Case Report of Multi-Generational GD Highlights Importance of Cascade Screening

Cascade screening — a systematic analysis performed in a family to identify the risk of any member developing a genetic disease — should be performed in families with a genetic predisposition to conditions such as Gaucher disease, a case report suggests.

The study, “Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening,” was published in Molecular Genetics and Metabolism Reports.

Gaucher disease is a genetic condition that affects 1 in 50,000 to 100,000 people in the general population, but its incidence is much higher (1 in 500-1,000) in people of Ashkenazi Jewish heritage.

The condition is caused by mutations in the GBA gene, which holds the instructions to produce the enzyme glucocerebrosidase. This enzyme breaks up a kind of lipid that accumulates in the cells of people with Gaucher disease, impairing the functions of various organs.

Symptoms include enlargement of the liver and spleen, anemia, easy bruising caused by a low level of platelets, bone pain, and fractures.

The most common type of Gaucher disease is type 1. This type does not affect the nervous system, but apart from that, the manifestations vary greatly from patient to patient.

Researchers reported the case of a 66-year-old woman, from a non-consanguineal Ashkenazi Jewish family, who developed colon cancer in her 50s.

The cancer was surgically removed, and doctors found Gaucher cells — cells that present increased lipid accumulation characteristic of Gaucher disease. The patient also had fragile bones and gallstones, but her symptoms had never been related to any genetic condition.

The patient had a normal-sized liver and spleen but presented involuntary movements in the neck. Testing for glucocerebrosidase showed reduced activity, and genetic analysis showed that she had a mutation in the GBA gene (N370S/N370S). This mutation is frequently found in the Ashkenazi Jewish population.

These results confirmed the diagnosis for type 1 Gaucher disease. Because the patient had only mild symptoms, she did not receive any treatment.

The patient’s father and one of her sons had colon cancer and were diagnosed with Gaucher disease in their 30s. The family had previously been tested for familial colon cancer markers, but the results were negative. However, they shared the same mutation in the GBA gene.

“Colon cancer is not a known comorbidity of [Gaucher disease]; interestingly, all three members with GD in our report had early-stage colon cancer that was cured following surgical resection,” the investigators said. “One may speculate a connection between GD and colon cancer in these three persons, who are the only ones in the [family] with GD and the only ones with colon cancer.”

Cases of multigenerational Gaucher disease are very uncommon because the probability of having two carriers in a non-consanguineous marriage is very low, and even between carriers there is only a 25 percent chance of having a child with the condition.

However, researchers concluded that “multi-generational disease should be suspected in founder populations, such as the Ashkenazi Jewish [even in non-consanguineous marriages], and cascade screening of family members offered irrespective of age or symptoms.”

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