OVERVIEW

What is Gaucher's disease?

Gaucher's disease is one of the more common lysosomal storage disorders, first reported in 1882 by French physician Phillipe Gaucher, also known as Gaucher disease.

This disease is a very rare autosomal recessive genetic disorder caused by mutations in the GBA gene leading to deficiency of β-glucosidase (also called glucocerebrosidase). The lack of β-glucosidase causes glucocerebroside to accumulate in the lysosomes of macrophages in the liver, spleen, bones, and central nervous system, resulting in pathological changes in affected tissues and organs. Patients often exhibit symptoms involving multiple organs that progressively worsen.

Enzyme replacement therapy with imiglucerase can be administered with good treatment outcomes. Prenatal genetic diagnosis can prevent the birth of affected children.

What are lysosomes?

Lysosomes can be understood as the waste recycling stations within cells. As organelles, lysosomes contain over 60 types of acid hydrolases that degrade various biological macromolecules such as nucleic acids, proteins, lipids, mucopolysaccharides, and glycogen, processing and recycling these cellular components.

The various biological macromolecules that make up cells are in a dynamic equilibrium, constantly being broken down and resynthesized. Biological macromolecules taken in through endocytosis also need to be broken down into different components before they can be utilized. The breakdown of these macromolecules occurs within lysosomes.

What are lysosomal storage disorders?

Each enzyme in lysosomes has its own encoding gene. A defect in any particular enzyme directly leads to the inability to properly degrade a specific biological macromolecule, causing it to accumulate in lysosomes. The common result is swelling of lysosomes, abnormal cell morphology, severely impaired cell function, and ultimately disease onset. These diseases are collectively called lysosomal storage disorders.

What are the types of Gaucher's disease?

Based on whether the nervous system is affected, Gaucher's disease can be mainly classified into non-neuronopathic type (Type I) and neuronopathic types (Type II and Type III). Other subtypes (perinatal lethal type, cardiovascular type, etc.) have also been reported but are extremely rare.

Is Gaucher's disease common?

Gaucher's disease falls under the category of rare diseases, with a very low incidence rate.

Type I Gaucher's disease is more common among Ashkenazi Jews, with approximately 1 in 50 individuals carrying the abnormal heterozygous gene, resulting in a relatively high incidence rate of 8.3 per 100,000. Outside the Jewish population, the incidence is extremely low, at only 1 per 100,000.

Currently, there are no statistical reports on the prevalence and incidence of Gaucher's disease in mainland China. Based on epidemiological data from various Asian countries, it is estimated that the total number of Gaucher's disease patients in China is about 1,000, with 300-400 patients currently diagnosed.

SYMPTOMS

What are the characteristics of Gaucher disease type I?

Gaucher disease type I (non-neuronopathic type) is the most common form of Gaucher disease. Its clinical features include:

• It can occur at any age, with about two-thirds of patients developing symptoms in childhood. The severity of symptoms varies widely. Generally, the earlier the onset, the more severe the symptoms.

• Organ damage is primarily characterized by hepatosplenomegaly, accompanied by hypersplenism or even splenic rupture.

• Hematological abnormalities mainly include thrombocytopenia, anemia, and leukopenia, with possible coagulation disorders. Patients often present with pallor, fatigue, skin and gum bleeding, heavy menstrual bleeding, or even life-threatening hemorrhage.

• Advanced patients may experience bone pain in the limbs or even pathological fractures.

• A small number of patients may develop rare symptoms such as pulmonary issues, abnormalities in glucose and lipid metabolism, cholelithiasis, or immune system disorders.

What are the characteristics of Gaucher disease type II?

Gaucher disease type II (acute neuronopathic type) has the following clinical features:

• It typically manifests in the neonatal to infant period, progresses rapidly, and has a high mortality rate.

• Symptoms such as hepatosplenomegaly, anemia, and thrombocytopenia are similar to type I.

• Neurological symptoms develop quickly, including eye movement disorders, seizures, etc.

• Some severe patients may develop joint contractures.

What are the characteristics of Gaucher disease type III?

Gaucher disease type III (chronic or subacute neuronopathic type) has the following clinical features:

• It usually appears between the age of 2 and adolescence, progresses slowly, and patients have a longer lifespan.

• Early symptoms resemble type I, but central nervous system symptoms gradually emerge, such as myoclonic seizures, incoordination, confusion, etc.

What other diseases can Gaucher disease cause?

