Letters to the Editor
1342
1992). This unstable DNA sequence shows expansion in successive generations and provides, for the first time, a molecular basis for the differences in severity between the generations with DM as well as for the more general problem of anticipation. Studies in the future must systematically investigate the factors that effect the expansion of the DNA sequence in the offspring of affected females and might resolve the currently not-well-understood clinical observations about congenitally affected children and their DM mothers. MANUELA C. KOCH,* TIEMO GRIMMT HELEN G. HARLEY,$ AND PETER S. HARPER$ :.Institut fur Humangenetik, Universitat Marburg, Marburg; tInstitut fur Humangenetik, Universitit Wfirzburg, Wiirzburg; and lInstitute of Medical Genetics, University of Wales College of Medicine, Cardiff References Goodship J, Gibson DE, Burn J, Honeyman J, Cubey BB, Schofield I (1992) Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 50:1340-1341 Green JR, Grennan DM (1991) Testing for haplotype sharing by siblings with incomplete information of parental haplotypes. Ann Hum Genet 55:243-249 Harley HG, Brook JD, Rundle SA, Crow S, Reardon W, Buckler AJ, Harper PS, et al (1992) Expansion of an unstable DNA region and phenotype variation in myotonic dystrophy. Nature 355:545-546 Howeler CJ, Bush HTM (1990) An asymptomatic mother of children with congenital myotonic dystrophy. J Neurol Sci 98 [Suppl]: 197 Koch MC, Grimm T, Harley HG, Harper PS (1991) Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 48:1084-1091 Sandkuyl L, Ott J (1989) Determining informativity of marker typing for genetic counseling in a pedigree. Hum Genet 82:159-162 Ott J, Caesar K, Machler M, Schinzel A, Schmid W (1990) Presymptomatic exclusion of myotonic dystrophy in a one-generation pedigree of half-siblings. Hum Hered 40: 305-307 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0026$02.00
Am. J. Hum. Genet. 50:1342, 1992
Maternal Age, Somatic Mosaicism, and Alzheimer Disease To the Editor:
The article by Dr. Huntington Potter amplifies, in a very interesting way, the notion that Alzheimer disease (AD) may result from somatic mosaicism of chromosome 21 (Potter 1991). Potter, however, does not mention that evidence for and against this idea can be obtained by examining maternal age in AD. If maternal age is raised in AD, this would make the somatic mosaicism hypothesis less tenable-a conclusion arrived at as follows: It has been proposed that there are three main mechanisms whereby mosaicism in Down syndrome (DS) might occur (Sachs 1971). In the first, a trisomy 21 zygote caused by nondisjunction in the mother later loses the extra chromosome by anaphase lagging in some of the resultant somatic cell lines. In the second, a normal zygote undergoes nondisjunction followed by later anaphase lagging; and, in the third, a normal zygote undergoes nondisjunction at a later division, producing trisomic cell lines in addition to the existing normal cell lines. This third scheme is the one Potter proposes for AD. Sachs studied the maternal ages of his 10 mosaic DS cases and found that they were no different than maternal ages of DS controls (translocation patients were excluded). Maternal ages in both groups were significantly higher than those of a normal population matched for year of birth. From this, albeit a small sample, he concluded that mosaicism in DS arises from a trisomy 21 zygote, the first of the three mechanisms he had noted. If one accepts the view that, in DS, higher maternal age is causally related to the occurrence of meiotic nondisjunction only, then it would follow that, if AD-or some forms of it-originates from somatic cell mosaicism, then, unlike in DS, a maternal age effect would not be anticipated. What then is the evidence from maternal age studies in AD? The balance of the evidence to date is in line with the occurrence of somatic cell mosaicism in AD; that is, a maternal age effect is not confirmed (De Braekeleer et al. 1988). It should be noted, however, that many of the 15 or so studies of maternal age contain serious methodological problems. Should it be shown that, in fact, maternal age in AD is raised, then this would be evidence against the somatic mosaicism hypothesis in AD; mosaicism aris-
Letters to the Editor
ing from a trisomic zygote would not seem likely, since it might be expected that the phenotype of the affected individual would be likely to contain many of the features of DS. In light of the potential importance of the above issues, there would seem to be a good case for conducting further studies of maternal age effects in AD and mosaic DS. ROGER HOWELLS Section of Neuropsychiatry Institute of Psychiatry London References De Braekeleer M, Froda S, Tetreault H, Gauvreau D (1988) Parental age and birth order in Alzheimer's disease: a case-control study in the Saguenay-Lac-St-Jean area (Quebec, Canada). Can J Neurol Sci 15:139-141 Potter H (1991) Alzheimer disease and Down syndromechromosome 21 nondisjunction may underlie both disorders. Am J Hum Gen 48:1192-1200 Sachs ES (1971) Trisomy G/normal mosaicism, a cytological and clinical investigation. Stenfert Kroese, Leiden o 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0027$02.00
Am. J. Hum. Genet. 50:1343, 1992
Reply to Howells To the Editor:
