6 new GBA1 mutations tied to Gaucher type 1: Case series
Discovery of new variants may aid diagnosis, researchers say
Researchers identified six previously unknown mutations in the GBA1 gene linked to Gaucher disease, according to a case series report.
All clinical signs and symptoms associated with these new mutations were consistent with a diagnosis of Gaucher disease type 1, the most common type of the condition, characterized by the absence of neurological symptoms.
“The identification of new mutations in patients with symptoms referable to Gaucher disease increases the molecular knowledge related to the GBA1 gene and offers to clinicians significant support for the accurate diagnosis of the [disease],” the researchers wrote.
Case series details were published in the International Journal of Molecular Sciences in the study, “Identification of Novel Mutations in Patients Affected by Gaucher Disease.”
Gaucher disease is caused by mutations in both copies of the GBA1 gene, one inherited from each biological parent. Such mutations disrupt the production and/or function of glucocerebrosidase (GCase), an enzyme that helps break down certain fatty molecules inside cells. The resulting lack of GCase activity leads to the buildup of those molecules, giving rise to tissue and organ damage and the onset of Gaucher disease symptoms.
Gaucher types and symptom severity
The condition is divided into three types based on the presence and severity of neurological symptoms. Gaucher disease type 1, the most common form, does not cause neurological symptoms, while type 2 is marked by severe, early-onset neurological symptoms. People with type 3 have milder and gradually progressive neurological symptoms.
More than 700 mutations have been linked to Gaucher. Still, predicting the disease type or how it will progress based solely on the genetic mutations remains challenging because there’s no apparent connection between GCase activity and disease severity or type. Patients with the same mutations can experience widely different symptoms.
“The discovery of new genetic variants is essential to expand the database of known mutations and improve genetic diagnosis,” wrote researchers who described, for the first time, six new Gaucher-causing mutations in the GBA1 gene.
The first case was a 55-year-old man with symptoms including an enlarged liver, bone fragility, low levels of red blood cells (anemia), swollen lymph nodes, and elevated levels of iron-storage protein ferritin. He also had motor symptoms similar to those seen in people with Parkinson’s disease.
Lab tests revealed relatively low levels of GCase activity and high levels of lyso-Gb1, a marker for GCase deficiency. Genetic analysis showed two different GBA1 mutations: c.1093 G>A, which has been associated with Gaucher, and c.1142 G>T, a new mutation. The researchers noted that the new mutation was located in the same gene position as a mutation called c.1141 T>G, which is linked with severe Gaucher.
Treatment with Cerezyme (imiglucerase), a GCase enzyme replacement therapy, reduced liver volume, eased Parkinson’s symptoms, lowered ferritin levels, and generally normalized blood tests. However, lyso-Gb1 remained above the normal range over two years of treatment. Further genetic testing of the patient’s mother and daughter, who showed no symptoms of Gaucher, revealed only the newly identified c.1142G>T mutation. This finding confirms that the patient inherited this mutation from his mother and the known c.1093G>A mutation from his father.
In the second case, a 1-year-old boy with an enlarged spleen and low platelet counts was investigated for Gaucher. Blood tests revealed a markedly low level of GCase activity. Genetic tests detected a common Gaucher mutation, c.1226 A>G, and a second previously unknown mutation, c.955 A>C. No treatment information was reported.
The child’s father, who showed cognitive and growth delays and low platelet counts, had no GCase activity and carried the same two mutations. His asymptomatic mother had normal GCase activity but also carried the c.1226 A>G mutation.
The third case was an 11-year-old girl with multiple signs of Gaucher, including an enlarged liver and spleen, anemia, and low platelet and white blood cell counts. She had also undergone liver transplantation due to cholestasis, a condition marked by the slowing or stalling of bile, a digestive fluid. Tests revealed low GCase activity and high lyso-Gb1. Genetic analysis then detected a known mutation called c.1226 A>G and a new mutation called c.857 A>G. Treatment information was not provided.
Case 4 was a 45-year-old man with an enlarged spleen, bone fragility, anemia, low platelet counts, and high ferritin. Consistent with Gaucher, his GCase activity levels were low and his lyso-Gb1 levels were high. The common c.1226 A>G mutation was detected alongside a new mutation called c.1578_1581dup, which leads to a shortened version of GCase. Cerezyme therapy normalized most blood tests and reduced spleen volume and ferritin levels. While his lyso-Gb1 levels dropped, they remained markedly above the normal range.
In the fifth case, a 17-year-old girl examined for Gaucher had typical symptoms such as enlarged spleen and liver, anemia, low white blood cell counts, low GCase, and high lyso-Gb1. The known c.1226 A>G mutation was revealed, plus a second new mutation called c.1308dup. No treatment information was provided.
The sixth case was a 44-year-old man with anemia, high ferritin, low platelets, bone fragility, reduced GCase, and high lyso-Gb1. The known mutation, c.1226 A>G, was identified with c.1593 C>A, an unknown mutation. Two years of Cerezyme therapy normalized lyso-Gb1 levels and improved blood tests and clinical signs.
“The patients examined had several clinical manifestations, which included [enlarged liver/spleen] and bone and [blood] involvement,” the researchers wrote, and “considering the absence of enzyme activity, this suggests that the new mutations described here are associated with type I Gaucher disease.”
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