|
1
|
Mardy A, Whitney M. Management of Maternal Genetic Conditions in Pregnancy, Part 1: Disorders of the Connective Tissue, Muscle, Vascular, and Skeletal Systems. Obstet Gynecol Surv 2025; 80:99-111. [PMID: 39924336 DOI: 10.1097/ogx.0000000000001359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Importance The number of patients with various genetic syndromes who are or seek to become pregnant is increasing due to advances in medical care and assisted reproductive technologies. Management of these patients requires multidisciplinary care teams and knowledge of the risks of increased morbidity and mortality. In addition, many of these inheritance patterns are autosomal dominant, with a 50% risk of an offspring inheriting the disorder with each pregnancy. Objectives In this first of a 2-part series, common syndromes with connective tissue, muscle, vascular, or skeletal involvement will be discussed regarding surveillance and management of mother and fetus. Evidence Acquisition A literature search was performed for important updates in the literature regarding management of patients with genetic connective tissue disorders, aortopathies, muscular dystrophies, vascular disorders, and skeletal dysplasias. Results Updates have been incorporated since the last publication in 2011, including updated diagnostic criteria for several conditions (such as Marfan syndrome), international guidelines in management of aortopathies and achondroplasia, an expanded section on hypermobile Ehlers-Danlos syndrome, and a new section on familial cerebral cavernous malformation. Conclusions Since the last publication, many guidelines have been published or updated regarding management of pregnancies in patients with genetic disorders and are reviewed in this article. Relevance Clinicians who care for pregnant patients with genetic disorders should be aware of updated guidelines and recommendations in order to optimize their care during pregnancy.
Collapse
Affiliation(s)
- Anne Mardy
- Assistant Professor, Department of Women's Health, University of Texas at Austin/Seton Medical Center, Austin, TX
| | - Madeline Whitney
- Resident, University of Texas at Austin/Dell Medical School, Austin, TX
| |
Collapse
|
|
2
|
Braun M, Shoshani S, Teixeira J, Mellul Shtern A, Miller M, Granot Z, Fischer SE, Garcia SMA, Tabach Y. Asymmetric inheritance of RNA toxicity in C. elegans expressing CTG repeats. iScience 2022; 25:104246. [PMID: 35494247 PMCID: PMC9051633 DOI: 10.1016/j.isci.2022.104246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/01/2022] [Accepted: 04/07/2022] [Indexed: 11/18/2022] Open
Abstract
Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases and cause RNA toxicity and multisystemic symptoms that worsen with age. Through an unclear mechanism, RNA toxicity can trigger severe disease manifestation in infants if the repeats are inherited from their mother. Here we use Caenorhabditis elegans bearing expanded CUG repeats to show that this asymmetric intergenerational inheritance of toxicity contributes to disease pathogenesis. In addition, we show that this mechanism is dependent on small RNA pathways with maternal repeat-derived small RNAs causing transcriptomic changes in the offspring, reduced motility, and shortened lifespan. We rescued the toxicity phenotypes in the offspring by perturbing the RNAi machinery in the affected hermaphrodites. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring, causing disease phenotypes through intergenerational epigenetic inheritance.
Maternal origin of expanded CUG repeats induces RNA toxicity in Caenorhabditis elegans offspring Offspring of affected hermaphrodites show molecular and phenotypic disease phenotypes The RNAi machinery is directly related to the maternal inheritance of RNA toxicity Altering the RNAi machinery in affected hermaphrodites rescues toxicity in offspring
Collapse
Affiliation(s)
- Maya Braun
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Shachar Shoshani
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Joana Teixeira
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland
| | - Anna Mellul Shtern
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Maya Miller
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Zvi Granot
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Sylvia E.J. Fischer
- Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Susana M.D. A. Garcia
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00790 Finland
- Corresponding author
| | - Yuval Tabach
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
- Corresponding author
| |
Collapse
|
|
3
|
Morales F, Vásquez M, Corrales E, Vindas-Smith R, Santamaría-Ulloa C, Zhang B, Sirito M, Estecio MR, Krahe R, Monckton DG. Longitudinal increases in somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 are associated with variation in age-at-onset. Hum Mol Genet 2021; 29:2496-2507. [PMID: 32601694 DOI: 10.1093/hmg/ddaa123] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 04/13/2020] [Accepted: 06/16/2020] [Indexed: 12/26/2022] Open
Abstract
In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8-15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.
