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Triple repeat diseases and unstable gonadal function
LETTERS TO THE EDITOR Paul G. McDonough, M.D. Associate Editor Triple repeat diseases and unstable gonadal function To the Editor: The recent article on fragile X, ‘‘The FMR1 Premutation and Reproduction’’ (1), was a wonderful review and commentary. We would like to add that the University of Virginia Obstetrics and Gynecology Department has performed studies in women regarding pretest motivations about fragile X premutation testing (2). Participants either had a particular infertility diagnosis (regular menstrual cycles and diagnosis of diminished ovarian reserve through elevated levels of FSH) or were menopausal before age 45 years. None of the participants had a relative with fragile X syndrome. We obtained patient reactions to four versions of an educational handout, and the final version (publicly available for downloading at http://www.healthsystem.virginia.edu/internet/ obgyn/research.cfm) incorporates the input from the study participants. We found that about three quarters of the women wanted to know whether they have the fragile X premutation and anticipated having the test if their physician recommended it. Potential deterrents to being tested included having to pay out-of-pocket and maintaining confidentiality insurancewise. Lisa M. Pastore, Ph.D. JoAnn V. Pinkerton, M.D. Department of Obstetrics and Gynecology University of Virginia Charlottesville, Virginia Christopher D. Williams, M.D. Reproductive Medicine and Surgery Center of Virginia Charlottesville, Virginia March 27, 2007 REFERENCES 1. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87:456–65. 2. Pastore LM, Karns LB, Pinkerton JV, Silverman LM, Williams CD, Camp TR. Acceptance of fragile X premutation genetic screening in women with ovarian dysfunction. Am J Obstet Gynecol 2006;194: 738–43.
doi:10.1016/j.fertnstert.2007.07.023
Reply of the Authors: We thank Pastore and colleagues for their kind comments regarding our article and for their work in assessing the acceptance of FMR1 testing in women with ovarian dysfunction (1, 2). 0015-0282/07/$32.00
Michael D. Wittenberger, M.D. Lawrence M. Nelson, M.D. Reproductive Biology and Medicine Branch National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland June 11, 2007 REFERENCES 1. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87:456–65. 2. Pastore LM, Karns LB, Pinkerton JV, Silverman LM, Williams CD, Camp TR. Acceptance of fragile X premutation genetic screening in women with ovarian dysfunction. Am J Obstet Gynecol 2006;194:738–43.
doi:10.1016/j.fertnstert.2007.07.022
Editorial Commentary Triple repeat diseases and unstable gonadal function To date fragile X syndrome is the most frequent form of inherited mental retardation (1 in 1,250 males), and FMR1 is the most common single gene abnormality associated with premature ovarian failure. The association of the CGG repeat size in the high normal range (35–55) with premature ovarian failure was first described by Charles Schwartz of the Greenwood Genetics Clinic in 1994 (1). The strength of this clinical association has gradually taken shape over the past decade. The continuing evidence of a nonrandom association between premature ovarian failure and the FMR1 premutation has been a stimulus to explore the molecular biology of the relationship between triple repeat diseases and ovarian dysfunction. It is increasingly clear that clinicians should look for Xlinked mental retardation in families and should consider requesting FMR1 testing when investigating premature ovarian failure. Fragile X testing is important whether or not the patient is concerned about her fertility because of the extended family implications. For example, patients with premature ovarian failure may be considering IVF with donor eggs from relatives, who are themselves at risk of being premutation carriers. In this situation the extended family will have to deal with the possibility of being carriers and perhaps transmitting the full mutation to a child who will be affected with the fragile X syndrome. To date it appears that the manifestation of ovarian dysfunction in the fragile X syndrome could be influenced both by the pattern of interruption of the CGG repeat and by the skewing of X inactivation (2). At this time results from chorionic villi sampling and preimplantation genetic diagnosis testing must be interpreted
Fertility and Sterility Vol. 88, No. 5, November 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
1477
