Paternal transmission of the congenital form of myotonic dystrophy type 1: A new case and review of the literature

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. © 2001 Wiley‐Liss, Inc.     

Prenatal diagnosis of Fukuyama type congenital muscular dystrophy by polymorphism analysis

Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by a combination of primary muscular dystrophy of early infantile onset and brain malformation (lissencephaly type II). The identification of the FCMD gene locus at 9q31 opened the theoretical possibility of prenatal diagnosis. The authors conducted prenatal diagnosis in two unrelated FCMD families by analysis using nine microsatellite CA-repeat polymorphic markers flanking the FCMD locus, and calculated phenotype probabilities in fetuses with a computer program, LINKAGE. The fetus in family 1 showed a 99% probability of being healthy either as a normal homozygote or a heterozygote carrier and was born without signs of FCMD. In family 2, the fetus was diagnosed to have FCMD with at least 86% probability. The parents of this family decided to terminate the pregnancy and an abortus showed brain malformations characteristic of an FCMD fetus. © 1996 Wiley-Liss, Inc.     

Epidemiology of myotonic dystrophy in Italy: re-apprisal after genetic diagnosis

Before the discovery of the myotonic dystrophy (DM) gene, the DM epidemiological rates could not be accurately estimated. The aim of this study was to calculate the DM prevalence rates in Padova (North-East Italy) and in four provinces of North-West Tuscany (Central Italy) and, as of 30 June 1999, to do so using molecular genetic testing. A minimum prevalence rate of 9.31x10(-5) inhabitants was found, consistent with epidemiological rates worldwide, and more than two times as high as those of two previous studies conducted in the same areas during the era prior to molecular genetic testing. This study, the first in Italy since the discovery of the DM gene, underlines the importance of direct genetic diagnosis of DM, especially in detecting mildly affected patients, a fundamental step in correctly estimating the risk of disease transmission in affected families.     

Prenatal diagnosis in Becker muscular dystrophy

Prenatal diagnosis in a pregnancy at risk for Becker muscular dystrophy is reported. The diagnosis was made prior to 12 weeks of gestation by typing a CVS sample for DNA markers.     

Preimplantation genetic diagnosis for myotonic dystrophy type 1: upon request to child

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for patients at risk of transmitting an inherited disease such as myotonic dystrophy type 1(DM1) to their offspring. In this paper, the clinical application of preimplantation diagnosis for DM1 upon request to children born is described in a large cohort of risk couples. PGD could be offered to all 78 couples opting for PGD regardless of the triplet repeat size. The incidence of major complications was minimalised following a careful assessment in affected DM1 females anticipating possible cardiological, obstetrical and anaesthetical problems. A live-birth delivery rate per cycle with oocyte retrieval of 20% was the outcome. Forty-eight of the 49 children born are in good health and have normal psychomotor development.     

Detection of the CTG repeat expansion in congenital myotonic dystrophy

Summary Myotonic dystrophy (DM) is caused by an abnormal expansion of an unstable CTG trinucleotide repeat in the 3′ untranslated region of mRNA encoding a putative serine/threonine protein kinase. We analyzed 59 patients with DM (28 congenital DM families: 27 families with maternal transmission and 1 paternal transmission) and 27 normal control subjects to evaluate their CTG repeat size between DM patients and the normal controls, and to search for a correlation between the clinical characteristics of congenital DM (CDM) and CTG repeat expansions. Analysis was on the basis of the Southern blot and polymerase chain reaction (PCR) methods, and by direct sequencing of PCR amplified CTG repeats. Analysis of intergenerational differences in the CTG repeat size for mother-child pairs showed a positive correlation (y=1.0384x+1265.2,r ²=0.311). In addition to the strong parental bias, this group showed genetic anticipation. There was a significant correlation of the CTG repeat expansion with disease severity. The largest CTG repeat expansion (2,293 CTG repeats) on average belonged to the severe CDM group, and the smallest (129 CTG repeats) to the subclinical DM group. The mutant allele of an asymptomatic father in the paternally transmitted pedigree revealed 75 CTG repeats, demonstrating that he was a DM protomutation carrier.     

Prenatal diagnosis of Fukuyama type congenital muscular dystrophy in eight Japanese families by haplotype analysis using new markers closest to the gene

We conducted prenatal diagnosis by haplotype analysis, using newly developed microsatellite markers, in eight Fukuyama type congenital muscular dystrophy (FCMD) families. In addition to six new families, two previously reported families were re-examined by haplotype analysis including detection of an ancestral founder haplotype (138–183–301) for 3 microsatellite markers closest to the FCMD gene, designated D9S2105–D9S2107–D9S172, the distances of which from the FCMD gene are presumed to be ∼140, ∼20, and ∼280 kb, respectively. Five fetuses from five families were diagnosed as nonaffected, and were subsequently confirmed to be healthy. Three fetuses of the other three families were diagnosed as having a high probability of being affected by FCMD. In the prenatal diagnosis conducted for these eight families, the ancestral founder allele was observed in 13 of 16 (81%) FCMD-bearing chromosomes. Detection of the ancestral haplotype facilitated achieving accurate prenatal diagnosis of FCMD. The brains of all three fetuses prenatally diagnosed as FCMD-affected showed the initial stage of cortical dysplasia, strong evidence of FCMD. Am. J. Med. Genet. 77:310–316, 1998. © 1998 Wiley-Liss, Inc.     