Collapse
Affiliation(s)
- Fernando Morales
- Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica
| | - Melissa Vásquez
- Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica
| | - Eyleen Corrales
- Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica
| | - Rebeca Vindas-Smith
- Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica
| | | | - Baili Zhang
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mario Sirito
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marcos R Estecio
- Department of Epigenetics & Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ralf Krahe
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Darren G Monckton
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| |
Collapse
|
|
4
|
Lanni S, Pearson CE. Molecular genetics of congenital myotonic dystrophy. Neurobiol Dis 2019; 132:104533. [PMID: 31326502 DOI: 10.1016/j.nbd.2019.104533] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/29/2019] [Accepted: 07/11/2019] [Indexed: 12/26/2022] Open
Abstract
Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the DMPK gene. Congenital Myotonic Dystrophy (CDM1) represents the most severe form of the disease, with prenatal onset, symptoms distinct from adult onset DM1, and a high rate of perinatal mortality. CDM1 is usually associated with very large CTG expansions, but this correlation is not absolute and cannot explain the distinct clinical features and the strong bias for maternal transmission. This review focuses upon the molecular and epigenetic factors that modulate disease severity and might be responsible for CDM1. Changes in the epigenetic status of the DM1 locus and in gene expression have recently been observed. Increasing evidence supports a role of a CTCF binding motif as a cis-element, upstream of the DMPK CTG tract, whereby CpG methylation of this site regulates the interaction of the insulator protein CTCF as a modulating trans-factor responsible for the inheritance and expression of CDM1.
Collapse
Affiliation(s)
- Stella Lanni
- Program of Genetics & Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto M5G 0A4, Ontario, Canada
| | - Christopher E Pearson
- Program of Genetics & Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto M5G 0A4, Ontario, Canada; University of Toronto, Program of Molecular Genetics, Canada.
| |
Collapse
|
|
5
|
Abstract
The life expectancy and quality of life of women with genetic disorders continues to improve, resulting in more women reaching reproductive age and desiring fertility. It is becoming increasingly important that obstetricians become familiar with common genetic disorders and their associated risks in pregnancy. The authors review pregnancy in women with various genetic disorders, including review of pregnancy outcomes, management recommendations, and genetic risk assessment. Most data on pregnancies in women with genetic conditions are based on case reports and literature reviews. Additional studies, including pregnancy registries, are needed to improve our understanding and care of this patient population.
Collapse
Affiliation(s)
- Sarah Harris
- University of North Carolina at Chapel Hill School of Medicine, 3010 Old Clinic Building, CB 7516, Chapel Hill, NC 27516, USA
| | - Neeta L Vora
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill School of Medicine, 3010 Old Clinic Building, CB 7516, Chapel Hill, NC 27516, USA.
| |
Collapse
|
|
6
|
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE. CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy. Am J Hum Genet 2017; 100:488-505. [PMID: 28257691 PMCID: PMC5339342 DOI: 10.1016/j.ajhg.2017.01.033] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 01/26/2017] [Indexed: 12/13/2022] Open
Abstract
CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10−12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.
Collapse
|
|
7
|
Ho G, Cardamone M, Farrar M. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions. World J Clin Pediatr 2015; 4:66-80. [PMID: 26566479 PMCID: PMC4637811 DOI: 10.5409/wjcp.v4.i4.66] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 08/07/2015] [Accepted: 09/25/2015] [Indexed: 02/06/2023] Open
Abstract
Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised.