with caution because the methylation status of the FMR1 gene is not yet established in chorionic villi at the time of sampling. Chorionic villi sampling and preimplantation genetic diagnosis, although being standard techniques for early prenatal diagnosis, may lead to a situation where follow-up amniocentesis is necessary to resolve an ambiguous result. Fragile X syndrome is not the only triple repeat disease that has been associated with gonadal failure. The frequent association of myotonia dystrophica and premature testicular failure in males was known for many decades before the molecular biology of this neurologic disorder was deciphered. Ovarian compromise in females with myotonia dystrophica appears to be infrequent or infrequently recognized. These clinical associations suggest that a gene regulating gonadal development may be closely linked to one of the two genes causing myotonia dystrophica. The gene causing myotonia dystrophica is an autosomal dominant gene, transmitted from affected individuals to 50% of their offspring. Myotonic dystrophy or dystrophia myotonica (DM) is the most common muscular dystrophy of adult life with a frequency of 3 to 15 per 100,000 in most populations. Muscle weakness involving the face is a particularly conspicuous feature of early disease. The facial features of affected individuals suggest that they are permanently ‘‘mad’’ at the world. With time, cataracts, frontal balding, degrees of cognitive decline, and gonadal atrophy are part of the syndrome. Many of the features of DM may blend imperceptibly with the normal aging process. Most individuals with DM are minimally affected until they reach adulthood, but there is extreme intrafamilial and interfamilial variability in age of onset and severity. Physicians not familiar with the disease may fail to recognize the early symptoms. The biochemical basis for DM is also a gene expansion phenomenon in which trinucleotide repeats (CTG) in the 30 untranslated region of myotonic dystrophy protein kinase gene (DMPK) on chromosome 19 (19q13.3) are amplified to several times their normal number. In this case the expansion results in a reduction in the level of activity of the DMPK gene. The reduction in ‘‘effective dosage’’ of the gene product brought about by the extinction of one allele is thought to contribute to many aspects of the pathology. Similar to fragile X syndrome the triplet repeat in families with DM is unstable and tends to expand when transmitted. In contrast to the fragile X syndrome there is no sex preference for extreme expansion of the DM triplet repeat. The combined occurrence of myotonic dystrophy and premature gonadal failure suggests that the expansion of the trinucleotide repeat alters the expression of a specific protein kinase involved in a signaling pathway shared by muscle, testis, and ovary. In approximately 20% or more of men with DM testicular failure develops, and in a small number of women with DM ovarian failure may develop in the fourth decade of life (3). The author had one patient with DM and ovarian failure with onset of the hypergonadotropism at 31 years of age. The severity of the hypogonadism in the male with DM tends to correlate with the CTG repeat size and the levels of serum gonadotropins (4). 1478
Letters to the Editor
One wonders if the onset of ovarian failure in affected women tends to occur closer to natural menopause and is infrequently recognized as being related to DM. Alternatively it seems possible that ovarian failure might be the first manifestation of DM with other symptoms to follow at a later date. In this case the gynecologist may make the diagnosis of premature ovarian failure but overlook the more subtle symptoms of DM. This phenomenon has been reported in the male by Futterweit and colleagues where azoospermia and elevated FSH levels preceded the onset of any DM symptoms by 1 year (5). Unfortunately women with documented DM have not been looked at critically for elevations of serum gonadotropin levels and testing of ovarian reserve. In addition there is increasing evidence for multiple genes (DM2 on chromosome 3) and also for multiple pathways that may be operative in mediating the pathogenic effects of the triplet repeat expansion in the DM1 gene. This heterogeneity further complicates the clinical phenotype and suggests that clinically unaffected women in families with DM might benefit from a survey of ovarian function (6). Given the phenotypic overlap between these neuropsychiatric disorders and gonadal function the gene targets (RNAs) of their proteins may be considered a treasure chest of candidate genes for helping to understand the workings of the brain and the gonad. Paul G. McDonough, M.D. Associate Editor Letters Medical College of Georgia Augusta, Georgia REFERENCES 1. Schwartz CE, Dean J, Howard-Peebles PN, Budge M, Mikelsen M, Tommerup N, et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 1994;51:400–2. 2. Bodega B, Bione S, Dalpra L, Toniolo D, Ornaghi F, Vegetti W, et al. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod 2006;21:952–7. 3. Marinkovic Z, Prelevic G, Wurzburger M, Nogic S. Gonadal function in patients with myotonic dystrophy. Exper Clin Endocrinol 1990;96:37–44. 4. Dallapiccola B. Male hypogonadism in myotonic dystrophy is related to (CTG)n triplet mutation. J Endocrinol Invest 1994;17:381–3. 5. Futterweit W, Mechanick JI. Myotonic dystrophy presenting as male infertility: a case report. Int J Fertil 1987;32:142–4. 6. McDonough PG. Selected enquiries into the causation of premature ovarian failure. Hum Fertil (Camb) 2003;6:130–6.
