Pediatric Gaucher's disease

　　Pediatric Gaucher's disease (GD) is an autosomal recessive genetic disease caused by the deficiency of β-glucosidase-galactocerebrosidase, leading to the accumulation of glucocerebroside in mononuclear macrophages in the liver, spleen, bones, and central nervous system. The causative gene of Gaucher's disease is located on chromosome 1. It has been found that many different GBA point mutations are related to the disease. The gene encoding GC is located on chromosome 1q21, with a length of 7kb and containing 8 exons. There is a highly homologous pseudogene 16kb downstream of this gene. GD patients can be seen with missense mutations, splicing mutations, frame-shift mutations, gene deletions, and gene-pseudogene fusions, with missense mutations being the most common, leading to a decrease in the catalytic function and stability of GC. Variations in genotypes among different ethnic groups are different, such as the N370S mutation is most common in the Ashkenazi Jewish population, seen only in type I patients and is mild in heterozygotes, while this variant is not found in the Asian population. The L444P mutation is seen in pure heterozygotes in types I, II, and III patients, often with neurological symptoms.

　　The main complications of this disease are splenic infarction or splenic rupture, which can be life-threatening. The normal structure of the spleen is destroyed and fibrotic, and the liver has varying degrees of fibrosis. Patients with this disease may have pathological fractures, commonly seen in fractures of the lower end of the femur, as well as fractures of the femoral neck and spine.

　　Children with Gaucher's disease (GD) may have significant differences in symptoms due to the different degrees of enzyme deficiency, but those affected in the same family have the same type. GD is divided into three types according to the urgency of onset, the extent of visceral involvement, and the presence or absence of nervous system symptoms, namely, the chronic type (non-neurological, adult type, type I), the acute type (type II, neurological type), and the subacute type (type III, neurological type). At the same time, according to the clinical manifestations of subacute type patients, it is further divided into IIIa, IIIb, and IIIc.

　　One, clinical manifestations

　　Due to the different degrees of deficiency of β-galactosidase, there are significant differences in clinical manifestations. Growth and development may lag or even regress, splenomegaly and hepatomegaly are progressive, especially splenomegaly is more obvious, liver function abnormalities, splenic hyperactivity, and patients may also have lymphadenopathy, involvement of bones and joints, and pathological fractures. X-rays show osteoporosis, localized bone destruction, and the distal femur is dilated like a flask. Some may have fractures of the femoral neck or compression fractures of the spine, with delayed ossification nucleus healing and portal hypertension and pulmonary hypertension. Lung involvement may present with cough, dyspnea, and cyanosis. The eyes may show ocular movement disorders, strabismus, difficulty in horizontal gaze, symmetrical brownish yellow wedge-shaped plaques on the conjunctiva. The skin may show ichthyosis, and brownish yellow spots may be seen on exposed skin. Central nervous system involvement may cause disturbance of consciousness, language disorders, neck stiffness, opisthotonos, spasticity of the limbs, scissors legs, difficulty in walking, general muscle atrophy, trismus, difficulty in swallowing, laryngospasm, and convulsive seizures.

　　Two, clinical classification

　　According to the extent of organ involvement, the urgency of onset, and whether there is nervous system involvement, it is divided into 3 types.

　　1. Type I:The chronic type, also known as the non-neurological type, is the most common, especially with a high incidence in Jewish populations. Children and adults can be affected, with a higher incidence in pre-school children. The onset is slow and the course is long, without symptoms of nervous system involvement. 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. According to the progression of the disease, it can be divided into 3 stages.

　　Early stageThe general condition is good, with only splenic enlargement and mild normochromic anemia, and growth and development are close to normal.

　　Middle stageThe liver gradually increases in size, but the spleen is more prominent, superficial lymph nodes are usually not enlarged. With the worsening of anemia, the complexion gradually becomes pale. Due to splenic hyperactivity, white blood cells and platelets are also often reduced, reticulocytes are slightly increased, and they appear in a special brownish yellow color on exposed parts and the skin. Some patients may have joint symptoms earlier, with hidden pain in bones and joints.

