When to Consider Gaucher Disease and How to Diagnose It Early and Correctly
Considering Gaucher disease (GD) as a cause of a patient's problems, especially in the case of splenomegaly and bleeding manifestations, is very important, regardless of age. Screening using the dry blood spot method is available and very simple.
Etiopathogenesis
Gaucher disease (GD) is the most common lysosomal storage disorder. It is autosomally recessive inherited, with its prevalence in the Czech Republic estimated at 1 in 88,500 live births.
As a result of mutations in the GBA gene, of which more than 300 have been described, a defective enzyme β-glucocerebrosidase is produced. Under normal circumstances, lysosomal glucocerebrosidase cleaves glucocerebroside into glucose and ceramide. In case of its malfunction, uncleaved glucocerebroside accumulates in the lysosomes of affected cells and impairs their function.
GD is characterized by complex changes in various organs, symptoms can be nonspecific, and many patients endure a long journey before their difficulties are correctly diagnosed and identified. Initial problems can appear in early childhood but can also emerge in adulthood.
Classification
According to the severity of the condition, GD is divided into three types:
Type 1
This is the most common type of the disease. Previously referred to as adult, visceral, or non-neuropathic. The first symptoms usually appear in preschool and school age or early adulthood. The most common symptoms are fatigue, bone and joint pain, and a feeling of fullness after eating. Bleeding manifestations may be present.
Disrupted blood supply to a specific bone area can lead to so-called bone infarction, resulting in very severe pain. This is known as a bone crisis, and this condition might be accompanied by fever and inflammatory changes. It is often mistaken for osteomyelitis, which can further delay the correct diagnosis. Aseptic necroses of the bones, frequent fractures of long bones, or compression fractures of vertebrae may occur.
With accumulation, the red bone marrow is gradually replaced by accumulated glucocerebroside, leading to decreased production of platelets and potentially erythrocytes and leukocytes. Bleeding manifestations are related to thrombocytopenia. Hepatomegaly and splenomegaly result in abdominal enlargement, children are often hypotrophic, of shorter stature, and delayed puberty is commonly observed. In this type of GD, intellect is not affected, and no clear dysmorphia is present.
Type 2
This represents a severe early form of the disease with symptoms present in early infancy. Most commonly it includes hypotrophy, strabismus, seizures, opisthotonus, skin changes like ichthyosis, massive enlargement of the liver and spleen. The disease progresses rapidly and is usually fatal within the first two years of life.
Type 3
This involves severe visceral, hematological, and bone involvement. The disease is accompanied by secondary epilepsy and symptoms of psychomotor retardation. Chest deformity or severe scoliosis may be present.
Diagnosis
If the correct diagnosis is not established, treatment can be delayed for many years. Early diagnosis is crucial because currently available therapeutic modalities (both enzyme replacement therapy and substrate reduction therapy) are safe and effective in preventing the progressive development of the disease.
The diagnosis of Gaucher disease is based on clinical judgment, anamnesis data regarding the child's development, and symptoms such as bone pain or episodes of so-called bone crises. Details about potential bleeding are very important. Clinical findings typically include hepatosplenomegaly and hematomas. In the differential diagnosis of organomegaly and bleeding manifestations, hematologic malignancy is often excluded.
Basic blood tests may show various degrees of thrombocytopenia, anemia, or leukopenia. Coagulation tests often reveal a mildly prolonged activated partial thromboplastin time (aPTT) and high D-dimer levels. Hyperimmunoglobulinemia or hyperferritinemia may be present. If a bone marrow aspiration is done as part of the differential diagnosis, morphologically typical storage cells with an eccentrically located nucleus due to accumulated glucocerebroside may be observed. Screening for typical biomarkers confirming increased activity of macrophage system cells during accumulation – tartrate-resistant acid phosphatase (ACP), angiotensin-converting enzyme (ACE), chitotriosidase, and glucosylsphingosine (lyso-GL‑1) is important.
Definitive diagnosis confirmation is based on demonstrating reduced glucocerebrosidase activity using the dry blood spot screening method and in isolated leukocytes from peripheral blood, and further on by molecular genetic examination confirming specific mutations in the GBA gene.
Dry Blood Spot Method Examination
GD can be confirmed or excluded by a simple enzymatic blood test. The method is minimally invasive, requiring only four drops of blood. The blood sample is then transferred onto filter paper and dried (known as DBS – dried blood spot). In children under six months of age, the blood sample can be taken from a heel prick; from six months of age, it is recommended to take the sample from a finger or a vein. The cards with blood samples are then sent to the laboratory.
Watch the animated video - Understanding Gaucher Disease.
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Sources:
1. Malinová V. Gaucher Disease – Current Treatment Options. Pharmacotherapy Review 2019; 4 (5): 640−645.
2. Motta I., Filocamo M., Poggiali E. et al. A multicenter observational study for early diagnosis of Gaucher disease in patients with splenomegaly and/or thrombocytopenia. Eur J Haem 2015; 96: 362−359, doi: 1111/ejh.12596.
3. Gaucher Disease. Sanofi, 2023. Available at: www.spravnadiagnoza.cz/cs/gaucherova-nemoc
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