doi:10.1016/j.fertnstert.2007.07.021
‘‘Statute of limitations’’ redeemed by cyberspace To the Editor: The supplement to the April 2007 volume of Fertility and Sterility, entitled ‘‘IFFS Surveillance 07,’’ was dedicated to the laws, regulations, and guidelines in the field of assisted reproductive technology (ART) in 57 selected countries Vol. 88, No. 5, November 2007
doi:10.1016/j.fertnstert.2007.07.023
Reply of the Authors: We thank Pastore and colleagues for their kind comments regarding our article and for their work in assessing the acceptance of FMR1 testing in women with ovarian dysfunction (1, 2). 0015-0282/07/$32.00
Michael D. Wittenberger, M.D. Lawrence M. Nelson, M.D. Reproductive Biology and Medicine Branch National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland June 11, 2007 REFERENCES 1. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87:456–65. 2. Pastore LM, Karns LB, Pinkerton JV, Silverman LM, Williams CD, Camp TR. Acceptance of fragile X premutation genetic screening in women with ovarian dysfunction. Am J Obstet Gynecol 2006;194:738–43.
doi:10.1016/j.fertnstert.2007.07.022
Editorial Commentary Triple repeat diseases and unstable gonadal function To date fragile X syndrome is the most frequent form of inherited mental retardation (1 in 1,250 males), and FMR1 is the most common single gene abnormality associated with premature ovarian failure. The association of the CGG repeat size in the high normal range (35–55) with premature ovarian failure was first described by Charles Schwartz of the Greenwood Genetics Clinic in 1994 (1). The strength of this clinical association has gradually taken shape over the past decade. The continuing evidence of a nonrandom association between premature ovarian failure and the FMR1 premutation has been a stimulus to explore the molecular biology of the relationship between triple repeat diseases and ovarian dysfunction. It is increasingly clear that clinicians should look for Xlinked mental retardation in families and should consider requesting FMR1 testing when investigating premature ovarian failure. Fragile X testing is important whether or not the patient is concerned about her fertility because of the extended family implications. For example, patients with premature ovarian failure may be considering IVF with donor eggs from relatives, who are themselves at risk of being premutation carriers. In this situation the extended family will have to deal with the possibility of being carriers and perhaps transmitting the full mutation to a child who will be affected with the fragile X syndrome. To date it appears that the manifestation of ovarian dysfunction in the fragile X syndrome could be influenced both by the pattern of interruption of the CGG repeat and by the skewing of X inactivation (2). At this time results from chorionic villi sampling and preimplantation genetic diagnosis testing must be interpreted
Fertility and Sterility Vol. 88, No. 5, November 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
1477
with caution because the methylation status of the FMR1 gene is not yet established in chorionic villi at the time of sampling. Chorionic villi sampling and preimplantation genetic diagnosis, although being standard techniques for early prenatal diagnosis, may lead to a situation where follow-up amniocentesis is necessary to resolve an ambiguous result. Fragile X syndrome is not the only triple repeat disease that has been associated with gonadal failure. The frequent association of myotonia dystrophica and premature testicular failure in males was known for many decades before the molecular biology of this neurologic disorder was deciphered. Ovarian compromise in females with myotonia dystrophica appears to be infrequent or infrequently recognized. These clinical associations suggest that a gene regulating gonadal development may be closely linked to one of the two genes causing myotonia dystrophica. The gene causing myotonia dystrophica is an autosomal dominant gene, transmitted from affected individuals to 50% of their offspring. Myotonic dystrophy or dystrophia myotonica (DM) is the most common muscular dystrophy of adult life with a frequency of 3 to 15 per 100,000 in most populations. Muscle weakness involving the face is a particularly conspicuous feature of early disease. The facial features of affected individuals suggest that they are permanently ‘‘mad’’ at the world. With time, cataracts, frontal balding, degrees of cognitive decline, and