　　Late stageVarious symptoms gradually worsen, anemia is significant, white blood cells and platelets are significantly reduced, often accompanied by infections and a tendency towards skin and mucosal bleeding. Lymph nodes may slightly enlarge, and if there is extensive liver infiltration, liver function damage, esophageal varices, and a decrease in coagulation factors may occur, especially a common deficiency of factor IX. Bone marrow infiltration can cause bone pain and joint swelling, and sometimes it needs to be differentiated from rheumatoid arthritis. The conjunctiva of both eyes presents with symmetrical brownish yellow wedge-shaped plaques, with the base at the edge of the cornea and the tip pointing towards the canthus. They first appear on the nasal side and then on the temporal side.

　　2, Type II:The acute type, also known as the nervous type, usually occurs within one year of age, with symptoms appearing as early as 1-4 weeks after birth. The severity of the disease varies with the time of onset, with obvious neurological symptoms in type I, and most of them die before the age of 2. This type has the lowest activity of GBA, almost undetectable.

　　3, Type III:The subacute type, also known as the nervous type, is slower in onset than type II, and can occur in infancy, with 1 item of mild to moderate neurological manifestations in addition to visceral involvement. Most of them appear around the age of 10. This type of intellectual disability is relatively mild, with an IQ of about 70. According to the degree of neurological involvement, it is further divided into:

　　Type IIIa:With two or more neurological involvement manifestations, mild visceral involvement.

　　Type IIIb:Only eye movement disorders, accompanied by progressive visceral involvement.

　　Type IIIc: Eye movement disorders accompanied by progressive valvular calcification of the heart and visceral involvement.

　　The activity of GBA in this type of patients is equivalent to 13% to 20% of normal people, and for patients with younger ages, it may be possible to have neurological symptoms later, so re-typing should be observed.

　　In terms of the prevention of this disease, prenatal diagnosis of hereditary metabolic diseases is one of the effective measures to prevent the occurrence of genetic diseases, and is the practical application of human genetics knowledge, an important measure for eugenics. After determining the genotype of the patient with this disease, prenatal genetic diagnosis can be performed during the mother's next pregnancy, or a heterozygote examination can be conducted.

　　Amniocentesis can be performed through the abdominal wall during the second trimester, 17-20 weeks of pregnancy. Amniotic fluid cells are the epithelial cells shed by the fetus, which can be used for enzyme activity determination or gene analysis after culture. This method has a fetal loss rate of 0.5%, and it is still an important means of prenatal diagnosis to this day.

　　The villi come from the embryonic trophoblast, and can be aspirated through the abdominal wall at 10-12 weeks of pregnancy. They can be used for enzyme activity determination or gene analysis. The advantage is that it is 2 months earlier than amniocentesis, does not require culture, and can obtain the results of prenatal diagnosis earlier. Once the fetus is sick, the pregnant woman can choose induced abortion in time, and the subsequent operations can be carried out more easily, and the psychological burden of the pregnant woman can be relieved earlier.

　　The prerequisite for prenatal diagnosis is to make an accurate diagnosis of the proband, so that it may be possible to purposefully check for a specific enzyme or gene detection during prenatal diagnosis when the mother becomes pregnant again. Especially for prenatal genetic diagnosis, in addition to detecting gene defects directly through methods such as deletion and PCR/ASO, other linkage analysis methods are based on clinical diagnosis as a premise. The reason is that certain genetic diseases have genetic heterogeneity, and the same disease phenotype can be caused by mutations in multiple gene loci, for example, muscular dystrophy, which is more common is DMD/BMD, but other gene mutations can also lead to muscular dystrophy. If the clinical diagnosis is not accurate, using the polymorphic sites of Disease A for the gene diagnosis of Disease B will inevitably lead to misdirection and diagnostic errors. Secondly, it is necessary to avoid sample contamination, and the contamination of maternal DNA in fetal material should not be ignored. Bloody amniotic fluid is often one of the causes of diagnostic errors, and severe bloody amniotic fluid must be removed by culturing to eliminate the leukocytes of the pregnant woman. After collecting the villi, it is necessary to examine and select under an inverted microscope, and remove endometrial tissue.

　　It is important to clearly determine whether the fetus is affected before birth. Some can even make a prenatal diagnosis in the early stage of pregnancy, which has the significance of 'prevention' in eugenics. Because based on the clear results of prenatal diagnosis, it is possible to prevent the birth of the fetus in clinical practice, which is not only the only feasible eugenic measure but also can alleviate the burden on the family and society, and improve the quality of the population.

　　Pediatric Gaucher disease is caused by the accumulation of glucocerebroside in mononuclear-macrophage cells in the liver, spleen, bones, and central nervous system. The specific clinical examination of this disease is as follows.

