBA point mutations are involved in the pathogenesis. The gene encoding GC is located on autosome 1q21, the gene is 7kb long, contains 8 exons, and 16kb downstream of this gene. There is a highly homologous pseudogene, and GD patients can see missense mutations, splicing mutations, metastasis mutations, gene deletions, gene and pseudogene fusion, etc., with missense mutations being the most common, leading to a decrease in the catalytic function and stability of 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. The homozygous condition is mild, but in the Asian population, there is no such variant. L444P is in type I, II and III patients. There are cases of homozygous disease in the middle, and there are often neurological symptoms. There are more than 100 genetic mutations identified in GD patients. The genotype of Chinese GD has been reported in 10 cases, of which 5 cases are type G46E/L444P, F37V. /L444P, N188S/L444P, Y205S/L444P and R48W/R120W; 2 cases of type II are F213I/L444P; 3 cases of type III are N409H/N409H, G202R/N409H and L444P/L444P, of which L444P genotype is the most common, Allele The occupation of 40%, and appears in various types of GD in, F37V and Y205C for the Chinese people's unique de novo mutation.

Gaucher disease 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. The mother's second pregnancy can be used for prenatal genetic diagnosis, but also for heterozygous examination.

Amniocentesis can be performed through the abdominal wall 17 to 20 weeks of pregnancy. The amniotic fluid cells are epithelial cells that are shed by the fetus. After culture, enzyme activity or genetic analysis can be performed. 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. They can be taken from the abdominal wall by 10 to 12 weeks of gestation. They can be used for enzyme activity determination or genetic analysis. The advantage is that the amniocentesis is 2 months earlier than the amniocentesis. It is not necessary to culture, and the prenatal diagnosis can be obtained earlier. As a result, once the fetus is sick, the pregnant woman can choose artificial abortion in time, the subsequent operation is relatively easy, and the psychological burden of the pregnant woman can be relieved as soon as possible.

Prerequisites for prenatal diagnosis are accurate diagnosis of the proband. It is only possible for the mother to check for an enzyme or a genetic test in the prenatal diagnosis when she is pregnant again, especially the prenatal genetic diagnosis, except for the missing and The PCR/ASO method can directly detect gene defects, and 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 of multiple loci, for example. Muscular dystrophy, more common is DMD/BMD, but there are other genetic mutations that can cause 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 introduced. Misleading, leading to diagnostic errors, and 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 diagnostic errors, severe bloody amniotic fluid must be removed by culture to remove pregnant women's white blood cells, villi After collection, it is necessary 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 first trimester of pregnancy. It has the meaning of "prevention" in eugenics, because it can prevent the birth of the fetus in clinical according to the 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.

Gaucher disease complications Complications spleen rupture

1. The main complication is spleen infarction or spleen rupture and life-threatening, the normal structure of the spleen is destroyed and fibrosis; the liver has different 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.

Gaucher disease symptoms Common symptoms Bleeding tendency convulsions Swallowing difficulties Bone pain Acute abdomen angle Anterior angina

Any age can be ill from birth to age 80, but it is more common in children and children, 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. It is more common in Jews (Ashkenazi-Jewish nation), but it is found in all ethnic groups. Up to 5,000 cases, can start from any age, often go to the spleen for treatment, the progress can be fast or slow, slow progress, especially spleen, sometimes spleen infarction or spleen rupture and acute abdomen symptoms, the liver is progressive Swelling, but not as obvious as spleen enlargement, the disease is long, the skin and mucous membrane are tea yellow, often misdiagnosed as jaundice, exposed parts such as neck, hands and calves are most obvious, brownish yellow, often have wedge-shaped splitting on the conjunctiva of the eyeball The bottom is at the edge of the cornea, the tip points inward, the external hemorrhoids, initially yellowish white, then turns brownish yellow, the lungs can affect the gas exchange and symptoms in time, the late patients may have bone pain in the limbs, even pathological fractures, to the femur The lower end is the most common, and may also involve the femoral neck and spine bone. When there is hypersplenism, there may be bleeding tendency due to thrombocytopenia. The height and weight of children are often affected.

2. Infant type (type II) Children can have large liver and spleen after birth. It is obvious after 3 to 6 months. It has sucking, difficulty in swallowing, poor growth and development, prominent nervous system symptoms, and stiff neck. Head reclining, muscle tension increased, horn arch reversal, tendon reflexes, and finally become soft palate, no response, cranial nerve involvement may have internal oblique, facial paralysis and other symptoms, easy to concurrent infection, due to short course, more than infants The period of death, so the liver, spleen enlargement is not as obvious as the adult type, no skin pigmentation, bone changes are not significant.

3. Juvenile type (type III) often occurs from the age of 2 to adolescence. The splenomegaly is often found during physical examination. It is usually moderately swollen, and the disease progresses slowly. The central nervous system symptoms gradually appear, such as: myoclonic convulsions. The movement is uncoordinated, the spirit is insane, and finally bedridden, the liver is often slightly swollen, but it can also be swollen and severely damaged by liver function.

Gaucher's disease check

Laboratory inspection

1. Blood routine can be normal, and splenomegaly can be seen to reduce the three lines, or only thrombocytopenia.

2. Bone marrow smear can be found in the tail of the Gossip cell, this cell is large, about 20 ~ 80m in diameter, rich in cytoplasm, filled with interlaced into a network or onion skin-like stripe structure, with one or several eccentric nucleus . Glycogen and acid phosphatase staining are strongly positive glycoside inclusion bodies, and are also seen in liver, spleen, and lymph nodes.

3. Enzymatic examination GC is a peripheral membrane protein, which is often aggregated with the activating protein Saposin C in human cells. When measuring enzyme activity, it needs to be dissolved with sodium detergent sodium taurocholate to measure the white blood cells of patients. Or GC activity in skin fibroblasts can be diagnosed for GD. This method is also used for prenatal diagnosis. It is determined whether the fetus is normal by measuring the enzyme activity in the villi and amniocytes.