Collapse
|
|
8
|
Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1. Eur J Hum Genet 2014; 23:646-53. [PMID: 25052313 DOI: 10.1038/ejhg.2014.138] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 06/02/2014] [Accepted: 06/18/2014] [Indexed: 12/27/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat (g.17294_17296(45_1000)) with more repeats associated with increased disease severity and reduced age at onset. Expanded disease-associated alleles are highly unstable in both the germline and soma. Germline instability is expansion biased, providing a molecular explanation for anticipation. Somatic instability is expansion biased, size- and age-dependent, features that have compromised genotype-phenotype correlations and intergenerational studies. We corrected these confounding factors by estimating the progenitor allele length in 54 father-offspring and 52 mother-offspring pairs in Costa Rican DM1 families. Not surprisingly, we found major parental allele length effects on the size of the allele transmitted, the magnitude of the intergenerational length change, the age at onset in the next generation and the degree of anticipation in both male and female transmissions. We also detected, for the first time, an age-of-parent effect for both male and female transmission. Interestingly, we found no evidence for an intrauterine effect in the transmission of congenital DM1, suggesting previous reports may have been an artefact of age-dependent somatic instability and sampling bias. These data provide new insights into the germline dynamics of the CTG repeat and opportunities for providing additional advice and more accurate risk assessments to prospective parents in DM1 families.
Collapse
|
|
9
|
Reicherter K, Veeramani AI, Jagadeesh S. Cartilage-hair hypoplasia caused by novel compound heterozygous RMRP mutations. Indian Pediatr 2012; 48:559-61. [PMID: 21813924 DOI: 10.1007/s13312-011-0086-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition.
Collapse
Affiliation(s)
- Kerstin Reicherter
- Center for Pediatrics and Adolescent Medicine and Faculty of Biology, University of Freiburg, Freiburg, Germany
| | | | | |
Collapse
|
|
10
|
Martorell L, Cobo AM, Baiget M, Naudó M, Poza JJ, Parra J. Prenatal diagnosis in myotonic dystrophy type 1. Thirteen years of experience: implications for reproductive counselling in DM1 families. Prenat Diagn 2007; 27:68-72. [PMID: 17154336 DOI: 10.1002/pd.1627] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES To analyse the results obtained from prenatal diagnoses in myotonic dystrophy type 1 (DM1) performed in our hospitals during the last 13 years. METHODS Molecular analyses were conducted on chorionic villi or cultured amniotic fluid samples obtained for prenatal diagnosis of DM1. CTG expansion was analyzed by polymerase chain reaction (PCR) and Southern blot techniques. RESULTS From 154 prenatal diagnoses performed in 13 years, 51% were found to be healthy and 49% affected. Considering the 75 carriers of the mutation, in 65.3% of the cases, the mother was the transmitting parent versus 36.5% of fathers. From these female transmissions, 31/49 foetuses had expansion in the neonatal form range, namely, congenital myotonic dystrophy (CMD). CONCLUSIONS In our series, no significant deviation of the 50% expected frequency of transmission in autosomal dominant disorder was seen. We show that when the disease is transmitted by a male, the mean intergenerational variation is minimal (mean = 56 CTG, SD = 177 CTG). However, this does not occur in the affected mothers, where the mean intergenerational expansion is very high (mean = 948 CTG, SD = 815 CTG) and the difference is statistically significant (t-Student p < 0.0001). Our data have important implications for the genetic counselling of DM1 families.
Collapse
Affiliation(s)
- Loreto Martorell
- Molecular Genetics Section, Hospital Sant Joan de Déu, Barcelona, Spain.
