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-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 -synthase deficiency but also in a variety of other conditions.2,4,5 Cystathionine -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 -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 -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{at}uchsc.edu
S. Harvey Mudd, M.D.
National Institute of Mental Health
Bethesda, MD 20892
Editor's note: The University of Colorado and Dr. Stabler hold patents on the use of homocysteine, cystathionine, and methylmalonic acid in the diagnosis of folate deficiency and vitamin B12 deficiency. A company has been formed at the University of Colorado to perform the assays. Dr. Stabler holds patents on combination vitamin treatment of homocysteine.
References
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{at}hkusua.hku.hk
References
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{at}mednet.ucla.edu
References
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