I. Overview Gaucher′s disease, also known as glucoserbroside lipidcsis, is caused by a decrease or lack of β-glucocerehrosidase, which prevents the breakdown of glucoserbroside into galactosides or glucose and N-acylsphingosine, resulting in the proliferation of tissue cells. As a result, glucosylcerbroside cannot be broken down into galactosylcerbroside or glucose and N-acylsphingosine, which results in the massive deposition of glucosylcerbroside in the organs of the monocyte-macrophage system, causing the proliferation of tissue cells. There are different clinical types of the disease due to different enzyme activities in different tissues. The disease is autosomal recessive, and is more common among Jews, with about 1 in 50 people carrying the abnormal heterozygote gene, so the incidence rate is high, up to 8.3 per 100,000 people. In 1982, Yang’s syndrome reported 46 cases, and Beijing Children’s Hospital treated 40 cases in 30 years. Diagnosis can be made on the basis of hepatomegaly, splenomegaly or central nervous system symptoms, bone marrow aspiration smear with Rachel’s staining to find Gaucher cells, and increased serum acid phosphatase. The body of Gaucher cells is very large, with a diameter of about 20-80 μm, mostly ovoid, containing one or several eccentric nuclei, the nucleus is round, oval or unshaped, and the chromatin is very rough. The cytoplasm was abundant, without vacuoles, and light blue in color, showing coarse and dark interweaving into a reticulated striped structure, like wrinkled paper. Electron microscopy showed specific tubular cerebroside inclusions in the cytoplasm. Glycogen histochemical staining (PAS) and acid phosphatase staining were strongly positive, and Sudan black staining was positive or weakly positive. Cells similar to Gaucher cells are seen in cases of massive and rapid destruction of leukocytes, such as in bone marrow slices of chronic granulocytic leukemia, and occasionally in bone marrow of thrombocytopenic purpura. This is not due to a deficiency of β-glucosidase, but rather to an accumulation of glucosinolates due to massive destruction of blood cells and massive entry of erythrocyte glucosinolates and lactosylsphingosine into phagocytes, which exceeds their ability to mediate glycolipids. Early detection of neurologic infiltration by electroencephalography, with widespread abnormal slow waves and other wave patterns before the onset of neurologic symptoms, can be helpful in differentiating the adult from the juvenile type before the onset of neurologic symptoms. Biochemical tests often show increased serum acid phosphate activity. In some cases, there is a decrease in coagulation factors, such as factors V, VII, VIII, IX, X, and Ⅺ, with a decrease in factor IX being more common, and serum ferritin is elevated in this condition. Glucoencephalosidase activity is decreased in both tissue and tissue culture. Glucoencephalosidase activity is commonly measured in the laboratory on washed venous blood leukocytes, platelets, and in vitro cultured fibroblasts. In most cases, the glucosinolase activity of washed leukocytes and in vitro cultured skin fibroblasts is about 1/2 to 1/3 of that of normal subjects. Diagnosis of heterozygous carriers of HGH is difficult because the enzyme activity of heterozygous carriers is mildly reduced, whereas the enzyme activity of normal subjects is subject to wide individual variability. Intrauterine diagnosis can be made by amniocentesis of glucosinolipase activity in fetal cell culture extracts to identify the fetus as a heterozygous or pure carrier of Gaucher’s disease. It should be noted that: (i) the amniotic cells of the suspected fetus should be cultured under the same conditions as those of the normal fetus, and then the extracts should be taken for measurement; (ii) the two cultures should be cultured for the same period of time for comparison. In addition, the ratio of β-glucosylceramide to galactosylceramide in skin fibroblasts can also be measured as a diagnostic criterion, with a normal value of 0.16±0.08, which is reduced to 0.04±0.02 in patients with type Ⅰ. III. Therapeutic Measures Symptomatic treatment is the mainstay of treatment for type Ⅱ. Splenectomy can be done in type III and type I children due to extreme splenomegaly secondary to hypersplenism. Symptoms can be significantly improved after surgery, but it cannot prevent the occurrence and development of neurological symptoms of type III. Bone pain can be treated with analgesics, and short-term application of prednisone can reduce the symptoms. At present, the trial of β-glucose encephalinase extracted from human placenta is injected intravenously, and the drug rapidly enters the liver after the drug is used, so that the content of glucose encephalin in the