bubble_chart Overview

Gaucher's disease, also known as glucocerebroside lipidosis, is caused by a deficiency or reduction of β-glucocerebrosidase. This enzyme deficiency prevents the breakdown of glucocerebroside into galactocerebroside or glucose and N-acylsphingosine, leading to the accumulation of glucocerebroside in the mononuclear phagocyte system of various organs and causing massive proliferation of histiocytes. Different clinical types may occur due to varying enzyme activity levels in different tissues. This disease is inherited in an autosomal recessive pattern and is more common among Jewish populations, with approximately 1 in 50 individuals carrying the abnormal heterozygous gene. As a result, the incidence rate is relatively high, reaching 8.3 per 100,000. Numerous cases have been reported in China. In 1982, Yang et al. summarized 46 cases, and Beijing Children's Hospital treated a total of 40 cases over 30 years.

bubble_chart Pathogenesis

This disease is caused by a deficiency of β-glucosidase, leading to the accumulation of glucocerebroside in the mononuclear-macrophage cells of the liver, spleen, bones, and central nervous system, resulting in hepatosplenomegaly, bone involvement, and neurological symptoms.

Glucocerebroside is a glycolipid, soluble in water, formed by the linkage of a long-chain aminoalcohol sphingosine and a long-chain fatty acid at the C₂ position. This compound is called N-acylsphingosine (ceramide), with a molecule of glucose attached to the C₁ position of sphingosine via a β-glycosidic bond. Under normal conditions, glucocerebroside is hydrolyzed by β-glucosidase into glucose and N-acylsphingosine.

Due to the deficiency of β-glucosidase, glucocerebroside accumulates. The glucocerebroside accumulated in macrophages originates from: ① globoside in aging red blood cells, which is the main component of red blood cell glycolipids; ② the major glycolipid in aging white blood cells and platelets—ceramide lactoside; ③ sphingomyelin in blood group glycosphingolipids. The glucocerebroside accumulated in the brain originates from gangliosides. Additionally, since sphingolipids are components of mammalian cell membranes, the accumulated glucocerebroside can also come from various tissues in the body, such as the liver, kidneys, and muscle tissues.

Normally, each gram of spleen tissue (wet weight) contains 60–280 μg of glucocerebroside, while in patients, the content ranges from 3 to 40.5 mg, nearly a hundred times higher than normal. However, the levels of other neutral sphingosine glycolipids and galactocerebroside remain normal.

bubble_chart Clinical Manifestations

Due to varying degrees of enzyme deficiency, symptoms can differ significantly; however, affected individuals within the same family exhibit the same type. Based on the extent of organ involvement, the speed of onset, and the presence or absence of neurological involvement, the disease is classified into three types: ① Adult or chronic type; ② Infantile or acute type; ③ Juvenile or subacute type.

1. Type I (Chronic Type)  The onset is slow and can occur at any age, most commonly in school-aged children. Previously referred to as the adult type, this classification is now considered inappropriate. This type is the most common, accounting for 15 out of 46 cases in Yang's statistics. The activity of β-glucosidase is approximately 12–45% of normal levels, with earlier onset cases showing relatively lower enzyme activity.

The onset is insidious, and the course is slow, often presenting with hepatosplenomegaly and anemia. As the disease progresses, skin, eye, and bone/joint symptoms may appear, but neurological symptoms are absent. The progression can be divided into late stage [third stage]: ① Initial stage [first stage]: General condition is good, with only splenomegaly and grade I normochromic anemia, and growth and development are nearly normal. ② Intermediate stage [second stage]: The liver gradually enlarges, though not as prominently as the spleen. Superficial lymph nodes are usually not enlarged. As anemia worsens, the complexion becomes progressively pale. Due to hypersplenism, leukocytes and platelets are often reduced, and reticulocytes show grade I elevation. The skin in exposed areas may develop a distinctive brownish-yellow hue. Some patients experience early bone/joint symptoms, such as dull pain in bones and joints. ③ Advanced stage: Symptoms of all types gradually worsen, with significant anemia, marked reduction in leukocytes and platelets, and granulocytes potentially dropping below 10,000/L. Infections and skin/mucous membrane bleeding tendencies are common. Lymph nodes may also show grade I enlargement. Severe liver infiltration can lead to liver dysfunction, even cirrhosis, esophageal varices, and reduced clotting factors, particularly factor IX deficiency. Bone and marrow infiltration may cause bone pain and joint swelling, sometimes requiring differentiation from wind-dampness arthritis. X-rays may reveal widened medullary cavities, generalized osteoporosis, and localized bone destruction; a classic finding is distal femoral expansion, resembling a flask, often accompanied by femoral neck and vertebral compression fractures. Ossification nuclei fuse later. Symmetrical brownish-yellow wedge-shaped patches appear on the conjunctiva, with the base at the corneal margin and the apex pointing toward the canthus, first seen nasally and later temporally. This sign is more common in adults and rare in children. Affected children often have height and weight at the lower limits of normal.

