Summary
The discriminatory power of a quantitative heterozygote test for Maple Syrup Urine Disease (MSUD) which we have been using is analyzed on the presumption that a single rare mutant allele is involved in MSUD. Bayes theorem then predicts that only a small portion of persons from the general population with activities in the heterozygous range really are heterozygotes.
In addition, overlap of heterozygous and normal homozygous activity distributions requires rather high activities in first-cousin matings of a patient's sib in order to obviate the necessity for prenatal diagnosis.
Thus, the principle emerges that quantitative heterozygote tests for rare autosomal recessive diseases cannot fulfill the task they were designed for.
Zusammenfassung
In der vorliegenden Arbeit wird der Wert eines quantitativen Heterozygotentestes für Ahornsirupkrankheit, wie wir ihn in den vergangenen Jahren ausgeführt haben, für die genetische Beratung kritisch analysiert.
Unter der Annahme, daß nur ein einziges, sehr seltenes abnormes Allel im homozygoten Zustand zur Ahornisirupkrankheit führt, kann durch Anwendung von Bayes' Theorem vorausgesagt werden, daß nur ein geringer Teil der Personen ohne Angehörige mit Ahornsirupkrankheit, die eine Aktivität im heterozygoten Bereich haben, wirklich Heterozygote sind.
Außerdem muß wegen des Überlappens der Aktivitätsverteilungen von Normalen und Heterozygoten der Partner in einer Vetter-Basen-Ehe eines Patienten-Geschwisters vergleichsweise hohe Enzymaktivitäten haben, damit eine pränatale Diagnose unnötig wird.
Prinzipiell sind also quantitative Heterozygotenteste für die genetische Beratung bei seltenen autosomal-recessiven Krankheiten nur von beschränktem Wert.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bayes, T.: An essay towards solving a problem in the doctrine of chances. Philos. Trans. 53, 376–418 (1763)
Dorfman, A. (ed.): Antenatal diagnosis. Chicago-London: University of Chicago Press 1972
Emery, A. E. H., Morton, R.: Genetic counseling in lethal X-linked disorders. Acta genet. (Basel) 18, 534–542 (1968)
Goedde, H. W., Richter, E., Hüfner, M., Sixel, B.: Arbeitsvorschrift eines vereinfachten Heterozygotentests für die Ahornsirupkrankheit. Klin. Wschr. 42, 818–819 (1964)
Gold, R. J. M., Maag, U. R., Neal, J. L., Scriver, C. R.: The use of biochemical data in screening for mutant alleles and in genetic counseling. Ann. hum. Genet. 37, 315–326 (1974)
Kaback, M. M.: Tay-Sachs disease: A model for prevention of genetic disease. 4th Int. Conf. Birth Def.; Excerpta Medica Int. Congr. Ser. (Amsterdam) No. 297, 13–14 (1973)
Kaback, M. M., Zeiger, R. S.: Heterozygote detection for Tay-Sachs disease (TSD) in a sample American-Jewish population. Pediat. Res. 6, 362 (1972)
Kirkman, H. N.: Enzyme defects. In: Progress in medical genetics (eds.) A. G. Steinberg and A. G. Bearn, Vol. 8, pp. 125–168. New York-London: Grune & Stratton 1972
Kueppers, F.: Identification of the heterozygous state for the α1 antitrypsin deficiency gene in man. Biochem. Genet. 3, 283–288 (1969)
Langenbeck, U., Rüdiger, H. W., Schulze-Schenking, M., Keller, W., Brackertz, D., Goedde, H. W.: Evaluation of a heterozygote test for maple syrup urine disease in leucocytes and cultured fibroblasts. Humangenetik 11, 304–315 (1971)
Menkes, J. H., Hurst, P. L., Craig, J. M.: New syndrome: Progressive familial infantile cerebral dysfunction associated with unusual urinary substance. Pediatrics 14, 462–466 (1954)
Milunsky, A.: The prenatal diagnosis of hereditary disorders. Springfield (Ill.): Thomas 1973
Modiano, G., Scozzari, R., Gigliani, F., Santolamazza, C., Spennati, G. F., Saini, P.: Enzyme activity in two red cell adenylate kinase phenotypes. Amer. J. hum. Genet. 22, 292–297 (1970)
Murphy, E. A., Mutalik, G. S.: The application of Bayesian methods in genetic counseling. Hum. Hered. 19, 126–151 (1969)
Nicholis, E. M., Stark, A. E.: Bayes' theorem. Med. J. Aust. 2, 1335–1339 (1971)
Rüdiger, H. W., Langenbeck, U., Goedde, H. W.: A simplified method for the preparation of 14C-labelled branched-chain α-oxo acids. Biochem. J. 126, 445–446 (1972)
Sachs, L.: Statistische Auswertungsmethoden, 3. Aufl. Berlin-Heidelberg-New York: Springer 1972
Srivastava, S. K., Beutler, E.: Studies on human β-D-N-acetylhexosaminidases. III. Biochemical genetics of Tay-Sachs and Sandhoff's disease. J. biol. Chem. 249, 2054–2057 (1974)
Veltkamp, J. J., Drion, E. F., Loeliger, E. A.: Detection of the carrier state in hereditary coagulation disorders. II. Thrombos. Diathes. haemorrh. (Stuttg.) 19, 403–422 (1968)
Wendel, U., Rüdiger, H. W., Passarge, E., Mikkelsen, M.: Maple syrup urine disease: Rapid prenatal diagnosis by enzyme assay. Humangenetik 19, 127–128 (1973)
Westwood, A., Raine, D. N.: Some problems of heterozygote recognition in inherited metabolic disease with special reference to phenylketonuria. In: Treatment of inborn errors of metabolism. S.S.I.E.M. Symp. No. 10 (eds. J. W. T. Seakins, R. A. Saunders and C. Toothill), pp. 63–76. Edinburgh-London: Livingstone 1973
Author information
Authors and Affiliations
Additional information
This investigation was in part supported by grants from the Deutsche Forschungsgemeinschaft.
Rights and permissions
About this article
Cite this article
Langenbeck, U., Grimm, T., Rüdiger, H.W. et al. Heterozygote tests and genetic counseling in Maple Syrup Urine Disease. Hum Genet 27, 315–322 (1975). https://doi.org/10.1007/BF00278424
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00278424