liver, red blood cells and blood freezing decreases. Beijing Children’s Hospital has used β-glucoencephalosidase produced by the University of Pittsburgh Pharmaceuticals to treat 2 cases of type III Gaucher’s disease, starting with a surprise dose, and later with a maintenance dose, and according to the activity of the enzyme and the clinical symptoms of the reduction of the amount of drugs and the extension of the interval, in which 1 case of β-glucoencephalosidase activity increased by a factor of 3, and the clinical symptoms of the improvement of the growth of the height, the improvement of the appetite, and the shrinkage of the liver. However, this is an alternative therapy, and the complete treatment needs to be further observed by gene therapy or bone marrow transplantation to implant cells containing β-glucoencephalosidase. There is also a trial of bone marrow transplantation, implantation of cells containing β-glucoencephalosidase, and its efficacy needs to be further observed. Pathogenesis Due to β-glucosidase deficiency, gluccerebroside accumulates in the monocytes of liver, spleen, bones and central nervous system, resulting in hepatosplenomegaly, bone involvement and neurological symptoms. Glucosinolates are glycolipids that are soluble in water and are composed of long-chain aminoalcohol sphingvside and long-chain fatty acids linked at the C2 site, a compound called N-acyl sphingosine (ceramide). One molecule of glucose is synthesized by linking a β-glycoside to the C1 site of the sphingosine. Under normal conditions glucosinolates hydrolyze glucose and N-acylsphingosine by β-glucosidase. Due to β-glucosidase deficiency, glucosylceramide accumulates. The cerebrosides accumulated in macrophages are derived from: (1) erythrocyte globoside in senescent erythrocytes, which is the major component of erythrocyte glycolipids; (2) lactosyl sphingosine, which is the major glycolipid in senescent leukocytes and platelets; (3) sphingolipids in the blood group; (4) glucosyl sphingolipids in macrophages; (5) glucosyl sphingolipids in senescent leukocytes and blood platelets; (6) glucosides in senescent macrophages; (7) glucosides in macrophages; (8) glucosidic acid in senescent macrophages. (iii) Blood group glycosphingolipids. Brain accumulation of glucose cerebrosides from gangliosides (Tanglioside); in addition, because the nerve sphingolipids are components of mammalian cell membranes, so the accumulation of glucose cerebrosides can also come from a variety of tissues in the body, such as the liver, kidneys and muscle tissue. Normal people per gram of splenic tissue (wet weight) containing glucoserebrosides 60 ~ 280μg, the patient’s content of 3 ~ 40.5mg, nearly a hundred times higher than the normal, but other neutral sphingomyelin glycolipids and galactocerebroside (galactocerebroside) is the content of normal. V. Clinical manifestations Due to the different degree of enzyme deficiency, the symptoms can vary greatly; but the same family are the same type of disease. According to the degree of organ involvement of the onset of the urgency, as well as the presence or absence of neurological involvement, categorized in the type: ① adult or chronic type; ② infant or acute type; ③ juvenile or subacute type. 1, type (chronic type) slow onset, can be seen at any age, to school-age children with the most onset, previously known as the adult type is not appropriate. This type is the most common, and accounted for 15 of the 46 cases in Yang’s statistics. The enzyme activity of beta-glucosidase is about 12-45% of that of a normal person, and the enzyme activity is relatively low in those with early onset of the disease. The onset of the disease is insidious and the course of the disease is slow, often with hepatosplenomegaly and anemia. As the disease progresses, skin, eye and bone and joint symptoms may appear, but no neurological symptoms. According to the progress of the disease, it can be divided into three stages: ①In the early stage: the general condition is good, with only splenomegaly and mild orthochromatic anemia, and the growth and development are close to normal. In the middle stage, the liver is also gradually enlarged, but not as obvious as splenomegaly. Superficial lymph nodes are not enlarged. With the aggravation of anemia, the color of the face is gradually pale. Due to hypersplenism, white blood cells and platelets are reduced, and network red blood cells are slightly increased. The skin in the exposed area shows a peculiar brownish-yellow color. Bone and joint symptoms appear earlier in some patients, and there may be hidden pain in bones and joints. (iii) Late stage: the symptoms of each type are gradually aggravated, anemia is obvious, white blood cells and platelets are obviously reduced, and the