2. Type II (Acute Type)  Onset typically occurs within the first year of life, sometimes as early as 1–4 weeks after birth. Less common than the chronic type, this type accounted for 9 out of 46 cases in Yang Jin's summary. β-glucosidase activity is lowest in this type, often undetectable.

The amount of glucocerebroside in brain tissue in this type remains unclear. Normally, brain tissue cerebrosides are almost entirely galactocerebrosides. Thin-layer chromatography confirms that a significant portion of cerebrosides accumulated in the brain, especially in the frontal lobe, are glucocerebrosides. Reports indicate that 70% of glycolipids in the gray matter of these patients are glucocerebrosides, while 30% are galactocerebrosides, compared to 100% galactocerebrosides in normal brain gray matter, suggesting elevated glucocerebroside levels in certain brain regions in Gaucher disease Type II.

Earlier onset correlates with faster progression. Initial symptoms often include digestive disturbances, later leading to growth retardation. Besides hepatosplenomegaly and anemia, neurological symptoms dominate, such as impaired consciousness, strabismus, neck stiffness, opisthotonus, increased limb muscle tone, scissoring of the lower limbs, trismus, dysphagia, and laryngeal stridor. Seizures may also occur. Extensive Gaucher cell infiltration in the lungs can cause cough, dyspnea, and cyanosis in severe cases. X-rays may show pulmonary infiltrates, but skeletal changes are less pronounced.

3. Type III (Subacute Type) This can occur in infancy or childhood. According to Yang's statistics, this type accounted for 9 cases. The activity of β-glucosidase is approximately 13-20% of that in normal individuals.

The onset is insidious, with progressive hepatosplenomegaly and mild to grade II anemia being common. Neurological symptoms typically appear gradually around the age of 10, often including epileptic seizures, strabismus or horizontal gaze palsy, and doll's eye phenomenon. The electroencephalogram shows widespread abnormalities. As the disease progresses, limbs gradually become stiff, generalized muscle wasting and atrophy occur, leading to difficulty in walking and speech impairment. Beijing Children's Hospital once observed a family with three boys, two of whom were twins and developed symptoms simultaneously. Both underwent splenectomy at the age of 6, followed by epileptic seizures. The third child later developed similar neurological symptoms. The distinguishing feature of this type from Type II, apart from the age of onset, is the absence of severe intellectual disability, with an IQ around 70, which helps differentiate it from Type II.

In the advanced stage, bone marrow symptoms appear, and pathological fractures are occasionally seen. Due to thrombocytopenia, bleeding symptoms are common.

Among the 46 cases analyzed by Yang, 12 were too young at the time of diagnosis to exhibit neurological symptoms, necessitating follow-up observation for definitive classification.