The parents of the children are heterozygous, and their enzymatic activities are between normal and children. Because the enzymatic activity of heterozygotes overlaps with the normal low limit, it cannot be used for heterozygous examination. A small number of GD patients with normal enzyme activity should be considered as a defect in the activation protein Saposin C, which enhances the ability of GC to hydrolyze 4MU/GLC. Increased levels of various enzyme activities in plasma of GD patients, including acid phosphatase and other lysosomal enzymes, such as hexosaminidase, will support the diagnosis of GD. The determination of -glucocerebrosidase activity is usually carried out by using peripheral blood leukocytes or cultured skin fibroblasts. Since human tissues contain various -glucosidases, if the selected method is improper, the results are not reliable and must be note.

4. The ratio of skin fibroblast GC to galactocerebroside was 0.16 ± 0.08, and the ratio of type I patients was reduced to 0.04 ± 0.02.

5. Genetic diagnosis is superior to enzymological diagnosis. It is qualitative and enzymatic diagnosis is quantitative, and the specimen is stable. The prognosis of the disease can be inferred by the analysis of the mutant type. For example, screening for L444P can confirm GD, and the patient with N370S genotype is both Homozygous, prognosis is good, generally no neurological symptoms, after the genotype of the child is determined, the mother can do prenatal genetic diagnosis again, can also be detected in heterozygotes.

Gene diagnosis can be performed using a two-step PCR method with no definitive link between genotype and clinical phenotype.

6. Other liver function and blood coagulation tests should be performed. The bone marrow, spleen, liver or lymph node puncture fluid of the children should be tested.

Film degree exam

1. X-ray examination of extensive osteoporosis affects the femur, humerus, humerus, etc., showing a sponge-like porous transparent zone change, worm-like bone destruction, broadening of the backbone or widening of the lower end of the femur. Malformation; thinning of the cortical bone, and the development of the bone nucleus is relatively late and other developmental disorders.

2. EEG examination can detect nervous system infiltration early.

3. B-ultrasound can indicate hepatosplenomegaly.

Diagnosis and differentiation of Gaucher disease

diagnosis

According to the liver, splenomegaly or central nervous system symptoms, bone marrow examination shows typical Gaucher cells, serum acid phosphatase increased to make a preliminary diagnosis, further diagnosis should be done for leukocyte or skin fibroblast GC activity, notable Yes, sometimes a pseudo gaucher's cell similar to Gaucher cells is seen in the bone marrow, which can occur in chronic myeloid leukemia, thalassemia, multiple myeloma, Hodgkin's lymphoma, Plasmacytoid lymphoma and chronic myelogenous leukemia, which differ from Gaucher cells in that there is no typical tube-like structure in the cytoplasm, and GC enzyme activity can be determined in differential diagnosis.

EEG can detect the infiltration of the nervous system early. There are a wide range of abnormal waveforms before the symptoms of the nervous system. Patients with type III are difficult to differentiate with type I before the symptoms of the nervous system appear. EEG can predict the future of the patient. Is it possible to have neurological symptoms?

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 bone marrow, spleen puncture or liver biopsy specimens. Cell culture without cerebroside esterase activity can be clearly diagnosed. Gaucher disease can be prenatally diagnosed by amniocentesis or villus sampling. DNA technology A specific Gaucher disease allele can be diagnosed, and the gene encoding the glucuronide is located at position Iq21 of the human chromosome.

Differential 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 yellow spot on the macula has cherry red spots. The specific 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 50%, yellow spotted cherry red spots, foam cells in the bone marrow, all have ugly face, large tongue, heart hypertrophy, X-ray film have multiple Sexual bone dysplasia changes, fucoside storage disease has skin thickening and difficulty breathing.

3. Diseases with hepatosplenomegaly, such as leukemia in blood diseases, Hodgkin's disease, Hand-Schüller-Christian disease, severe globin-producing anemia, identification is generally not difficult, Han - In addition to liver enlargement and splenomegaly, there are still bone defects and/or exophthalmos and/or diabetes insipidus. In addition, it should be differentiated from kala-azar and schistosomiasis.

4. Diseases with Gaucher cells Gaucher cells can be found in chronic myeloid leukemia, severe globin-producing anemia, chronic lymphocytic leukemia, in which -glucocerebrosidase is normal, but due to too many white blood cells For example, in chronic myeloid leukemia, the daily conversion rate of sphingolipids is 5 to 10 times normal; when heavy globin-producing anemia occurs, the sphingolipid conversion rate of red blood cells also increases, surpassing the catabolic ability of tissue macrophage system. And the deposition of glucocerebroside, the formation of Gaucher cells, AIDS and mycobacterial infections and Hodgkin's disease may also have Goss cells, the identification depends on clinical, auxiliary examination and -glucosamine Determination of lipase.

5. Spleen lymphoma/leukemia: microscopically consistent lymphoma cells/leukemia cell infiltration in the spleen, immunophenotypic clonal growth of heterotypic tumor cells, unexplained hepatosplenomegaly and mild anemia or associated Sexual stunting, mental retardation, pathological fractures should be thought of the possibility of the disease, bone marrow puncture smear, pathological section of the specimen to remove Gaucher cells, help the diagnosis of the disease, the diagnosis depends on blood leukocytes and skin fibroblast culture, The isotope-labeled glucoside was used as a substrate to measure -glucagonase activity, glucosidase activity was <20% (carriers were below 60%), and serum acid phosphatase activity was high.

The material in this site is intended to be of general informational use and is not intended to constitute medical advice, probable diagnosis, or recommended treatments.