gonadal atrophy are part of the syndrome. Many of the features of DM may blend imperceptibly with the normal aging process. Most individuals with DM are minimally affected until they reach adulthood, but there is extreme intrafamilial and interfamilial variability in age of onset and severity. Physicians not familiar with the disease may fail to recognize the early symptoms. The biochemical basis for DM is also a gene expansion phenomenon in which trinucleotide repeats (CTG) in the 30 untranslated region of myotonic dystrophy protein kinase gene (DMPK) on chromosome 19 (19q13.3) are amplified to several times their normal number. In this case the expansion results in a reduction in the level of activity of the DMPK gene. The reduction in ‘‘effective dosage’’ of the gene product brought about by the extinction of one allele is thought to contribute to many aspects of the pathology. Similar to fragile X syndrome the triplet repeat in families with DM is unstable and tends to expand when transmitted. In contrast to the fragile X syndrome there is no sex preference for extreme expansion of the DM triplet repeat. The combined occurrence of myotonic dystrophy and premature gonadal failure suggests that the expansion of the trinucleotide repeat alters the expression of a specific protein kinase involved in a signaling pathway shared by muscle, testis, and ovary. In approximately 20% or more of men with DM testicular failure develops, and in a small number of women with DM ovarian failure may develop in the fourth decade of life (3). The author had one patient with DM and ovarian failure with onset of the hypergonadotropism at 31 years of age. The severity of the hypogonadism in the male with DM tends to correlate with the CTG repeat size and the levels of serum gonadotropins (4). 1478
Letters to the Editor
One wonders if the onset of ovarian failure in affected women tends to occur closer to natural menopause and is infrequently recognized as being related to DM. Alternatively it seems possible that ovarian failure might be the first manifestation of DM with other symptoms to follow at a later date. In this case the gynecologist may make the diagnosis of premature ovarian failure but overlook the more subtle symptoms of DM. This phenomenon has been reported in the male by Futterweit and colleagues where azoospermia and elevated FSH levels preceded the onset of any DM symptoms by 1 year (5). Unfortunately women with documented DM have not been looked at critically for elevations of serum gonadotropin levels and testing of ovarian reserve. In addition there is increasing evidence for multiple genes (DM2 on chromosome 3) and also for multiple pathways that may be operative in mediating the pathogenic effects of the triplet repeat expansion in the DM1 gene. This heterogeneity further complicates the clinical phenotype and suggests that clinically unaffected women in families with DM might benefit from a survey of ovarian function (6). Given the phenotypic overlap between these neuropsychiatric disorders and gonadal function the gene targets (RNAs) of their proteins may be considered a treasure chest of candidate genes for helping to understand the workings of the brain and the gonad. Paul G. McDonough, M.D. Associate Editor Letters Medical College of Georgia Augusta, Georgia REFERENCES 1. Schwartz CE, Dean J, Howard-Peebles PN, Budge M, Mikelsen M, Tommerup N, et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 1994;51:400–2. 2. Bodega B, Bione S, Dalpra L, Toniolo D, Ornaghi F, Vegetti W, et al. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod 2006;21:952–7. 3. Marinkovic Z, Prelevic G, Wurzburger M, Nogic S. Gonadal function in patients with myotonic dystrophy. Exper Clin Endocrinol 1990;96:37–44. 4. Dallapiccola B. Male hypogonadism in myotonic dystrophy is related to (CTG)n triplet mutation. J Endocrinol Invest 1994;17:381–3. 5. Futterweit W, Mechanick JI. Myotonic dystrophy presenting as male infertility: a case report. Int J Fertil 1987;32:142–4. 6. McDonough PG. Selected enquiries into the causation of premature ovarian failure. Hum Fertil (Camb) 2003;6:130–6.
doi:10.1016/j.fertnstert.2007.07.021
‘‘Statute of limitations’’ redeemed by cyberspace To the Editor: The supplement to the April 2007 volume of Fertility and Sterility, entitled ‘‘IFFS Surveillance 07,’’ was dedicated to the laws, regulations, and guidelines in the field of assisted reproductive technology (ART) in 57 selected countries Vol. 88, No. 5, November 2007