A case report about two sisters in Brazil with Gaucher type 1 disease (GD1) and severe bone disease represents a new genetic profile, researchers say.
Although the uncommon genetic alterations have been reported previously, researchers suggest these are the first known GD patients with this combination of two mutations.
Gaucher disease (GD) is caused by mutations in the GBA gene, which provides instructions for producing the enzyme beta-glucocerebrosidase. In people with GD, this enzyme is made incorrectly, leading to the accumulation of a lipid (fat), called glucocerebroside, in macrophage cells (cells specialized in the destruction of bacteria and other organisms).
Different GBA mutations partially explain the diverse clinical presentation of this disorder.
The report describes the case of two sisters from a family with no other neurological symptoms.
The first patient was 47 years old and had been diagnosed at age 42 with GD1. She was referred to the hospital for elevated levels of ferritin (an iron-binding blood protein), chronic lumbar pain, and nosebleeds. Confirming the diagnosis, laboratory tests revealed low beta-glucocerebrosidase activity, but higher-than-normal activity of chitotriosidase — a GD biomarker produced by activated macrophages.
The second patient (sister of the first patient) was 50 years old and had been diagnosed with GD type 1 at age 45. Three years before the first appointment, she had undergone a total hysterectomy for uncontrollable bleeding during surgery to remove uterine polyps.
This second patient also had low beta-glucocerebrosidase activity, elevated activity of chitotriosidase, and high levels of ferritin. She also revealed mild enlargement of liver and spleen, as well as fat accumulation.
Neither sibling had other relevant changes in blood parameters. However, both had high bone marrow burden (BMB) scores, an estimation of bone marrow involvement in GD, “which may imply a more severe bone phenotype,” the researchers wrote.
The first patient started treatment with Zavesca (miglustat), a substrate reduction therapy, (therapy that uses small molecules to restore metabolic homeostasis), and a low-carbohydrate diet. Due to persistent gastrointestinal problems, the treatment was switched to Elelyso (taliglucerase alfa), and then to Cerezyme (imiglucerase), resulting in lessening of her symptoms.
The second patient also was started on Zavesca and switched three years later to Elelyso. After two years, blood parameters improved and chitotriosidase activity decreased, although ferritin remained high and bone marrow infiltration was still severe.
Genetic screening revealed that both patients had the same disease-causing mutations: one copy of the GBA gene had the E349K mutation, and the other copy had the S366N mutation. (Each gene has two copies — one inherited from the mother and the other from the father.)
“Overall, the patients could be described as having predominantly severe bone disease and few, mild visceral [organ] and hematological [blood] manifestations,” they wrote. Still, further reports are needed to better assess whether the patients’ novel genetic profile is the cause of their bone disease.