granulocytes can even be as low as below 10000/L. It is often combined with infections and tendency to bleed from skin and mucous membranes. Lymph nodes may be mildly enlarged. If liver infiltration is severe, liver function impairment, even cirrhosis, esophageal varices and reduced coagulation factors, especially the lack of IX factor are more common. Bone and bone marrow infiltration may cause bone pain, joint swelling and pain, and sometimes need to be differentiated from rheumatoid arthritis. X-ray examination shows widening of the medullary cavity, generalized osteoporosis, and limited bone destruction; typically, the distal femur is enlarged and flask-like, often combined with compression fractures of the neck of the femur and spine. The nucleus pulposus heals late. Symmetrical brownish-yellow wedge-shaped plaques appear in the conjunctiva of both eyes, the base of which is at the edge of the cornea, and the tip of which points to the canthus, first on the nasal side, and then on the temporal side; this symptom is mostly seen only in adults, and is less common in children. The height and weight of these children are usually at the low limit of normal. 2. Type II (acute type) The onset of symptoms occurs within 1 year of age, and may occur as early as 1 to 4 weeks after birth. It is less common than the chronic type. Yang Jin’s summarized that this type accounted for 9 out of 46 cases. This type has the lowest β-glucosidase activity and is almost undetectable. The amount of glucosinolates in the brain tissue of this type is unknown. Normally, almost all cerebrosides in brain tissue are galactose cerebrosides. Thin-layer chromatography has confirmed that a large proportion of the cerebrosides accumulated in the patient’s brain tissue, especially in the frontal lobe, are glucosinolates. It has been reported that 70% of the glycolipids in the gray matter of these patients are glucosylcerophospholipids and 30% are galactosylcerophospholipids, whereas 100% of the gray matter of normal human brains are galactosylcerophospholipids, suggesting that at least some parts of the brain tissues of Gaucher’s disease type II contain elevated levels of glucosylcerophospholipids. The earlier the onset of the disease, the faster it progresses. Dyspeptic symptoms are often present at first and later lead to growth retardation. In addition to hepatosplenomegaly and anemia, neurological symptoms such as impaired consciousness, strabismus, cervical ankylosis, ankyloglossia, increased muscle tone in the limbs, scissor-like crossing of the lower limbs, clenching of the teeth, dysphagia, laryngeal wheezing, and convulsions are the mainstays of the disease. A large number of Gaucher’s cells infiltrate the lungs, and when the disease is severe, there is coughing, even dyspnea and cyanosis. x-ray shows infiltrative lesions in the lungs, and skeletal changes are not obvious. Type III (subacute type) may develop in infancy or childhood, and Yang’s statistics show that there are 9 cases of this type. The activity of beta-glucosidase is equal to 13%-20% of normal. The onset of the disease is slow, and progressive hepatosplenomegaly and mild to moderate anemia are common. Neurologic symptoms gradually appeared mostly around the age of 10 years, mostly epileptiform seizures, strabismus or difficulty in horizontal injection gaze and doll’s eyes. The EEG is widely abnormal. When the disease progresses, the limbs gradually stiffen, the whole body muscle consumption atrophy, walking difficulties, speech disorders. Beijing Children’s Hospital has seen a family of three boys, two cases of twins with simultaneous onset, both of whom underwent splenectomy at the age of 6 years, and later developed epileptiform seizures, and the third child later developed the same neurological symptoms. The difference between this type and type II is that in addition to the age of onset, there is generally no serious intellectual disability, with an IQ of about 70, which distinguishes it from type II. Bone marrow symptoms appear in the later stages, with occasional pathologic fractures, and bleeding symptoms are often present due to thrombocytopenia. Among the 46 cases analyzed by Yang, 12 cases have not yet shown neurological symptoms because of their young age at the time of diagnosis, and they need to be tracked and observed before they can be typed. Prognosis Type II most often die within 1 year of the onset of secondary respiratory infections, a few can survive for more than 2 years. After the appearance of neurological symptoms, type III is gradually consumed and has movement disorders, and most of them die from recurrent secondary infections. Type I progresses very slowly, and after splenectomy can survive to normal age with completely normal intelligence.