| | | | | | | | | | | |
Collapse
|
|
11
|
Lesca G, Haÿs S, Bourgeois J, Bost M, Ollagnon-Roman E, Putet G. [Diagnosis of congenital myotonic dystrophy in a neonate: its familial consequences]. Arch Pediatr 2003; 10:466-7. [PMID: 12878346 DOI: 10.1016/s0929-693x(03)00100-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
|
|
12
|
Zeesman S, Carson N, Whelan DT. Paternal transmission of the congenital form of myotonic dystrophy type 1: a new case and review of the literature. AMERICAN JOURNAL OF MEDICAL GENETICS 2002; 107:222-6. [PMID: 11807903 DOI: 10.1002/ajmg.10141] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide repeat disorder that shows anticipation. The mildest manifestations of the DM gene are usually noted in individuals with the smallest repeat sizes, while congenital myotonic dystrophy (CDM) is the most common clinical outcome of the larger expansions. For many years, it was thought that CDM could only be maternally transmitted. However, in the last few years, cases of paternal transmission of CDM have been described. We report a child with the CDM phenotype and 1, 800 CTG repeats born to an asymptomatic father with 65 repeats and compare this case to the four currently in the literature. We note that polyhydramnios was present in the majority of cases and that all fathers whose status was known had small repeat sizes and/or were asymptomatic at the time of their child's birth. Although it may be unusual, the possibility of the paternal transmission of CDM should be mentioned when counseling families with DM. The men who are at highest risk may be those who have small repeats sizes and are asymptomatic.
Collapse
Affiliation(s)
- Susan Zeesman
- Department of Pediatrics, McMaster University, Ontario, Canada.
| | | | | |
Collapse
|
|
13
|
Rudnik-Sch�neborn S, Nicholson GA, Morgan G, R�hrig D, Zerres K. Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19981204)80:4<314::aid-ajmg3>3.0.co;2-i] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
|
|
14
|
Affiliation(s)
- J D Waring
- Solange Gauthier Karsh Laboratory, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | | |
Collapse
|
|
15
|
Geifman-Holtzman O, Fay K. Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: Case report and literature review. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19980707)78:3<250::aid-ajmg8>3.0.co;2-t] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
|
|
16
|
|
|
17
|
de Die-Smulders CE, Smeets HJ, Loots W, Anten HB, Mirandolle JF, Geraedts JP, Höweler CJ. Paternal transmission of congenital myotonic dystrophy. J Med Genet 1997; 34:930-3. [PMID: 9391889 PMCID: PMC1051123 DOI: 10.1136/jmg.34.11.930] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We report a rare case of paternally transmitted congenital myotonic dystrophy (DM). The proband is a 23 year old, mentally retarded male who suffers severe muscular weakness. He presented with respiratory and feeding difficulties at birth. His two sibs suffer from childhood onset DM. Their late father had the adult type of DM, with onset around 30 years. Only six other cases of paternal transmission of congenital DM have been reported recently. We review the sex related effects on transmission of congenital DM. Decreased fertility of males with adult onset DM and contraction of the repeat upon male transmission contribute to the almost absent occurrence of paternal transmission of congenital DM. Also the fathers of the reported congenitally affected children showed, on average, shorter CTG repeat lengths and hence less severe clinical symptoms than the mothers of children with congenital DM. We conclude that paternal transmission of congenital DM is rare and preferentially occurs with onset of DM past 30 years in the father.
Collapse
|
|
18
|
Gennarelli M, Novelli G, Andreasi Bassi F, Martorell L, Cornet M, Menegazzo E, Mostacciuolo ML, Martinez JM, Angelini C, Pizzuti A, Baiget M, Dallapiccola B. Prediction of myotonic dystrophy clinical severity based on the number of intragenic [CTG]n trinucleotide repeats. AMERICAN JOURNAL OF MEDICAL GENETICS 1996; 65:342-7. [PMID: 8923947 DOI: 10.1002/(sici)1096-8628(19961111)65:4<342::aid-ajmg18>3.0.co;2-u] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We carried out a genotype-phenotype correlation study, based on clinical findings in 465 patients with myotonic dystrophy (DM), in order to assess [CTG] repeat number as a predictive test of disease severity. Our analysis showed that the DM subtypes defined by strict clinical criteria fall into three different classes with a log-normal distribution. This distribution is useful in predicting the probability of specific DM phenotypes based on triplet [CTG] number. This study demonstrates that measurement of triplet expansions in patients' lymphocyte DNA is highly valuable and accurate for prognostic assessment.
Collapse
Affiliation(s)
- M Gennarelli
- Cattedra di Genetica Umana, Università Tor Vergata, Rome, Italy
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|