Dr. Howells, in his letter to the editor of The American Journal of Human Genetics, raises the very interesting point that, if Alzheimer disease originates from somatic cell mosaicism for trisomy 21, then a maternal age effect similar to that seen for Down syndrome should not occur. The possible influence of parental age on the development of Alzheimer disease has been most recently investigated by Farrer et al. (1991). In this careful study, a total of 237 patients with Alzheimer disease were each matched with five control subjects on the basis of sex, year of birth, survival age, and location of residence. No significant effect of advanced maternal age on the risk for Alzheimer disease was found. However, decreased paternal age increased somewhat the susceptibility to late-onset Alzheimer disease. Dr. Farrer and his colleagues suggest that the results might be explained by genetic im-
1343
printing, but they point out that social or environmental influences are hard to rule out. HUNTINGTON POTTER AND LISA N. GELLER Department of Neurobiology
Harvard Medical School Boston Reference Farrer LA, Cupples LA, Connor L, Wolf PA, Growden JH (1991) Association of decreased paternal age and lateonset Alzheimer's disease: an example of genetic imprinting? Arch Neurol 48:599-604 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0028$02.00
Am. J. Hum. Genet. 50:1343-1348, 1992
Ataxia-Telangiectasia: Linkage Evidence for Genetic Heterogeneity To the Editor:
The recent paper by Foroud et al. (1991) investigates genetic linkage between the recessive disease ataxiatelangiectasia (AT) and a number of chromosome 11 q markers. While the evidence for linkage to 1 1q23 markers displayed by the 111 families in this international study is overwhelming, a cautious interpretation as to the exact location of the AT gene or genes is warranted because of the existence of complementation groups in AT. Three complementation groupsA, C, and D-make up 55 %, 28%, and 14%, respectively, of tested patients (Jaspers et al. 1988). Other, less common complementation groups account for the remaining 3 % of affecteds. Sufficiently many group A and group C families are known that group A and group C genes can be confidently localized to the 11q23 region (Gatti et al. 1988; Ziv et al. 1991). Furthermore, the radiosensitivity of a group D fibroblast line has been corrected by introducing a normal chromosome 11 (Komatsu et al. 1990) and an 11q fragment (Ejima et al. 1990) into these cells. Recently, Kapp et al. (1991, 1992), who have reported cloning of a putative group D gene that maps, by means of radiation hybrids, to the region between markers THY1 and D11S83. This position, although still within the 11q23 region, is more distal than the
1342
1992). This unstable DNA sequence shows expansion in successive generations and provides, for the first time, a molecular basis for the differences in severity between the generations with DM as well as for the more general problem of anticipation. Studies in the future must systematically investigate the factors that effect the expansion of the DNA sequence in the offspring of affected females and might resolve the currently not-well-understood clinical observations about congenitally affected children and their DM mothers. MANUELA C. KOCH,* TIEMO GRIMMT HELEN G. HARLEY,$ AND PETER S. HARPER$ :.Institut fur Humangenetik, Universitat Marburg, Marburg; tInstitut fur Humangenetik, Universitit Wfirzburg, Wiirzburg; and lInstitute of Medical Genetics, University of Wales College of Medicine, Cardiff References Goodship J, Gibson DE, Burn J, Honeyman J, Cubey BB, Schofield I (1992) Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 50:1340-1341 Green JR, Grennan DM (1991) Testing for haplotype sharing by siblings with incomplete information of parental haplotypes. Ann Hum Genet 55:243-249 Harley HG, Brook JD, Rundle SA, Crow S, Reardon W, Buckler AJ, Harper PS, et al (1992) Expansion of an unstable DNA region and phenotype variation in myotonic dystrophy. Nature 355:545-546 Howeler CJ, Bush HTM (1990) An asymptomatic mother of children with congenital myotonic dystrophy. J Neurol Sci 98 [Suppl]: 197 Koch MC, Grimm T, Harley HG, Harper PS (1991) Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 48:1084-1091 Sandkuyl L, Ott J (1989) Determining informativity of marker typing for genetic counseling in a pedigree. Hum Genet 82:159-162 Ott J, Caesar K, Machler M, Schinzel A, Schmid W (1990) Presymptomatic exclusion of myotonic dystrophy in a one-generation pedigree of half-siblings. Hum Hered 40: 305-307 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0026$02.00
Am. J. Hum. Genet. 50:1342, 1992
Maternal Age, Somatic Mosaicism, and Alzheimer Disease To the Editor:
The article by Dr. Huntington Potter amplifies, in a very interesting way, the notion that Alzheimer disease (AD) may result from somatic mosaicism of chromosome 21 (Potter 1991). Potter, however, does not mention that evidence for and against this idea can be obtained by examining maternal age in AD. If maternal age is raised in AD, this would make the somatic mosaicism hypothesis less tenable-a conclusion arrived at as follows: It has been proposed that there are three main mechanisms whereby mosaicism in Down syndrome (DS) might occur (Sachs 1971). In the first, a trisomy 21 zygote caused by nondisjunction in the mother later loses the extra chromosome by anaphase lagging in some of the resultant somatic cell lines. In the second, a normal zygote undergoes nondisjunction followed by later anaphase lagging; and, in the third, a normal zygote undergoes nondisjunction at a later division, producing trisomic cell lines in addition to the existing normal cell lines. This third scheme is the one Potter proposes for AD. Sachs studied the maternal ages of his 10 mosaic DS cases and found that they were no different than maternal ages of DS controls (translocation patients were excluded). Maternal ages in both groups were significantly higher than those of a normal population matched for year of birth. From this, albeit a small sample, he concluded that mosaicism in DS arises from a trisomy 21 zygote, the first of the three mechanisms he had noted. If one accepts the view that, in DS, higher maternal age is causally related to the occurrence of meiotic nondisjunction only, then it would follow that, if AD-or some forms of it-originates from somatic cell mosaicism, then, unlike in DS, a maternal age effect would not be anticipated. What then is the evidence from maternal age studies in AD? The balance of the evidence to date is in line with the occurrence of somatic cell mosaicism in AD; that is, a maternal age effect is not confirmed (De Braekeleer et al. 1988). It should be noted, however, that many of the 15 or so studies of maternal age contain serious methodological problems. Should it be shown that, in fact, maternal age in AD is raised, then this would be evidence against the somatic mosaicism hypothesis in AD; mosaicism aris-
Letters to the Editor
ing from a trisomic zygote would not seem likely, since it might be expected that the phenotype of the affected individual would be likely to contain many of the features of DS. In light of the potential importance of the above issues, there would seem to be a good case for conducting further studies of maternal age effects in AD and mosaic DS. ROGER HOWELLS Section of Neuropsychiatry Institute of Psychiatry London References De Braekeleer M, Froda S, Tetreault H, Gauvreau D (1988) Parental age and birth order in Alzheimer's disease: a case-control study in the Saguenay-Lac-St-Jean area (Quebec, Canada). Can J Neurol Sci 15:139-141 Potter H (1991) Alzheimer disease and Down syndromechromosome 21 nondisjunction may underlie both disorders. Am J Hum Gen 48:1192-1200 Sachs ES (1971) Trisomy G/normal mosaicism, a cytological and clinical investigation. Stenfert Kroese, Leiden o 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0027$02.00
Am. J. Hum. Genet. 50:1343, 1992
Reply to Howells To the Editor:
Dr. Howells, in his letter to the editor of The American Journal of Human Genetics, raises the very interesting point that, if Alzheimer disease originates from somatic cell mosaicism for trisomy 21, then a maternal age effect similar to that seen for Down syndrome should not occur. The possible influence of parental age on the development of Alzheimer disease has been most recently investigated by Farrer et al. (1991). In this careful study, a total of 237 patients with Alzheimer disease were each matched with five control subjects on the basis of sex, year of birth, survival age, and location of residence. No significant effect of advanced maternal age on the risk for Alzheimer disease was found. However, decreased paternal age increased somewhat the susceptibility to late-onset Alzheimer disease. Dr. Farrer and his colleagues suggest that the results might be explained by genetic im-
1343
printing, but they point out that social or environmental influences are hard to rule out. HUNTINGTON POTTER AND LISA N. GELLER Department of Neurobiology
Harvard Medical School Boston Reference Farrer LA, Cupples LA, Connor L, Wolf PA, Growden JH (1991) Association of decreased paternal age and lateonset Alzheimer's disease: an example of genetic imprinting? Arch Neurol 48:599-604 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/92/5006-0028$02.00
Am. J. Hum. Genet. 50:1343-1348, 1992
Ataxia-Telangiectasia: Linkage Evidence for Genetic Heterogeneity To the Editor:
The recent paper by Foroud et al. (1991) investigates genetic linkage between the recessive disease ataxiatelangiectasia (AT) and a number of chromosome 11 q markers. While the evidence for linkage to 1 1q23 markers displayed by the 111 families in this international study is overwhelming, a cautious interpretation as to the exact location of the AT gene or genes is warranted because of the existence of complementation groups in AT. Three complementation groupsA, C, and D-make up 55 %, 28%, and 14%, respectively, of tested patients (Jaspers et al. 1988). Other, less common complementation groups account for the remaining 3 % of affecteds. Sufficiently many group A and group C families are known that group A and group C genes can be confidently localized to the 11q23 region (Gatti et al. 1988; Ziv et al. 1991). Furthermore, the radiosensitivity of a group D fibroblast line has been corrected by introducing a normal chromosome 11 (Komatsu et al. 1990) and an 11q fragment (Ejima et al. 1990) into these cells. Recently, Kapp et al. (1991, 1992), who have reported cloning of a putative group D gene that maps, by means of radiation hybrids, to the region between markers THY1 and D11S83. This position, although still within the 11q23 region, is more distal than the
