Segregation distortion in myotonic dystrophy.

Myotonic dystrophy (DM) is an autosomal dominant disease which, in the typical pedigree, shows a three generation anticipation cascade. This results in infertility and congenital myotonic dystrophy (CDM) with the disappearance of DM in that pedigree. The concept of segregation distortion, where there is preferential transmission of the larger allele at the DM locus, has been put forward to explain partially the maintenance of DM in the population. In a survey of DM in Northern Ireland, 59 pedigrees were ascertained. Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring. Where the transmitting parent was male, 58.3% of the offspring were affected, and in the case of a female transmitting parent, 68.7% were affected. Studies on meiotic drive in DM have shown increased transmission of the larger allele at the DM locus in non-DM heterozygotes for CTGn. This study provides further evidence that the DM expansion tends to be transmitted preferentially.     

Intestinal pseudo-obstruction in myotonic dystrophy.

We describe four myotonic dystrophy (DM) patients who developed recurrent intestinal pseudo-obstruction. Some episodes were associated with gastroenteritis, while abdominal crowding may have occurred in one case during the third trimester of pregnancy. In most instances, however, no apparent cause could be identified. Intestinal pseudo-obstruction may occur at any stage of DM. In one of our cases intestinal pseudo-obstruction preceded significant muscle weakness by 15 years. Intestinal pseudo-obstruction is usually treated effectively with conservative measures. These include restriction of oral intake, intravenous fluids, and multiple enemas or colonoscopy. Improved intestinal function was noted in one case treated with the prokinetic agent cisapride. A partial sigmoid resection was performed in three cases with dolichomegacolon. No abnormalities were reported on histological examination. Since intestinal pseudo-obstruction is a rare complication of DM, it is of interest that two of our cases are sibs. Review of published reports showed several reports of familial occurrence of specific complications. These include cardiac conduction disturbances, focal myocarditis, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, and dilatation of the urinary tract. Myotonic dystrophy may show a tendency to familial clustering of organ specific involvement.     

Presymptomatic diagnosis of myotonic dystrophy.

The discovery of an expanded (CTG)n repeat sequence in myotonic dystrophy (DM) has greatly improved our ability to detect DM gene carriers who have few or none of the classical signs of this disorder. We report here our experience with two such groups of gene carriers. We used a PCR based protocol that should be especially sensitive to small increases in CTG triplet number which might escape detection by conventional Southern blot analysis. Our analyses show that on 100 non-DM chromosomes the number of CTG triplets ranged from five to 37. We then studied 17 obligate gene carriers aged 55 years and over who showed no muscle weakness. All of the gene carriers in this group showed a relatively small increase in the number of CTG triplets (52 to 90 CTG triplets) with limited somatic mosaicism. We subsequently studied 11 subjects (aged 19 to 36 years) who had previously been identified as gene carriers by genetic linkage studies, but who lacked diagnostic signs. In this prospectively studied group, nine subjects showed an expanded allele, confirming the earlier prediction from linked genetic markers. The other two subjects had only two normal alleles and no expanded allele. Revision of the clinical data casts doubt on the original diagnosis of DM in their families. Preferential amplification of the normal non-expanded allele was noted in three asymptomatic gene carriers in this study (as well as in two of their clinically affected relatives). We caution that, at least in our hands, the DM mutation can be confidently excluded by this PCR based method only if both normal alleles have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical evidence for heterogeneity in myotonic dystrophy.

In a study of 35 index patients who developed myotonic dystrophy between birth and 30 years (neonatal cases aware excluded), 30 could be categorised into two clinical types. The 13 type 1 patients had a more severe limb weakness, of patchy distribution, associated with proportional facial weakness. The 17 type 2 patients had a milder and more diffuse limb weakness; their facial weakness, however, was very pronounced and preceded the limb weakness by several years. All but one of the 25 affected relatives who were examined belonged to the same category as their index relative, providing evidence that the cause of the clinical heterogeneity was genetic. Subsequent observations showed that mental retardation, male infertility, and neonatally affected offspring were commoner in type 2 patients. Congenital myotonic dystrophy could occur among the offspring of either affected males or affected females, but neonatal symptoms were confined to the offspring of affected women. The overall risk for having neonatally affected offspring for this prospective study of young adult patients was 7 in 38, and for the offspring of affected females 7 in 27. The risk for having a surviving child whose mental or physical handicap or both required special schooling was 1 in 12 for males and 4 in 27 for females.     

Altered motor neuron excitability in myotonic dystrophy.

Using standard electrophysiologic techniques motor conduction velocity (MCV), motor action potential amplitude (Mmax), minimum F latency (Flat), maximum F amplitude (Fmax), F chronodispersion (Fdisp), Fmax/Mmax, and F persistence (Fpers) were measured in median, ulnar, peroneal, and tibial nerves (N = 60) in 15 patients with myotonic muscular dystrophy (DM). The results were compared to data from 80 nerves in 20 healthy controls. The DM group (mean age = 39.7 yrs, mean duration of symptoms = 20.8 yrs) had diminished or absent biceps, triceps, knee, and ankle reflexes but retained 4- or better strength (modified MRC Scale) in the respective muscles. Thirteen nerves in 6 patients had absent F waves. For the remaining 47 nerves, no statistically significant difference was noted in parameters primarily related to conduction through peripheral nerve fibers (MVC, Flat, Fdisp) or Fmax/Mmax. Fmax, Fpers and Mmax were significant (p less than or equal to .02) diminished in all nerve subgroups in the DM patients. The results indicate that in DM there is altered excitability of the motorneuron pool. This may underlie the early loss of DTR's and produce the characteristic distal pattern weakness.     

