Genetic Screening Questioned for Gaucher Disease

JERUSALEM, Sept. 19 -- A broad screening program to identify carriers of Gaucher Disease among Asheknazi Jews may not meet intended goals, Israeli researchers reported.

The aim of carrier screening is to prevent severe, untreatable genetic disease by identifying couples at risk before the birth of an affected child, according to Ephrat Levy-Lahad, M.D., of Hebrew University here, and colleagues.

Yet, they noted in the Sept. 19 issue of the Journal of the American Medical Association, screening for Gaucher disease an autosomal recessive storage disorder seen with relative frequency among Ashkenazi Jews, is controversial because common type 1 Gaucher is a low-penetrance disease, effective treatment exists, and the test does not fully predict disease severity.

Nevertheless, the researchers said, screening is offered to Ashkenazi Jews worldwide and has been offered in Israel since 1995 and in New York since 1994.

The most common Gaucher mutation in Ashkenazi Jews, N370S, leads to type 1 disease with an extremely variable phenotype, from symptomatic disease in early childhood to asymptomatic status throughout life. Estimates suggest that up to 90% of N370S homozygotes are mildly symptomatic or even asymptomatic.

To examine the outcomes of a nationwide Gaucher screening program, the Israeli researchers collected data from January 1, 1995 through March 31, 2003 provided by 10 Israeli genetic centers.

Carrier couples were interviewed by phone from January 21, 2003 through August 31, 2004, using a structured questionnaire for relevant outcome measures.

From January 1995 through March 2003, 10 of 12 Israeli genetic centers offered carrier screening. Carrier frequency was 5.7%, and 83 carrier couples were identified among an estimated 28,893 individuals screened.

There were 82 couples at risk for offspring with type 1Gaucher disease, including 70 (85%) at risk for asymptomatic or mildly affected offspring and 12 (15%) at risk for moderately affected offspring.

At postscreening, 65 interviewed couples reported 90 singleton pregnancies and, after prenatal diagnosis in 68 pregnancies, 16 fetuses (24%) were detected with Gaucher disease.

Only one couple was found at risk for severe type 2/3 disease, which is too rare to justify screening, the researchers said.

Pregnancies were terminated for two of 13 fetuses (15%) predicted to be asymptomatic or mildly affected and two of three fetuses (67%) with predicted moderate disease.

There were significantly fewer terminations among couples who had medical counseling (including a discussion of enzyme replacement therapy) with a Gaucher disease expert in addition to genetic counseling (one of 13 [8%] versus three of three with no medical counseling, P=0.007).

The main practical outcome of screening was a 66% reduction in birth prevalence for moderate type 1Gaucher disease, for which the estimated frequency is one in 27,000, and a 15% reduction in the birth prevalence of asymptomatic or mild type 1 disease, for which the estimated frequency is one in 1,300.

This was achieved through termination of pregnancy for fetuses either treatable or likely to be asymptomatic, and it is debatable whether this represents a true benefit, Dr. Levy-Lahad said.

However, factors favoring screening in Gaucher disease should be recognized, the researchers said. These include consumer-related competition between institutions, fear of litigation, and a real concern that severity cannot be absolutely defined.

The main possible benefit of screening is allowing couples at risk to be identified and to make an informed choice, the researchers said.

Applying the classic carrier-screening paradigm to common, low-penetrance disease leads to inevitable dilemmas, and programs offering such screening should determine whether the true goal is knowledge and presymptomatic risk assessment or pregnancy termination of fetuses with a specified genetic status, Dr. Levy-Lahad said.

The study suggests that to avoid pregnancy termination for generally mild conditions, screening programs would require a combination of traditional, nondirective genetic counseling with medical counseling by professionals familiar with the specific disease, he concluded.

In an accompanying editorial, Ernest Beutler, M.D., of the Scripps Research Institute in La Jolla, Calif., wrote that attempting to analyze the costs and benefits of a screening program for Gaucher disease is much more complex than doing so for severe high-penetrance disorders.

What is the price for the anguish of parents of a fetus diagnosed as homozygous for the N370S genotype? To what extent will the pychological development for the child be impaired? Will his parents overprotect him? How many millions of dollars will be spent on unnecessary enzyme replacement therapy for children who will never develop clinical disease?

The study authors point out that the Israeli Medical Geneticists' Association has recommended against Gaucher disease screening, yet it appears that this recommendation has not had much effect in Israel, Dr. Beutler said

"Not until clinicians and researchers better understand the factors that determine whether a patient homozygous for the N370S mutation will develop severe disease or none at all will screening for Gaucher disease become useful. Until then," Dr. Beutler wrote, "screening for Gaucher disease will likely do more harm than good."

Co-author Ari Zimran, M.D., reported receiving consulting fees from Shire Human Genetic Therapeutics and Protalix Biopharmaceutics, receiving a grant from Genzyme Corporation for participation in the International Gaucher Registry, and receiving honoraria from Genzyme Corporation and Actelion. He also reported holding Protalix Biopharmaceutics stock options.

None of the other authors reported financial conflicts.

Dr. Beutler, the editorial author, reported that he holds patents that enable screening for Gaucher disease and has a paid position on the scientific advisory board for Protalix Bio-Therapeutics, which manufactures a treatment for Gaucher disease.

This work was supported by the Stein Endowment Fund.