Researchers have found two new mutations associated with Gaucher disease type 1 (GD1) in four Indian adults. The researchers also reported, for the first time, the estimated carrier frequency of the most common Gaucher-causative mutation in the general Indian population.
The study, “Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro — a common Gaucher disease mutation in India,” was published in BMC Medical Genetics.
Gaucher disease is caused by mutations in the GBA1 gene, leading to the production of a glucocerebrosidase enzyme with abnormal and unstable 3D structures — called a misfolded enzyme — and reduced activity.
As a result, there is an accumulation of specific fat molecules in different tissues, mainly in macrophages (a type of white blood cell), which transform into so-called “Gaucher cells.” These cells accumulate at sites including the spleen, liver, or bone marrow, leading to a variety of symptoms.
This diverse clinical presentation, when manifested in adulthood, may result in misdiagnosis or late diagnosis of Gaucher disease.
GD1, which accounts for 94% of all Gaucher patients, may cause an enlarged spleen and liver, low platelet levels, anemia (low levels of red blood cells or hemoglobin), and bone disease.
Gaucher disease is often inherited in an autosomal recessive manner, meaning a child must acquire two defective copies of that gene — one from the father and one from the mother — to develop the disease. While people with only one mutated copy of the gene do not develop the disease, they can still transmit the mutated gene to their children and are called carriers.
In India, endogamous marriage — marriage within a specific social group, caste or ethnic group — has increased the frequency of several autosomal recessive diseases, including Gaucher disease, within communities. Therefore, it is important to assess carrier frequency in this population and refer for genetic counseling those carriers who are planning families.
While previous studies have shown that Leu444Pro is the most common Gaucher disease-causative mutation in India, its carrier frequency in this population remains undetermined. Also, few cases of adult GD1 have been identified in the country.
Researchers in India have now reported the clinical and genetic data of seven patients with GD1 manifested in adulthood, and determined the Leu444Pro carrier frequency in a sample of the general Indian population.
These seven unrelated GD1 patients (four women and three men), ages 20-40, were referred between 2012 and 2016 with a clinical suspicion of adult Gaucher disease. All had an enlarged spleen, four showed anemia, low platelet levels, and/or the presence of Gaucher cells in the bone marrow, and three had an enlarged liver.
Genetic analysis revealed the presence of two new mutations (Ala448Thr and Val17Gly) associated with GD1. Structural analysis showed that both mutations resulted in a misfolded glucocerebrosidase enzyme and were thus disease causative.
Three patients carried the Ala448Thr mutation, while Val17Gly mutation was found in only one patient. None of the four patients showed bone damage at this stage, suggesting that these mutations may be associated with GD1 without bone involvement.
The researchers say these findings support the need to suspect Gaucher disease in adults with unexplained anemia, enlarged spleen or liver, and/or low levels of platelets.
Next, the team analyzed the presence of Leu444Pro mutation in one GBA gene copy in 1,200 healthy unrelated people with no history of Gaucher disease in the family, from five regions of India.
The results showed that two were Leu444Pro carriers, suggesting that the carrier frequency of Leu444Pro mutation in India is 1 in 600 people.
The team noted that in areas where endogamous marriage is more common, the carrier frequency is likely to be higher, and that pre-marital counseling, especially in communities that practice endogamous marriage, may reduce the frequency of Gaucher disease in the Indian population.