Gaucher disease is a genetic disease characterized by a violation of lipid metabolism, insufficiency of lysosomal enzymes, accumulation of glycolipids in cellular structures. Symptoms are determined by the type of pathology. Common signs are an increase in the liver, spleen, and a decrease in blood clotting. In type I, disorders of the bone system are detected: osteoporosis, frequent fractures, bone infections. In type II and III, neurological symptoms dominate: convulsions, paralysis, strabismus, mental retardation. The diagnosis is based on a biochemical analysis of a deficient enzyme. Treatment includes enzyme replacement, substrate-reducing and symptomatic therapy.
E75.2 Other sphingolipidoses
Gaucher disease got its name from the name of the French doctor Philippe Gaucher. In 1882, he described the symptoms and pathanatomic features of the structure of the spleen of a patient who died of sepsis. Several decades later, in a similar clinical case, Gaucher determined the accumulation of glucocerebroside in the spleen and the insufficiency of the enzyme glucocerebrosidase. Gaucher’s disease (sphingolipidosis, glucosylceramide lipidosis) belongs to the group of lysosomal accumulation diseases – hereditary pathologies in which the functions of the cellular organelles of lysosomes are altered. The frequency of the disease ranges from 1:40 thousand to 1:70 thousand. The prevalence is greatest in communities where marriages between close relatives are permissible, for example, among Ashkenazi Jews. The carrier of the mutational gene is determined in about 1 person out of 400.
Glucosylceramide sphingolipidosis is the most common form of hereditary fermentopathies. The cause of its development is considered to be a defect in the GBA gene, which encodes the enzyme lysosome beta-glucosidase (glucocerebrosidase), responsible for the breakdown of lipids. The inheritance of the disease occurs in an autosomal recessive way, for the formation of fermentopathy, the presence of a pair of altered genes is necessary: one from the mother, the other from the father. In a married couple where both parents are carriers of the mutation, the probability of having a sick child is 25%. The risk of transmission of one defective gene, that is, the risk of carrying without developing the disease in such families is 50%. In the presence of two mutant alleles in the genotype, the function of glucocerebrosidase decreases by 15-30% from the normal level.
The pathogenetic basis of the disease is a decrease in the catalytic activity of beta-glucosidase. As a result, the process of cleavage of glycosphingolipids (complex compounds of lipids and carbohydrates) to glucose and ceramide is disrupted. Abnormally progressive accumulation of macromolecules occurs in cells that are characterized by an increased rate of their renewal – in macrophages. Non–hydrolyzed lipids are concentrated in lysosomes, special accumulation cells are formed – Gaucher cells. Primary metabolic failure provokes secondary disorders of biochemical processes and cellular functions. Due to the pathology of fat metabolism, macrophage activation syndrome develops. Monocytopoiesis is stimulated, the content of macrophages in the liver, spleen, and bone marrow increases. This causes splenomegaly, hepatomegaly, and infiltration of the bone marrow. Disorder of the regulatory function of macrophages is a provoking factor of cytopenia, bone and joint damage.
Gaucher disease symptoms
According to the age of the debut and the features of the clinical picture, there are three types of the disease. The first type is the most common, has a chronic course. Symptoms are more often manifested by the age of 30-40, less often the disease manifests in childhood. The increase in the size of the liver and spleen begins immediately after birth, but clinically manifests itself later. The first signs of pathology are anemia, increased bleeding. The suppression of the hematopoiesis system is accompanied by a decrease in the level of hemoglobin and platelets. Changes in the musculoskeletal system are represented by pain in the bones and joints, frequent fractures, deformities (as a rule, the femur changes). In adults, hyperpigmentation on the face and legs is noticeable: the skin darkens, acquires a shade from yellowish to yellow-brown. There may be flat red spots with a typical localization in the area around the eyes. The growth of patients is below average.
The second type of disease (acute infantile or acute neuropathic) is very rare, develops between birth and one and a half years, most often symptoms debut in the first three months of life. It is characterized by a rapid course, poor response to treatment. Neurological disorders triggered by the accumulation of Gaucher cells in the central nervous system come to the fore. Children scream weakly, suck sluggishly. The swallowing reflex is impaired, respiratory cycle failures are often noted. There is a noticeable delay in mental and physical development. At the initial stage of the disease, muscle tone is reduced, 9-12 months after the debut, hypertonicity occurs, especially in the neck and limb muscles. Convulsions, strabismus, spastic paralysis develop. The liver and spleen are enlarged. Children often suffer from severe pneumonia.
The third type is juvenile or subacute neuropathic. The first signs – enlargement of the spleen and liver – occur in 2-3 years. Full symptoms unfold in the period from 6 to 15 years. Clinical manifestations of CNS lesions include muscle hypertonicity, spastic type paralysis, strabismus, involuntary spasms, convulsions, a difficult breathing cycle with difficulty inhaling, problems with swallowing. There are disorders of mental development: decreased intellectual functions, unformed speech and writing, emotional instability, psychosis. Children lag behind in sexual development. The course of the disease is steadily progressing.
