Pediatric Gaucher disease

Introduction to Pediatric Goshe disease Gauchersdisease (GD) is the most common type of lysosomal storage disease (LSD). It is autosomal recessive. Its clinical features are hepatosplenomegaly, bone pain, type II and III. The child has a manifestation of central nervous system involvement, and the Gaucher cell is a feature of this disease. basic knowledge The proportion of sickness: 0.00005% Susceptible people: children Mode of infection: non-infectious Complications: spleen rupture, fracture

The cause of pediatric 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 deficiency of -glucosidase-glucocerebrosidase.

(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.

Pediatric 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.

Pediatric Gosh disease complications Complications spleen rupture

1. The main complication is life-threatening spleen infarction or spleen rupture

2. Combined with pathological fractures, common in the lower femur fracture, can also be seen in the femoral neck and spinal fractures.

Symptoms of Pediatric Goshe disease Common symptoms Osteoporosis Osteoporosis, convulsions, Lung involvement, Cervical arch, Anterior cervical ankylosis, Closed liver function, Abnormal muscle atrophy

The symptoms may vary greatly depending on the degree of enzyme deficiency, but the same type of disease in the same family has the same type. According to the severity of GD and the degree of visceral involvement and the presence or absence of neurological symptoms, GD is divided into three types: Chronic (non-neurotype, adult, type I), acute (type II, neurological) and subacute (type III, neurological), and subdivided into IIIa according to the clinical manifestations of subacute patients, IIIb and IIIc.

Clinical manifestation

Due to the different degree of -glycereesterase deficiency, the clinical manifestations are quite different, the growth and development are backward, and even backward, the liver and spleen are progressively enlarged, especially the splenomegaly is more obvious, the liver function is abnormal, and the spleen is hyperactive. There are swollen lymph nodes, bone and joint involvement, pathological fractures, X-ray showing osteoporosis, localized bone destruction, distal femoral enlargement, like a flask, typical X-ray signs, some with femoral neck fracture or spinal compression Sexual fracture, late healing of the bone nucleus, portal hypertension, pulmonary hypertension, lung involvement with cough, difficulty breathing and cyanosis, X-ray chest radiograph with lung infiltration, eye movement disorders, strabismus, horizontal gaze difficulty, ball Conjunctival symmetry brown-yellow wedge-shaped plaque, the base is at the edge of the cornea, the tip is pointed at the eyelid, first seen on the nasal side and then on the temporal side, the skin can be seen with ichthyosis, the exposed part of the skin can be seen brown-yellow plaque, the central nervous system can be violated can be consciously , language barrier, neck stiffness, angular arch reflex, limbs rigidity, scissors legs, difficulty walking, muscle atrophy, closed jaws, difficulty swallowing, throat, Later episodes, EEG abnormalities.

2. Clinical classification

According to the degree of involvement of each organ, the onset of the disease, and the presence or absence of nervous system involvement, are classified into 3 types.

(1) Type I: Chronic type, also known as non-neurological type, is the most common, especially the incidence of Jewish species is high, children and adults can be ill, preschool children have more cases, slow onset, long course, no nervous system The affected symptoms, the earlier the onset, the lower the enzyme activity. Usually, the activity of GBA in type I patients is equivalent to 12% to 45% of normal people, and can be divided into three phases according to the progress of the disease:

Initial stage: general condition is good, only splenomegaly and mild positive pigmented anemia, growth and development is close to normal.

Mid-term: The liver gradually enlarges, but the spleen enlarges more obviously. The superficial lymph nodes are not swollen. As the anemia increases, the complexion gradually becomes pale. Due to hypersplenism, white blood cells and platelets are also reduced, and reticulocytes are slightly increased. In the exposed parts and skin, it has a special brownish yellow color. Some patients have early joint symptoms, and there may be bone and joint pain.

Late stage: various symptoms gradually worsen, anemia is significant, white blood cells and platelets are significantly reduced, often with infection and skin mucosal bleeding tendency, lymph nodes can be slightly enlarged, if the liver is extensively infiltrated, liver function damage, esophageal varices and coagulation can occur The reduction of factors, especially the deficiency of factor IX, is more common. When bone marrow infiltration can cause bone pain, joint swelling and pain, sometimes it must be differentiated from rheumatoid arthritis. Symmetrical brown-yellow wedge-shaped plaque can appear in the conjunctiva of both eyes, and the base is at the edge of the cornea. The tip points to the eyelids, first seen on the nasal side, and later on the temporal side.

(2) Type II: acute type, also known as neurological type, usually occurs within 1 year of age, and symptoms appear at the earliest 1 to 4 weeks after birth. The condition varies with the onset of disease, except for type I symptoms and signs, the nervous system. The symptoms are obvious, and most of them die before the age of 2, and this type of GBA has the lowest activity and is almost difficult to measure.

(3) Type III: Subacute type is also called nerve type. The onset is slower than type II. It can occur in infants and young children. In addition to visceral involvement, there may be one mild and moderate nervous system performance, most of which are around 10 years old. Appeared, this type of mental retardation is relatively light, IQ is around 70, according to the degree of involvement of the patient's nervous system, and then divided into:

Type 1IIIa: There are 2 or more manifestations of nervous system involvement and mild visceral involvement.

Type 2IIIb: only eye movement disorders, with progressive visceral involvement.

Type 3IIIc: ocular dysmotility with progressive heart valve calcification and visceral involvement.

The GBA activity of this type of patient is equivalent to 13% to 20% of normal people. For patients with younger age, neurological symptoms may occur later, so it should be observed and reshaped.

Pediatric Gaucher disease check

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 (Fig. 1); 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.

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.

Auxiliary inspection

EEG

Patients may have abnormal EEG waveforms before the onset of neurological symptoms, such as slow waves, spikes, etc.

2. Skeletal X-ray examination

Visible medullary cavity widening, generalized osteoporosis, and visible localized bone destruction, typically seen as distal femoral enlargement, like a flask, often with femoral neck fracture and spinal compression fracture, 3. X-ray Invasive lesions in the lungs can be seen.

4. Other

Bone age determination should be done; abdominal B-ultrasound measurement of liver and spleen size; pulmonary function test.

Diagnosis and diagnosis of pediatric 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.

Differential diagnosis

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.

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