• Symptomatic patients may die prematurely from complications such as splenic infarction, splenic rupture, post-splenectomy sequelae, severe bone disease, bleeding complications, infections, liver failure, or severe pulmonary disease.
• Advanced patients often suffer from pathological fractures, commonly in the distal femur, femoral neck, or spine.
• Additionally, Gaucher disease patients have an increased risk of hematological disorders and Parkinson’s disease. Previous studies indicate that Gaucher patients or carriers of high-risk genes have a significantly higher risk (20–30 times) of developing Parkinson’s disease.

CAUSES

What causes Gaucher disease?

Gaucher disease is caused by mutations in the glucocerebrosidase (GBA) gene.

Glucocerebroside is a soluble glycolipid and a cellular component widely present in the body. Mutations in the GBA gene can lead to either no production of glucocerebrosidase or the production of inactive glucocerebrosidase. This results in the ineffective hydrolysis of glucocerebroside in mononuclear-macrophage cells, causing excessive accumulation of glucocerebroside in the lysosomes of mononuclear-macrophage cells in the liver, spleen, bones, bone marrow, lungs, and brain tissues. This accumulation forms typical Gaucher cells and leads to multi-organ dysfunction.

Is Gaucher disease inherited?

Yes. Gaucher disease is an autosomal recessive genetic disorder.

What is an autosomal recessive genetic disorder?

The disease-causing gene in autosomal recessive inheritance is located on an autosome. Each cell nucleus in the human body contains 22 pairs of autosomes, with countless gene segments on each chromosome's DNA. Each gene segment consists of two genes.

In autosomal recessive inheritance, two mutated copies of the gene are required for the disease to manifest. If only one copy of the gene is mutated, the individual will not show symptoms and will appear normal.

For this type of genetic disorder, both parents are carriers of the disease-causing gene, making it more common in the offspring of consanguineous marriages. If affected parents have another child, the risk of the child inheriting the disease is 25%.

Which groups are more susceptible to Gaucher disease?

Gaucher disease can occur at any age (from birth to 80 years old), but it is more common in children and adolescents, with the majority of cases occurring before the age of 7.

DIAGNOSIS

How is Gaucher disease diagnosed?

Due to its rarity and lack of specific symptoms, misdiagnosis and missed diagnosis are common in clinical practice.

Clinicians typically make a comprehensive diagnosis based on the patient's clinical manifestations—such as unexplained splenomegaly, hepatomegaly, anemia, thrombocytopenia, bone pain, or neurological symptoms—combined with laboratory tests and pathological examinations.

What tests are needed to diagnose Gaucher disease?

• Glucocerebrosidase activity test: This is the "gold standard" for diagnosing Gaucher disease. A reduction in glucocerebrosidase activity to below 30% of the normal level in peripheral blood leukocytes or skin fibroblasts confirms the diagnosis.

• Genetic testing: Over 400 types of glucocerebrosidase gene mutations have been identified. Patients with similar symptoms may have different mutations, while those with the same mutation may exhibit varying clinical presentations, disease progression, and treatment responses. Genetic testing is therefore necessary, though it cannot replace biochemical enzyme activity testing. It serves as supplementary evidence to confirm the diagnosis.

• Bone marrow morphology examination: Most patients show characteristic "Gaucher cells." Their presence in bone marrow strongly suggests Gaucher disease but does not confirm it. Further glucocerebrosidase activity testing is required while ruling out other conditions.

• Others: Blood tests, radiographic imaging, EEG, and ultrasound can help assess the extent and severity of organ damage.

Besides Gaucher disease, what other conditions can show Gaucher-like cells?

Gaucher-like cells may appear in chronic myeloid leukemia, severe thalassemia, chronic lymphocytic leukemia, and other disorders. However, these are not true Gaucher cells but "pseudo-Gaucher cells," which differ in microstructure.

According to the 2015 Chinese Expert Consensus on Gaucher Disease Diagnosis and Treatment, mononuclear macrophages in bone marrow may engulf cell debris or lipid metabolites, forming pseudo-Gaucher cells. These can occur in chronic myelogenous leukemia, thalassemia, multiple myeloma, Hodgkin's lymphoma, and plasmacytoid lymphoma.

Thus, while detecting Gaucher-like cells in bone marrow raises suspicion for Gaucher disease, it is not definitive. Glucocerebrosidase activity testing must be performed to differentiate it from other conditions.

TREATMENT

Which department should I visit for Gaucher disease?

Hematology, Pediatrics.

How is Gaucher disease treated?

• Symptomatic treatment: Corresponding symptomatic management can be selected based on the patient's clinical symptoms and characteristics.