The most severe complications are detected in the second and third types of the disease. Damage to the spinal cord and brain leads to a violation of the respiratory cycle, sudden stops of breathing develop, the risk of laryngeal spasm and death from suffocation increases. Reduced platelet levels can cause extensive internal bleeding. In patients with pathology of the first type, a common complication is the destruction of bones, their increased fragility and infectious lesions. Mobility is limited, patients cannot move independently, need outside care.
Anamnesis collection and physical examination is performed by an endocrinologist and neurologist, additionally consultations of a geneticist, hematologist, ophthalmologist, pediatrician, psychiatrist are prescribed. Anamnestic data include the presence of Gaucher disease in relatives. The examination reveals typical signs: low growth, bone pathology, neurological symptoms (strabismus, ataxia, paralysis), hemorrhagic syndrome, hyperpigmentation of the skin. Sometimes a suspicion of the disease arises after the accidental detection of an enlarged spleen on ultrasound images, suppression of the hematopoietic system according to a general blood test. To confirm the diagnosis, exclude other metabolic hereditary pathologies, osteomyelitis, bone tuberculosis, viral hepatitis and oncological blood lesions, a specific diagnosis is carried out:
- Clinical, biochemical blood testing. Most patients have thrombocytopenia, leukopenia, anemia, which in children usually has an iron deficiency origin. The results of the biochemical analysis show a reduced activity of glucocerebrosidase.
- Enzyme analysis of cells. In Gaucher’s disease, insufficient glucosidase activity is detected in dry blood samples and in skin fibroblasts. The degree of enzyme deficiency has no direct correlation with the severity of symptoms. An additional biochemical marker is chitotriosidase. This enzyme is synthesized by activated macrophages, characterized by an increase in its activity by 6-10 times.
- Morphological study of bone marrow. The presence of structures specific to this disease – Gaucher cells – is confirmed. The result makes it possible to exclude hemoblastosis and lymphoproliferative disease.
- Study of the structure of bone tissue. In order to assess the severity of the lesion of the osteoarticular system, densitometry, radiography and / or MRI of skeletal bones are performed. Diffuse osteoporosis is possible, Erlenmeyer flasks, foci of osteolysis, osteosclerosis and osteonecrosis can be visualized. In the early stages of the disease, osteopenia, infiltration of the bone marrow is noted.
- Visualizing examination of the spleen, liver. Ultrasound and MRI of internal organs are performed. According to the results, the presence or absence of focal lesions is determined, the volume of the enlarged organ is measured. The initial indicators subsequently allow monitoring the effectiveness of therapy.
- Molecular genetic research. DNA diagnostics is an optional procedure. Confirmation of a mutation in the GBA gene may be necessary in case of ambiguity of biochemical studies, as well as in the framework of prenatal and preimplantation examinations.
Specialized care for patients with the first and third types of Gaucher disease is aimed at eliminating symptoms and compensating for the primary genetic defect – increasing the amount of missing enzyme, increasing the catabolism of glycosphingolipids. With type 2 pathology, therapeutic measures are not effective enough, the efforts of doctors are reduced to alleviating clinical manifestations – pain, convulsions, respiratory disorders. The general scheme includes the following directions:
- Enzyme replacement therapy. The main method of treatment is lifelong enzyme replacement therapy (FZT) using recombinant glucocerebrosidase. The effectiveness is quite high – the symptoms are completely stopped, the quality of life of patients increases. FZT is appropriate for the third and first type of disease. The drugs are administered intravenously. Frequent infusions sometimes cause inflammatory diseases of the veins (phlebitis).
- Substrate-reducing therapy. This direction is new in the treatment of Gaucher’s disease, it is relatively widespread in the USA and European countries. It is aimed at reducing the rate of glycosphingolipid substrate production and accelerating the catabolism of accumulating macromolecules. Specific glucosylceramide synthase inhibitors act as drugs. The method is indicated for type 1 disease with mild to moderate symptoms.
- Symptomatic therapy. With the phenomena of osteoporosis, complex therapy is prescribed, including taking calcium-containing drugs, vitamin D and following a diet enriched with calcium. These measures can slow down the loss of bone mass, increase bone strength, and prevent fractures. For skeletal complications, analgesics (NSAIDs) and antibacterial therapy are used. Symptoms of neurological disorders are stopped by antiepileptic drugs, nootropics, muscle relaxants.
Prognosis and prevention
A favorable outcome is most likely in patients with type 1 of Gaucher disease – a comprehensive therapeutic approach allows normalizing the functionality of glucocerebrosidase, preventing the development of complications, and avoiding disability. With type 3, the prognosis depends on the nature of the course of the disease, the individual reaction of the body to therapeutic measures. Type 2 has extremely severe manifestations and ends with the death of the patient. Prevention is carried out during pregnancy planning and at its initial stages. Medical and genetic counseling is recommended for families with close relatives with this pathology. With a high risk of transmission of the mutation to the unborn child in the first trimester, the level of the enzyme in the amniotic fluid is examined, the issue of termination of pregnancy is resolved.