Paternal transmission of congenital myotonic dystrophy.

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.     

Risk estimates for neonatal myotonic dystrophy.

Children who inherit the autosomal dominant gene for myotonic dystrophy from their mother rather than their father may develop the severe neonatal type rather than the late onset type. The families of 22 neonatal type probands and 59 late onset type probands were studied to determine the risk of occurrence and recurrence of the neonatal type. The frequency of the neonatal type in sibs of neonatal type probands was 29%, or 37% if cases of neonatal deaths are counted as affected. This is significantly higher than the 6% of the neonatal type found in the offspring of affected women not ascertained through a child with the neonatal type. These data suggest that certain women carrying the gene for myotonic dystrophy are predisposed to have children affected with the neonatal type rather than the late onset type. The female near relatives of these women do not seem to share this predisposition. The data should be useful for genetic counseling.     

Immune receptors (IgG-Fc and complement receptors) in normal human organs.

The presence of immune receptors (IgG-Fc and complement receptors) was examined in normal human tissues from various organs. Sheep erythrocytes sensitized with rabbit IgG antibody (IgG-EA) or with rabbit IgM antibody and human complement (IgM-EAC) were used for the detection of IgG-Fc receptors and complement receptors, respectively. IgG-Fc receptors were detected on sinuses of the lymph node, splenic red pulps, hepatic lobules, renal glomeruli, alveolar wall of the lung, intestinal villi, superifical layer of the synovium, and subcutaneous tissue. The presence of complement receptors was demonstrated in the follicles and the sinuses of lymph nodes, white pulp of the spleen, renal glomeruli, alveolar wall of the lung, and lamina propria of the intestine. The specific binding of IgG-EA was consistently inhibited by heat-aggregated human IgG or by a high concentration of native human IgG. The detection of immune receptors in these various tissues might be helpful for understanding why the immune complexes are often detected when immunologically mediated disease processes involve these tissues.     

Paternal transmission of congenital myotonic dystrophy.

The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counselling myotonic dystrophy patients and their families.     

A study of DNA methylation in myotonic dystrophy.

We have examined the hypothesis that the severe congenital form of myotonic dystrophy is caused by genomic imprinting at the level of differential DNA methylation of maternal and paternal alleles. Probes encompassing the 5', central, and 3' regions of the myotonic dystrophy protein kinase gene were used on blots of blood DNA from congenital and adult onset patients, digested with combinations of methylation sensitive and insensitive restriction enzymes. We observed similar patterns of methylation in each of the different classes of patient, and found no methylation differences between paternally and maternally derived alleles. Within the limitations of the experiment, our results provide no evidence for a role for genomic imprinting in congenital myotonic dystrophy and suggest that the explanation for this form of the disease will be found elsewhere.     

Origin of a regressed myotonic dystrophy allele.

A new case of regression of the CTG copy number in the myotonic dystrophy allele was observed in a 7 year old boy. His affected father had an expanded allele of about 100 repeats in his lymphocyte DNA while the child showed a 60 repeat allele, of the same size as the present in the grandfather. Analysis of the father's sperm DNA allowed us to detect an expanded fragment of approximately the same size (62 repeats) as that present in the child's and grandfather's lymphocytes. This fragment was not detectable in the father's lymphocytes. Thus the regression is constitutive in the child, being already present in his father's germline. It is therefore likely that the regressed allele is present in all the tissues of the child, allowing a favourable prognosis.     

Genotype -phenotype correlation in myotonic dystrophy

Myotonic dystrophy (DM) is caused by a mutation in the length of a trinucleotide (CTG) repeat in the 3' untranslated region of the myotonin protein kinase gene located on chromosome 19q13.3. The normal gene has between 5 and 36 CTG trinucleotide repeats, whereas minimally affected individuals have 50 copies and severely affected DM-patients have several thousands of such repeats. Since no information on a genotype–phenotype correlation in Austrian DM-patients is available, we examined a small group of these patients for the unstable trinucleotide repeat. Molecular analysis was used to clarify equivocal clinical diagnoses and confirm clinical findings. We studied eight DM-families, a total of 57 individuals, of whom 18 were diagnosed with a trinucleotide repeat expansion. Twenty-six unrelated individuals served as a control. Clinical assessment was based on the muscular disability rating scale (MDRS) and a sum of symptoms score (SSS). There was a significant correlation between the clinical scores (MDRS: Spearman r=0.51; p=0.029; SSS: Spearman r=0.538; p=0.0259) used and the size of the amplification of the trinucleotide repeat. The largest expansion found in our group of patients was 6 kb. Furthermore, we observed both expansion and contraction of the enlarged fragment during transmission from one generation to the next.     

Thin ribs in neonatal myotonic dystrophy

The recently described thin ribs seen in a neonate suffering from myotonic dystrophy represents a valuable sign for early detection of this condition. Thin ribs were found on chest radiographs of two siblings a short time after birth. This led in retrospect to the diagnosis of neonatal myotonic dystrophy. The diagnosis was confirmed by clinical and electromyographic data of myotonic dystrophy in the mother who was not previously known to have the disease. Both children died at the age of 2 days from respiratory distress. All children of affected mothers should have a chest radiograph soon after birth in order to help in diagnosis and to establish the frequency of this sign.