Gaucher disease is a rare inherited disorder characterized by the accumulation of a fatty substance called glucocerebroside within specific organs and tissues, particularly the spleen, liver, and bone marrow. This buildup occurs due to a deficiency of an enzyme called glucocerebrosidase, which is responsible for breaking down glucocerebroside.
Gaucher disease genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Gaucher disease is caused by mutations in the GBA gene, leading to reduced or absent glucocerebrosidase activity. The condition is inherited in an autosomal recessive manner, meaning an affected individual inherits two mutated copies of the GBA gene, one from each parent. The prevalence of GD is 1 in 60,000 people. The incidence in the Ashkenazi Jewish population is the highest, estimated at 1 case in 350-450 individuals.
There are three main types of Gaucher disease:
- Type 1 (Non-neuronopathic Gaucher Disease): This is the most common form of Gaucher disease and primarily affects the spleen, liver, and bone marrow. Individuals with Type 1 Gaucher disease usually do not have significant involvement in the nervous system.
- Type 2 (Acute Neuronopathic Gaucher Disease): This form is rare and severe and involves neurological complications. Symptoms typically appear in infancy, and affected individuals may experience brain damage, seizures, and other neurological problems.
- Type 3 (Chronic Neuronopathic Gaucher Disease): This intermediate form involves systemic and neurological symptoms. The onset of symptoms is typically later than in Type 2, and neurological involvement is less severe.
Critical features of Gaucher disease include:
- Enlarged liver and spleen
- Anemia and low platelet count
- Bone pain and fractures
- Easy bruising
- Fatigue
- Yellowish skin pigmentation (jaundice)
Diagnosis of Gaucher disease involves clinical evaluation, blood tests to measure enzyme activity and glucocerebroside levels, and genetic testing to identify mutations in the GBA gene. Imaging studies, such as MRI or bone scans, may also be used to assess organ involvement.
Treatment for Gaucher disease often involves enzyme replacement therapy (ERT), which provides the missing or deficient glucocerebrosidase enzyme. This can help reduce symptoms and prevent further organ damage. Substrate reduction therapy (SRT) is another treatment option that aims to decrease the production of glucocerebroside.
While there is no cure for Gaucher disease, these treatments can significantly improve the quality of life for affected individuals. Regular follow-up care, including monitoring for complications and addressing symptoms, is essential to managing Gaucher disease. Additionally, genetic counseling is recommended for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.
More than 400 pathogenic variants in the GBA gene have been described. The most common Gaucher disease-causing mutation is c.1226A>G, which accounts for approximately 75% of the alleles detected and is responsible for the high incidence of Gaucher disease in the Ashkenazi Jewish population.
Another relatively frequent variant in Gaucher disease patients is c.84dupG, which produces an early stop codon that produces the truncated and afunctional enzyme. In addition to Gaucher disease, c.84dupG can also occur in Parkinson's patients and some cases of dementia.
The c.1342G>C and c.1504C>T variants are common in Gaucher disease and patients with Ashkenazi Jewish ancestry.
It should be noted that the penetrance of the mutations is variable. There are cases of individuals who present the mutation in homozygosis and remain asymptomatic and others who develop the disease during old age. It should be noted that individuals can carry two pathogenic variants in GBA (compound heterozygosis) and develop the disease.
Gaucher disease genetic testing analyzes the 11 most frequent pathogenic mutations of the GBA1 gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