　　One, laboratory examination

　　1, Routine blood testThey can be normal, or in patients with splenic hyperfunction, there are decreases in all three lines, or only a decrease in platelets.

　　2, Bone marrow smear:Gaucher cells can be found at the end of the film, these cells are large, with a diameter of about 20-80 μm, rich in cytoplasm, filled with reticulate or onion skin-like striated structures, with one or more eccentric nuclei. Glycogen and acid phosphatase staining shows strong positive lysosomal inclusions. In addition, they can also be found in the liver, spleen, and lymph nodes.

　　3, Enzymatic examinationGC is a peripheral membrane protein that often aggregates with the activating protein Saposin C in human cells. When measuring enzyme activity, it is necessary to add detergent sodium taurocholate to dissolve it. Measuring the activity of GC in the patient's leukocytes or skin fibroblasts can be used to diagnose GD. This method is also used for prenatal diagnosis, by measuring the enzyme activity in the villi and amniotic fluid cells to determine whether the fetus is normal.

　　Two, auxiliary examination

　　1, ElectroencephalogramBefore the appearance of neurological symptoms, the patient may have abnormal electroencephalogram waveforms, such as slow waves and spike waves.

　　2, Iliac X-ray examinationIt can be seen that the medullary cavity is widened, there is generalized osteoporosis, and there are also localized bone destructions. The typical finding is the distal end of the femur is swollen like a bottle, often accompanied by femoral neck fracture and vertebral compression fracture.

　　3, X-ray chest filmIt can be seen that there are infiltrative lesions in the lungs.

　　4, Other:Bone age determination, abdominal ultrasound measurement of liver and spleen size, lung function examination, and other tests should be done.

　　Children with Gaucher disease should pay attention to a reasonable diet to ensure a comprehensive and balanced nutrition. It is advisable to eat foods rich in protein, iron, vitamin C, and B. It is taboo to eat spicy,刺激性, cold, and salty foods.

　　In the treatment of pediatric Gaucher disease (GD), in the past,对症治疗 was only provided for this disease, including support, nutrition, blood transfusion or red blood cell transfusion, and analgesics and antispasmodics were also needed for type II patients. With the development of science and technology, the current treatment methods have improved, mainly including the following methods.

　　1. Splenectomy

　　It is suitable for patients with massive spleen, splenic hyperfunction, and age above 4 to 5 years old, in order to prevent splenic rupture, improve hemorrhage and infection. Splenectomy is recommended for type I and some type III GD patients.

　　2. Enzyme Replacement Therapy

　　1. Ceredase: Ceredase substitution therapy for GD began in foreign countries in 1989, was officially promoted for clinical use in 1991, and to date, there are about 20,000 to 30,000 people with GD worldwide, of whom 20,000 have received substitution therapy in turn, which has a significant effect on extending the life span and improving the quality of life of patients. After nearly 10 years of experience, the vast majority of patients have improved symptoms, and the organs have stopped being affected.

　　2. Alglucerase Injection:The β-glucocerebrosidase extracted from human placental tissue for the first time has been processed and extracted to make the enzyme (glycoprotein) oligosaccharide chain rich in mannose at the non-reducing end. In this way, the enzyme can be recognized by carbohydrate receptors on specific macrophages and can enter the lysosomes of the mononuclear macrophage system to decompose glucocerebroside, achieving the therapeutic purpose. Time has proven that this enzyme is safe and effective.

　　3. Imiglucerase: The clinical application effect is the same as that of ceredase. Imiglucerase is mainly used for GD type I, and the efficacy on the nervous system manifestations of type III patients is not yet clear. Some studies have found that only at high doses can trace amounts of GBA be detected in cerebrospinal fluid. However, there is evidence that certain patients experience a decrease in Gaucher cells in cerebrospinal fluid after treatment, with symptoms of difficulty in horizontal gaze relief, but no improvement in rigidity, so it is suitable for stage III GD, especially type IIIc non-enzyme replacement therapy.

　　3. Gene Therapy

　　In recent years, the basic and clinical research on gene therapy for Gaucher disease has been carried out in foreign countries, and promising results have been achieved. The application of hematopoietic stem cell and myoblast transplantation to introduce the GBA gene into the body, and obtain a large number of cells containing GBA genes through their proliferative characteristics in the body, produces biologically active GBA, and has a sustained therapeutic effect.