bubble_chart Diagnosis

The diagnosis can be made based on hepatosplenomegaly or central nervous system symptoms, the identification of Gaucher cells in bone marrow smear with Wright's staining, and elevated serum acid phosphatase. Gaucher cells are very large, with a diameter of about 20–80 μm, mostly oval in shape, containing one or several eccentric nuclei. The nuclei are round, oval, or irregular, with coarse chromatin. The cytoplasm is abundant, non-vacuolated, pale blue, and exhibits a coarse, dark, interlaced striated structure resembling crumpled paper. Electron microscopy reveals specific tubular glucocerebroside inclusions in the cytoplasm. The histochemical staining for glycogen (PAS) and acid phosphatase is strongly positive, while Sudan black staining is positive or weakly positive. Cells similar to Gaucher cells may be seen in conditions with massive and rapid destruction of white blood cells, such as in bone marrow smears of chronic myeloid leukemia, and occasionally in the bone marrow of thrombocytopenic purpura. This is not due to a deficiency of β-glucosidase but rather results from the massive destruction of blood cells, leading to the influx of large amounts of erythrocyte glucocerebroside and lactosylceramide into phagocytes, exceeding their capacity to hydrolyze glycolipids, thus causing the accumulation of glucocerebroside.

Electroencephalography (EEG) can detect early central nervous system infiltration, showing widespread abnormal slow waves and other waveforms even before neurological symptoms appear, which may help differentiate between adult and juvenile types before neurological symptoms manifest.

Generation and transformation tests often reveal elevated serum acid phosphatase activity. Some cases show reduced coagulation factors, such as factors V, VII, VIII, IX, X, and XI, with factor IX deficiency being more common. Serum ferritin is elevated in this disease. Glucocerebrosidase activity is reduced in both tissues and tissue cultures. Laboratory tests commonly use washed venous leukocytes, platelets, and cultured fibroblasts to measure glucocerebrosidase activity. In most cases, the glucocerebrosidase activity of washed leukocytes and cultured skin fibroblasts is about 1/2 to 1/3 of that in normal individuals.

Diagnosing heterozygous carriers of Gaucher disease is somewhat challenging because the reduction in enzyme activity in carriers is mild, and there is significant individual variability in enzyme activity among normal individuals.

Prenatal diagnosis can be performed using amniocentesis to examine glucocerebrosidase activity in cultured fetal cell extracts to determine whether the fetus is a heterozygous or homozygous carrier of Gaucher disease. During monitoring, the following should be noted: ① Amniotic cells from the suspected fetus and a normal fetus should be cultured under identical conditions, and their extracts should be tested; ② The two types of cultured cells should be cultured for the same duration. Additionally, the ratio of β-glucocerebroside to galactocerebroside in skin fibroblasts can be used as a diagnostic criterion, with a normal value of 0.16 ± 0.08. In type I patients, this ratio decreases to 0.04 ± 0.02.

bubble_chart Treatment Measures

For type II, the treatment is mainly symptomatic. For type III and type I children with extreme splenomegaly and secondary hypersplenism, splenectomy may be performed. Postoperative symptoms can significantly improve, but it cannot prevent the occurrence or progression of neurological symptoms in type III. Bone pain can be managed with analgesics, and short-term use of prednisone may alleviate symptoms. Currently, intravenous injection of β-glucocerebrosidase extracted from human placenta is being trialed. After administration, the drug rapidly enters the liver, reducing the levels of glucocerebroside in the liver, red blood cells, and plasma. Beijing Children's Hospital once used β-glucocerebrosidase produced by the University of Pittsburgh's pharmaceutical factory to treat two cases of type III Gaucher's disease. An initial loading dose was administered, followed by a maintenance dose, with the dosage and interval adjusted based on enzyme activity and clinical symptoms. In one case, β-glucocerebrosidase activity increased threefold, clinical symptoms improved, height increased, appetite improved, and liver size decreased. However, this is a replacement therapy, and definitive treatment awaits gene therapy or bone marrow transplantation with cells containing β-glucocerebrosidase, which requires further observation.

Bone marrow transplantation with implantation of cells containing β-glucocerebrosidase has also been trialed, and its efficacy likewise requires further observation.

bubble_chart Prognosis

Type II often results in death within the first year due to secondary respiratory infections, with a few surviving more than two years. Type III leads to gradual wasting and motor impairment after the onset of neurological symptoms, with most deaths caused by recurrent secondary infections. Type I progresses very slowly, and after splenectomy, patients can survive to a normal age with completely normal intelligence.