Neonate with Congenital Myotonic Dystrophy Conceived via In Vitro Fertilisation by an Asymptomatic Mother
Congenital myotonic dystrophy 1 (CDM1) is characterised by severe hypotonia with difficulty in swallowing and respiration, facial diplegia, and increased risk of prematurity. We report a neonate with CDM1 born to an asymptomatic mother after in vitro fertilisation. Molecular analysis for the cytosine-thymine-guanine (CTG) triplet related DM1 was carried out and revealed over 1,000 CTG repeats, which was consistent with the clinical impression of CDM1. Gene analysis was carried out on the proband's family. In this family, the expanded CTG repeats were transmitted maternally, and earlier age of onset and increasing severity of the disease occurred in following generations.
Keyword : Congenital myotonic dystrophy
Myotonic dystrophy is an autosomal dominant, multisystemic disorder characterised by myotonia, progressive muscle weakness and atrophy, disturbances of heart rhythms, hypogonadism, frontal balding, and cataracts.1 Usually there is weakness of distal muscles, especially those of face, ankle, and feet. The two types of myotonic dystrophy (DM1 and DM2) are both caused by gene mutations. DM1 results from an expansion of a cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3'-untranslated region of the dytrophica myotonica protein kinase gene (DMPK gene) on chromosome 19q13.3. DM2 is due to mutations in the cellular nucleic acid-binding protein gene (CNBP gene) on chromosome 3q21.3 and generally milder. Myotonic dystrophy has heterogeneous clinical phenotype, ranging from the congenital form to an asymptomatic form. We report a neonate with congenital myotonic dystrophy 1 (CDM1) born to an asymptomatic mother after in vitro fertilisation (IVF) for a history of infertility.
Figure 1 Patient's mother (II-2), at age of 36 years (A) showing wasting of facial muscles and lack of facial expression. The proband at age of 9 months (B) showing lack of facial expression.
Figure 2 Family pedigree.
CDM1 is characterised by severe hypotonia with difficulty in swallowing and respiration, facial diplegia, and prematurity after birth. Overall perinatal mortality is 11% and mortality is associated with cardiorespiratory complications.2 Children who survive the critical neonatal period later show improved motor functions, but typically still have global developmental delay compared to normal children. Clinical myotonia do not appear until late in childhood although elecromyographic myotonia may develop after the first year. CDM1 is therefore a biphasic disease and should be considered as a possible diagnosis to neonates with hypotonia. Previous studies have documented a general tendency for the repeat number to increase with passage of generations because instability of the expanded CTG repeat during gametogenesis, which results in larger repeat size in the progeny.3 Moreover, there is a fairly strong correlation between earlier onset/greater severity and increasing repeat size. Normal populations have 5 to about 30 CTG repeats, whereas DM1 patients have 50-2,000 repeats.2 Patients with a CTG repeat size of 100 or less are likely to be either asymptomatic or only mild symptomatic. Neonatal form is associated with hypotonia, cardiorespiratory and feeding problems and may showed 1,000-2,500 CTG repeats. Although repeat size does seem to play a decisive role in the aetiology of the DM1 phenotype, it does not entirely explain it. The variability of the CTG repeat sizes among different tissues resulting from the somatic instability provides a basis for heterogenous expressivity of this pleiotropic disease.4 Inheritance of CDM1 is overwhelmingly maternal. This phenomenon emerges from the much greater likelihood for anticipation (e.g., expansion of CTG repeats) to occur in maternal compared with paternal transmission.
There is a 50% risk of the offspring being affected and 3-9% chance of having a severely affected child.5 The estimated incidence of CDM1 is very broad, ranging from 2.1 to 28.6 per 100,000 live births.6-8 In this family, the expanded CTG repeats were transmitted maternally, and earlier age of onset and increasing severity of the disease occurred in following generations. The proband's echocardiography revealed intermittent bradycardia and PR interval prolongation. Conduction delays are seen from 5 to 25% in DM1 patients.
Because DM1 is a known aetiology of infertility and is one of the most frequent adult myopathies,9 our experience shows the need to consider DM1 in infertility clinic. DM1 patients of both sexes can suffer from problems of infertility due to different causes, which are at times concomitant (ovarian dysfuction, multiple miscarriages, or azoospermia). About 20% of affected females show menstrual irregularities, infertility, miscarriage or early menopause.10 The development and generalisation of reproductive techniques have opened the possibility that asymptomatic carriers of the disease can conceive fetuses affected by more serious clinical phenotypes. Therefore, infertility clinics should test for DM1 with detailed history and exact physical examination of the couples.
None to declare.
We obtained informed consent to include photographs in this case report.
1. Hageman AT, Gabreels FJ, Liem KD, Renkawek K, Boon JM. Congenital myotonic dystrophy; a report on thirteen cases and a review of the literature. J Neurol Sci 1993;115:95-101.
2. Rudnik-Schöneborn S, Nicholson GA, Morgan G, Röhrig D, Zerres K. Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus. Am J Med Genet 1998;80:314-21.
3. Hunter A, Tsilfidis C, Mettler G, et al. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet 1992;29:774-9.
4. Kuo H, Huang C, Chu C, Wai Y, Hsiao K, Chu N. Congenital myotonic dystrophy: variability in muscle involvement and histopathological process. Acta Neurol Taiwan 2006;15:13-20.
5. Koch M, Grimm T, Harley H, Harper P. Genetic risks for children of women with myotonic dystrophy. Am J Hum Genet 1991;48:1084-91.
6. González de DJ, Martínez Frias ML, Egües Jimeno J, et al. Epidemiological study of Steinert's congenital myotonic dystrophy: dysmorphological characteristics. An Esp Pediatr 1999;51:389-96.
7. Campbell C, Levin S, Siu VM, Venance S, Jacob P. Congenital myotonic dystrophy: Canadian population-based surveillance study. J Pediatr 2013;163:120-5. e1-3.
8. Darin N, Tulinius M. Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden. Neuromuscul Disord 2000;10:1-9.
9. Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 2009;132:3175-86.
10. Goldstein J, Motulsky A. Genetics and endocrinology. Williams, RH. 1981.
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