Correspondence

Population Screening

N Engl J Med 2003; 348:1604-1605April 17, 2003

Article

To the Editor:

In their review article, Khoury et al. (Jan. 2 issue)1 suggest that homocystinuria should be screened for by Guthrie bacterial inhibition assay and treated with vitamin B₁₂ and methionine restriction. Homocystinuria occurs in several conditions, including cystathionine β-synthase deficiency and genetic disorders of homocysteine remethylation.2,3 Plasma total homocysteine levels may also be elevated because of folate deficiency or vitamin B₁₂ deficiency.2 The Guthrie test, designed to detect hypermethioninemia, fails to detect abnormalities of homocysteine remethylation. Hypermethioninemia occurs not only in cystathionine β-synthase deficiency but also in a variety of other conditions.2,4,5 Cystathionine β-synthase deficiency is readily differentiated from other disorders, since either plasma cystathionine will not be detected at all or the level will be very low in patients with this deficiency, whereas the level will be normal or elevated in patients with other conditions causing elevated methionine or total homocysteine levels.5

Methionine restriction may be therapeutic in cystathionine β-synthase deficiency but not in the latter conditions. Patients with such a deficiency may have a response to vitamin B₆. Methionine restriction and betaine are used in patients without a response to vitamin B₆. Vitamin B₁₂ and folate are sometimes used as adjuvant therapy.2 Vitamin B₁₂ is specifically indicated for disorders affecting methylcobalamin synthesis.3 Diagnosis and treatment of cystathionine β-synthase deficiency and errors affecting the homocysteine remethylation may prevent mental retardation and thromboembolic episodes. We recommend that disorders of methionine and homocysteine metabolism be classified according to the specific causative deficiency of enzyme activity or vitamin and that concurrent assays of plasma total homocysteine, cystathionine, and methionine be performed. Methylmalonate should be measured if disorders related to cobalamin are suspected. Assays of plasma S-adenosylmethionine and sarcosine can be performed for the rarer inborn errors.

Sally P. Stabler, M.D.
University of Colorado Health Sciences Center, Denver, CO 80262
sally.stabler@uchsc.edu

S. Harvey Mudd, M.D.
National Institute of Mental Health, Bethesda, MD 20892

5 References

1. 1

   Khoury MJ, McCabe LL, McCabe ERB. Population screening in the age of genomic medicine. N Engl J Med 2003;348:50-58
   Full Text | Web of Science | Medline

2. 2

   Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 2. New York: McGraw-Hill, 2001:2007-56.
   

3. 3

   Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill, 2001:3897-933.
   

4. 4

   Mudd SH, Cerone R, Schiaffino MC, et al. Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J Inherit Metab Dis 2001;24:448-464
   CrossRef | Web of Science | Medline

5. 5

   Stabler SP, Steegborn C, Wahl MC, et al. Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Metabolism 2002;51:981-988
   CrossRef | Web of Science | Medline

To the Editor:

The article by Khoury et al. missed several important points. The first principle set forth by Wilson and Jungner1 mandates that screening should be undertaken only for health problems that are important in terms of both the severity of disease and its frequency at the level of public health. Most monogenic disorders do not qualify in terms of frequency.

Fear of disease by laypersons, a defensive medicolegal culture, and a weakly regulated marketplace mean that purveyors of “at risk” testing will proliferate, resulting in unforeseen social and psychological harms. Once genetic variants are identified, what then?

Correctly recognizing that tandem mass spectrometry identifies many conditions for which no treatment, clear understanding of appropriate management, or preventive strategies exists, the authors justify this technique on the basis that it can help to eliminate the need for “diagnostic odysseys” if low-probability health problems emerge. They fail to mention that tandem mass spectrometry and similar methods for mass genetic screening almost guarantee an epidemic of therapeutic odysseys, as anxious parents seek multiple treatments for diseases that may never become symptomatic. We should not allow the potential hazards and costs of genetic screening to remain as underemphasized as they were in the article by Khoury et al.

Richard Fielding, Ph.D.
Wendy Lam, Ph.D.
Gabriel M. Leung, Ph.D.
University of Hong Kong, Hong Kong, China
fielding@hkusua.hku.hk

1 References

1. 1

   Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Pap 1968;34:11-163
   

Author/Editor Response

We agree with Stabler and Mudd that the screening of newborns for hypermethioninemia will identify only a subgroup of patients with homocystinuria and will identify patients who have hypermethioninemia for other reasons, including liver disease. The challenge for those desiring more comprehensive ascertainment of inborn errors of metabolism is to develop technological approaches that will be able to accommodate high sample throughput in a cost-effective manner.1,2 The application of tandem mass spectrometry to the screening of newborns offers detection to a much larger group of infants with specific inborn errors of metabolism than was previously possible.

Fielding et al. raise important issues regarding the selection of diseases for population-based screening. All 50 states and the District of Columbia have determined that newborn screening programs represent an important investment for the prevention of death and disability.3 These are decisions that must be made openly, with full representation of professionals and the public. The costs of investment in new technologies such as tandem mass spectrometry must be considered carefully.

Population screening requires assessment of the goals for the program and ongoing evaluation to ensure that its goals are being achieved. We appreciate the opportunity to expand the dialogue about screening.

Muin J. Khoury, M.D., Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333

Linda L. McCabe, Ph.D.
Edward R.B. McCabe, M.D., Ph.D.
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752
emccabe@mednet.ucla.edu

3 References

1. 1

   McCabe LL, McCabe ERB. Newborn screening as a model for population screening. Mol Genet Metab 2002;75:299-307
   CrossRef | Web of Science | Medline

2. 2

   McCabe LL, Therrell BL, McCabe ERB. Newborn screening: rationale for a comprehensive fully integrated public health system. Mol Genet Metab 2002;77:267-273
   CrossRef | Web of Science | Medline

3. 3

   Serving the family from birth to the medical home: newborn screening: a blueprint for the future -- a call for a national agenda on state newborn screening programs. Pediatrics 2000;106:389-422
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Ephrat Levy-Lahad. (2009) Population-based BRCA1/BRCA2 screening in Ashkenazi Jews: A call for evidence. Genetics in Medicine 11:9, 620-621
   CrossRef