Prenatal diagnosis of congenital sialidosis

Sasagasako N, Miyahara S, Saito N, Shinnoh N, Kobayashi T, Goto I. Prenatal diagnosis of congenital sialidosis.
Clin Genet 1993: 44: 8–11. © Munksgaard, 1993
A case of prenatally diagnosed congenital sialidosis is described in a 21-week-old male fetus, which was the fifth product of non-consanguineous parents. The proband, the second product, was diagnosed as having sialidosis by the enzyme assay in peripheral leukocytes after birth. At the 17th week of pregnancy, the fetus at risk was proven to have isolated sialidase deficiency after analyzing a sample of the cultured amniotic fluid cells. There were many cytoplasmic vacuoles and increased amounts of sialyloligosaccharides in the tissue of the aborted fetus, while the amount and the pattern of gangliosides in the central nervous system were normal.     

Prediction of myotonic dystrophy clinical severity based on the number of intragenic [CTG]n trinucleotide repeats

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. © 1996 Wiley-Liss, Inc.     

Somatic cell heterogeneity between DNA extracted fromllymphocytes and skeletal muscle in congenital myotonic dystrophy

Summary Myotonic dystrophy (DM) results from the expansion of an unstable CTG trinucleotide repeat in the 3 untranslated region of mRNA encoding a putative serine/threonine protein kinase. The degreeoof the CTG repeat amplification in genomic DNAs extracted from lymphocytes correlates with disease severity. We have analyzed the amplification of the CTG repeat of DNAs extracted from skeletal muscles and lymphocytes in five congenital DM patients. The amplification from skeletal muscles showed an increase of about 1.5 kb to 3.5 kb larger than that from lymphocytes in all patients. Furthermore, we have investigated the somatic instability of the CTG repeat in various tissues from a severe congenital DM patient.     

Duchenne muscular dystrophy and myotonic dystrophy in the same patient

We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels. © 1995 Wiley-Liss, Inc.     

Prenatal cytogenetic diagnosis: First 1,000 successful cases

From February 1969 to August 1976, we studied 1,048 amniotic fluids. Of these, 958 (91.4%) were primarily for prenatal cytogenetic diagnosis. Cytogenetic studies were attempted in 1,021 cases; the diagnosis was successful in 1,000 of these. The failure rate of obtaining a diagnosis from the amniotic fluid cell culture of the first amniocentesis was 5% (50 cases); 29 cases had a repeat tap and successful diagnosis was achieved in all. In 21 cases, a repeat tap was refused. Thus, the overall failure rate of obtaining a final cytogenetic diagnosis was 2.06% (21/1,021). There were 32 fetal losses after amniocentesis including 16 spontaneous second trimester abortions, 7 fetal deaths in utero and 9 stillbirths. In two additional cases, fetal death had occurred before amniocentesis. This number of fetal losses does not exceed the number that would be expected in the same maternal age group without amniocentesis. In our series, the frequencies of trisomy in maternal age groups 40 years and over, 37–39 years, 35–36 years, and under 35 years were 4.5, 3.14, 0 and 0% respectively. These frequencies are comparable to those reported from other prospective prenatal studies and higher than those of retrospective live born studies. Various problems and pitfalls in prenatal cytogenetic diagnosis are discussed.     

A study of the cognitive and psychological profile in 16 children with congenital or juvenile myotonic dystrophy

We report data on intelligence and on possibly associated psychopathology in 16 children and adolescents, between 7 and 18 years of age, with congenital or juvenile myotonic dystrophy. We found that all the subjects have an intelligence level below the population mean, four of them in the mentally retarded range. An unexpected number of subjects are in the clinical range on the Child Behavior Checklist. In nine of the 16 subjects, a child psychiatric diagnosis was found using a standardized psychiatric interview. The most frequent child psychiatric diagnosis was Attention Deficit Hyperactivity Disorder.     

Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland

Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n = 93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value = 0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population.     

Prenatal diagnosis of congenital myopathies and muscular dystrophies

Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life‐span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases.     

Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) in Croatia

We report on the prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase in 20 at-risk pregnancies (16 salt-wasting and 4 simple virilizing families). We have diagnosed 3 affected fetuses (2 males and 1 female), 3 healthy homozygotes (2 males and 1 female), and 14 healthy heterozygotes (7 females and 7 males). These data were collected over 4 years. In 16 fetuses, the diagnosis was made with measurements of 17-hydroxyprogesterone (17-OHP) and Δ-4-androstenedione (Δ) in amniotic fluid (AF), human leukocyte antigen (HLA) typing of amniotic cells, as well as karyotypes between the 16th and 18th weeks of gestation. In 4 fetuses, DNA analysis of amniotic cells was also performed. In 3 pregnancies in which affected fetuses were suspected (on the basis of HLA typing and measurements of 17-OHP and Δ concentrations in AF), the fetuses were electively aborted between the 17th to 19th weeks of gestation by parental decision. In all aborted fetuses, diagnosis was confirmed with HLA typing, autopsy findings of hyperplastic adrenal glands, and ambiguous genitalia in female fetuses. Postnatal diagnosis was confirmed in healthy fetuses with HLA typing and serum measurements of 17-OHP concentrations, and in 4 of them with DNA analysis. In 3 of the 4 families, DNA analyses revealed the following mutations: in Family 1, the index case mutation was Intron 2, Exon 3/Exon 6, and the fetus was Normal/Exon 6; in Family 2, the index case mutation was Ex1 Int2 Ex3/Int2, and the fetus was Ex1 Int2 Ex3/Normal; and in Family 3, the index case mutation was Ex8₃₅₆/Ex8₃₅₆, and the fetus was Ex8₃₅₆/Normal. We also report one case of prenatal diagnosis and treatment. Dexamethasone 0.5 mg BID (20 μg/kg/d) was given starting at 6th week of gestation. Prenatal diagnosis suggested, but did not prove, that the female fetus was a heterozygote as the fetus lacked the paternal mutation Ex8₃₁₈. No mutation was found in the mother. The fetus, the mother, and the affected sib shared a haplotype, further suggesting heterozygosity. The unaffected status was confirmed postnatally. Am J. Med. Genet. 72:302–306, 1997. © 1997 Wiley-Liss, Inc.     

Prenatal diagnosis and fetal therapy of congenital cystic adenomatoid malformation type I of the lung: a report of five cases

ABSTRACT  We experienced five pregnancy cases with type I congenital cystic adenomatoid malformation (CCAM) of fetuses and summarized here their clinical characteristics, pregnancy outcomes, and fetal therapies. Four of five cases were prenatally diagnosed using magnetic resonance imaging (MRI) as having lung abnormality, and the remaining case was prenatally diagnosed as having congenital diaphragmatic herniation (CDH). One fetus underwent the puncture of cysts in the lung, and two fetuses received in utero thoracoshunts between cysts and the amniotic fluid cavity (thoracoamniotic shunt). One pregnancy ended in artificial termination at 17 gestational weeks, and 4 pregnancies succeeded in live births. All these 4 infants underwent surgical operations for CCAM, and 1 infant underwent an additional operation for CDH. The MRI examinations were useful to prenatally identify CCAM, and the in utero thoracoamniotic shunt appears to be beneficial in preventing lung hypoplasia in the affected fetuses.     

Prenatal diagnosis of low level trisomy 15 mosaicism: review of the literature

Low level chromosome mosaicism found at amniocentesis is problematic for clinicians and patients. We report prenatal diagnosis of a fetus with a rare karyotype of 47.XX, + 15/46, XX. Second trimester amniocentesis was performed for advanced maternal age. Fetal ultrasound revealed a hypoplastic right ventricle and intrauterine growth retardation (IUGR). The rest of the fetal anatomy was within normal limits. A mosaic karyotype of 47.XX, + 15/46, XX was observed. The couple interrupted the pregnancy at 19 weeks by dilation and suction evacuation. Careful evaluation of multiple pieces of fetal parts and placenta revealed one abnormal finding: a single umbilical artery. Cytogenetic metaphase and fluorescent in situ hybridization (FISH) interphase analyses of cells from fetal lung, heart, placenta, and skin revealed the presence of the trisomic line in all tissues. Molecular analysis demonstrated that the origin of the extra chromosome 15 was maternal, the error most likely occurred in meiosis I and the diploid line was of biparental inheritance. This case report discusses the associated findings in this fetus and reviews the literature describing other cases of mosaic trisomy 15.     

Amniotic fluid secretor typing: Validation for use in prenatal prediction of myotonic dystrophy

Use of the well-established linkage of the secretor locus (Se) to the myotonic dystrophy locus (Dm) as an indirect means for prenatal prediction of myotonic dystrophy requires that the phenotypic expression of the fetal secretor locus be accurately and reliably assessed in amniotic fluid. Secretor status determinations on 89 amniotic fluids obtained by second trimester amniocentesis were compared with results of postnatal secretor typing of saliva samples collected from the resulting 89 offspring. The secretor types of the paired amniotic fluid-saliva samples were in agreement in all cases. The only unusual typing result was on an amniotic fluid from a blood group O secretor fetus in which the level of soluble H antigen was estimated to be about one-third that observed for other H secretors. Though it is possible that rare secretor fetuses with very low titers of soluble antigen at the time of amniocentesis could be mistyped as non-secretors, our results indicate that such an erroneous typing result would only occur in about 1-2% of all amniotic fluids tested. Constructed mixtures of 10% heparinized blood in non-secretor amniotic fluid or of 10% serum in amniotic fluid derived from secretor fetuses did not introduce sufficient levels of soluble antigen or of antibody to interfere with accurate secretor typing, thus providing reassurance that maternal and/or fetal blood contamination of amniotic fluid does not compromise accuracy of fetal secretor typing. This study documents the accuracy and reliability of amniotic fluid secretor typing for prenatal prediction of fetal risk for later development of myotonic muscular dystrophy.