Newborn Screening for α-Thalassemia — Keeping Up with Globalization — NEJM

Newborn Screening for α-Thalassemia — Keeping Up with Globalization
Edward J. Benz, Jr., M.D.

N Engl J Med 2011; 364:770-771
February 24, 2011


Thalassemias are inherited disorders of hemoglobin synthesis. In α-thalassemia, the biosynthesis of the α-globin subunit of adult hemoglobin, hemoglobin A, is deficient. In β-thalassemia, β-globin synthesis is diminished.1 Among the most common single-gene disorders in humans, thalassemias are a cause of substantial morbidity and mortality in Asia and the Mediterranean basin.2

Symptomatic thalassemia has historically been an uncommon illness in the United States. However, as Lal et al. report in this issue of the Journal, 3 a moderately severe symptomatic form of α-thalassemia, hemoglobin H (HbH) disease, is being encountered with increasing frequency as Asian migration increases to the West Coast of the United States. Moreover, a subtype of HbH disease, hemoglobin Constant Spring (HCS) disease, appears to account disproportionately for the burden of symptomatic disease. Their results highlight the dynamically changing effect of globalization on public health, as genetic disorders indigenous to specific populations become more common in the countries to which they migrate.

HbH disease arises by complex but clearly understood mechanisms. Since the human α-globin genes are duplicated, the normal diploid erythroblast expresses four functioning loci.3,4 In most patients with HbH disease, three of these four loci are deleted by mutation.4 Thus, only about 25% of the normal amount of hemoglobin A is produced, creating a hemoglobin deficit and microcytic anemia. β-Globin synthesis continues unabated, and the resultant unpaired β-globin chains aggregate to form homotetramers (β4) called HbH. HbH is useless for oxygen transport and biochemically unstable, precipitating both in erythroblasts during erythropoiesis and in circulating erythrocytes. This process causes impaired erythrocyte maturation (ineffective erythropoiesis) and a hemolytic anemia.

Less common nondeletional forms of HbH occur in which both α loci are deleted from one chromosome and the other chromosome contains one normally functioning allele and one severely hypofunctioning locus. The net effect is that only one fourth of loci are functioning adequately, as in the deletional form. In Asians, the most common of these nondeletional forms is HCS.4 The HCS allele, for complex molecular reasons, produces an unstable, structurally abnormal α chain that accumulates at only 1% the normal rate.3

The clinical severity of HbH disease is highly heterogeneous. Lal et al. make the important observation that in the United States, most but not all patients with severe early symptoms have HCS. They report that children with “classic” HbH disease generally had normal growth and development and infrequently required blood transfusion. In contrast, patients with HCS were more at risk for life-threatening anemia early in infancy.

These results make a strong case for newborn screening for α-thalassemia, at least in states with a substantial increase in their Asian populations. The gene frequency for these disorders is high (up to 25% in some subgroups), and the screening tests are both inexpensive and virtually 100% accurate. The clinical need for identifying patients at highest risk, notably those with HCS, is now well documented. Tighter surveillance of such children and early intervention for infection would clearly mitigate the need for the excessive use of transfusion and concomitant iron overload. In some of these children, the use of the appropriate hypertransfusion protocols with iron chelation might facilitate more normal growth and development. Through the identification of patients with HCS, the yield of cases in which detection would improve outcomes would be higher.

On a broader scale, these results point to the importance of agile real-time monitoring for both the natural history and incidence of inherited conditions that are indigenous to populations whose migration to the United States is altering our demographics. Similarly, the strategic methods of newborn screening must be constantly updated to account for dynamic changes in populations at risk. As is true for HCS, affordable laboratory methods for more precisely subtyping many genetic disorders are becoming more widely available. As the methods for identifying at-risk subgroups improve, screening becomes an increasingly efficient tool for personalized preventive medicine.

Natural history studies, such as the report by Lal et al., form an important part of the knowledge base needed by policymakers to update and optimize the use of resources for newborn screening. As the implementation and funding of health reform moves forward at both national and state levels, attention must be paid to adequate funding support for such studies, since they are not easily funded by traditional means. Yet, the yield both for quality of life and for avoidance of the need for high-cost care makes prenatal screening an outstanding investment in the nation's health.



full-text:
Newborn Screening for α-Thalassemia — Keeping Up with Globalization — NEJM