Carrier Screening for Gaucher Disease

Abstract

IT WAS A WARM SUMMER DAY MORE THAN 30 YEARS AGO when my laboratory assistant and collaborator, Wanda Kuhl, showed me some unusual results. Our laboratory had devised a facile method for measuring white blood cell glucocerebrosidase activity and was performing family studies to determine the efficiency of this technique for the detection of heterozygotes for Gaucher disease. But here was a sample from an obligate heterozygote, the mother of a patient with Gaucher disease, in which the range of enzyme activity was as low as in the patient. Bone marrow examination in this 72-year-old asymptomatic parent confirmed that she also had Gaucher disease. Discovery of Gaucher disease in an older, asymptomatic individual was by no means unique—the disease had previously been detected in such persons, including one person who was aged 86 years. However, many persons homozygous for the N370S mutation associated with Gaucher disease are never diagnosed; based on the discrepancy between the heterozygote frequency and the number of patients diagnosed, an estimated 60% of such homozygous patients may go undiagnosed. Herein lies the dilemma faced by Zuckerman and colleagues in their evaluation of prenatal screening for Gaucher disease reported in this issue of JAMA. Among an estimated 28 893 individuals screened at Israeli genetic centers, 82 couples were at risk for offspring with type 1 Gaucher disease, including 70 (85%) at risk for asymptomatic or mildly affected offspring and 12 (15%) at risk for moderately affected offspring. Following prenatal diagnosis in 68 pregnancies, 16 fetuses with Gaucher disease were detected. Of these pregnancies, 2 of 13 (15%) involving N370S homozygote fetuses and 2 of 3 (67%) involving compound heterozygote fetuses were terminated. Had the mother of my patient with Gaucher disease been conceived in Israel in this century, rather than in the early 1900s, she might never have been born. Her parents would have been informed that the fetus carried by the mother had Gaucher disease, and they might have elected to terminate the pregnancy. The clinical expression of Gaucher disease, like that of virtually all single-gene diseases, varies enormously. Physicians remember their patients with severe clinical manifestations—the patients who seek care. Often forgotten are those patients never diagnosed because they have no symptoms of the disorder. In the majority of single-gene genetic diseases, clinicians and genetics researchers have no clue as to the cause of the phenotypic variability, and therefore have no means by which to inform prospective parents whether their child will be severely affected by the disease or will have an asymptomatic life. Screening of newborns began more than 45 years ago with the introduction of the microbial inhibition test for phenylalanine for detecting possible phenyketonuria. Providing children with a phenylalanine-free diet in a timely fashion greatly ameliorated the mental retardation that is the clinical hallmark of phenylketonuria. This was soon followed by screening of newborns for galactosemia, allowing early treatment and prevention of the high incidence of neonatal mortality of infants with galactosemia. Before implementation of screening, infants who survived because they were treated were usually treated too late to avert the development of cataracts, cirrhosis, and mental retardation. Subsequently another approach to screening was introduced, the examination of parents for the carrier state, such as for Tay-Sachs disease, giving them the option after prenatal diagnosis to terminate a pregnancy. Although there is phenotypic variation in these severe genetic diseases, it is from bad to worse, rather than from bad to normal as with Gaucher disease. For example, galactosemia and phenylketonuria in adults who have never been treated are rare and are associated with mental retardation. Tay-Sachs disease, once known by the grim name of “amaurotic family idiocy,” is currently untreatable and leads to death after the first few years of life. Even these relatively straightforward screening programs have not been without some difficulties. One problem came to light with the discovery that some normal adults lacked serum hexosaminidase activity. Although this phenotype was rare, had these individuals been detected during fetal life as a con-