  • For the treatment of Gaucher disease, attention should be paid to nutrition and prevention of secondary infections.
  • Patients with severe anemia or significant bleeding may require blood component transfusions. Those with anemia can supplement with vitamins and iron.
  • Patients with an enlarged spleen or severe hypersplenism may consider splenectomy. However, while total splenectomy can reduce abdominal burden and alleviate anemia and bleeding tendencies, it may accelerate liver enlargement and bone destruction. Therefore, surgery should be delayed as much as possible. Partial splenectomy may be considered if necessary.
  • Management of bone lesions includes pain relief, physical therapy, fracture treatment, joint replacement, and supplementary calcium and bisphosphonates for osteoporosis.

• Enzyme replacement therapy (ERT):

  • In 1991, the U.S. FDA approved placental-derived glucocerebrosidase, followed by the approval of recombinant glucocerebrosidase [Imiglucerase for Injection] in 1994 for ERT in Gaucher disease. Clinical practice shows that Imiglucerase significantly improves the clinical symptoms and signs of type I Gaucher disease, maintains normal growth and development, and enhances quality of life. It is the standard treatment for type I Gaucher disease, with earlier treatment yielding better outcomes. Imiglucerase is currently the only specific treatment drug available for Gaucher disease in China. It has substantial evidence-based medical support for its efficacy and safety and is effective in treating Gaucher bone disease.
  • Other ERT drugs approved by the U.S. FDA include Velaglucerase alfa and Taliglucerase alfa. However, these drugs have not yet been submitted for or approved by Chinese regulatory authorities for this indication.

• Bone marrow transplantation: Allogeneic bone marrow transplantation can increase enzyme activity, reduce liver and spleen size, and decrease Gaucher cells. However, the risks and benefits of the procedure must be carefully weighed.

DIET & LIFESTYLE

What is the prognosis of Gaucher disease? How long can patients live?

In China, over 50% of Gaucher disease patients experience a diagnostic delay exceeding 5 years. Among traceable cases, the longest delay before diagnosis even surpassed 20 years. In fact, as a rare disease that can be effectively treated, early diagnosis and intervention can slow disease progression, thereby reducing disability or death caused by the condition.

Generally, Type I Gaucher disease progresses slowly. Patients can survive long-term after splenectomy with normal intelligence, though growth and development may lag. Enzyme replacement therapy yields remarkable results, offering the best prognosis. However, post-splenectomy Type I patients may die early from pulmonary/hepatic dysfunction, infections, or bleeding. Most Type II patients die within 1 year of onset due to secondary infections, though a few survive beyond 2 years. Type III patients often succumb to complications due to severe neurological symptoms. The prognosis has improved significantly with enzyme replacement therapy.

PREVENTION

How to Prevent Gaucher Disease?

Prenatal diagnosis of inherited metabolic diseases is one of the effective measures to prevent genetic disorders. It is a practical application of human genetic knowledge and an important measure for eugenics.

A prerequisite for prenatal diagnosis is an accurate diagnosis of the first affected patient. Only then can targeted testing for specific enzyme deficiencies or genetic defects be conducted during prenatal diagnosis when the mother becomes pregnant again.

Prenatal diagnosis can clearly determine whether the fetus is affected. Some cases can even be diagnosed in the early stages of pregnancy, serving a "preventive" purpose in eugenics. Based on clear prenatal diagnosis results, the birth of an affected fetus can be prevented. This is not only the only feasible eugenic measure but also reduces the burden on families and society while improving population quality.

How is Prenatal Diagnosis for Gaucher Disease Conducted?

When the mother of an affected patient becomes pregnant again, chorionic villus sampling or amniotic fluid cell enzyme activity testing can be performed for prenatal diagnosis. If the patient's genotype has been identified, prenatal genetic diagnosis can also be conducted. By measuring enzyme activity in chorionic villi and amniotic fluid cells, the health status of the fetus can be determined.

Chinese Expert Consensus on the Diagnosis and Treatment of Gaucher Disease (2015): For high-risk pregnancies, placental chorionic villi can be sampled at 9–13 weeks of gestation, or amniotic fluid can be collected at 16–22 weeks for fetal amniocyte culture to test glucocerebrosidase activity and/or DNA mutation analysis.

What is the Difference Between Chorionic Villus Sampling and Amniocentesis?

Compared to amniocentesis, chorionic villus sampling has the advantage of being performed two months earlier, eliminating the need for cell culture and allowing earlier prenatal diagnosis results. If the fetus is diagnosed with the disease, the mother can promptly opt for termination of pregnancy, making subsequent procedures easier and alleviating psychological stress sooner.