Cataract and myotonic dystrophy: the role of molecular diagnosis

Myotonic dystrophy (dystrophia myotonica), the commonest and most variable of the muscular dystrophies of adult life, has long been known to be associated with cataract, while slit-lamp examination for specific lens opacities has been one of the principal methods of presymptomatic detection of gene carriers. The recent discovery that the myotonic dystrophy mutation is an unstable DNA sequence, composed of varying numbers of CTG triplet repeats, now allows a specific molecular test for this disorder, as well as explaining the phenomenon of anticipation. A series of case reports is presented to illustrate the important practical applications of this development in relation to ophthalmic aspects of the disorder. Reassessment of the specificity of the ophthalmic changes may be required and it will be important for molecular analysis to be used alongside ophthalmic studies, when determining whether family members carry the mutation for myotonic dystrophy.     

Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies

A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations.     

Expanding complexity in myotonic dystrophy

Myotonic dystrophy (DM) is a highly variable multisystemic disease belonging to the rather special class of trinucleotide expansion disorders. DM results from dynamic expansion of a perfect (CTG)n repeat situated in a gene-dense region on chromosome 19q. Based on findings in patient materials or cellular and animal models, many mechanisms for the causes and consequences of repeat expansion have been proposed; however, none of them has enjoyed prolonged support. There is now circumstantial evidence that long (CTG)n repeats may affect the expression of any of at least three genes, myotonic dystrophy protein kinase (DMPK), DMR-N9 (gene 59), and a DM-associated homeodomain protein (DMAHP). Furthermore, the new findings suggest that DM is not a simple gene-dosage or gain-or-loss-of-function disorder but that entirely new pathological pathways at the DNA, RNA, or protein level may play a role in its manifestation.     

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.     

Extraocular muscle surgery in myotonic dystrophy

A 44-year-old woman with severe variant angina refractory to maximal medical therapy and at risk of sudden death was successfully treated by a NIR stent implantation on a moderate lesion of LAD. Six months later she was asymptomatic, without in-stent restenosis. This procedure represents an alternative treatment for patients with refractory vasospastic angina.     

Mechanisms of diarrhoea in myotonic dystrophy

BACKGROUND: Gastrointestinal (GI) symptoms are common in myotonic dystrophy (MD). Diarrhoea is one of the more disabling of these GI complaints. The mechanisms behind diarrhoea in MD have not previously been investigated systematically. OBJECTIVE: To elucidate the mechanisms behind diarrhoea in MD. METHODS: Twenty patients with MD and suffering from diarrhoea were investigated in order to detect malabsorption (blood tests and faecal fat excretion) and bile acid malabsorption ([75Se]selenahomocholic acid-taurine (SeHCAT) retention) and to study intestinal morphology (duodenal and rectal biopsies). RESULTS: Two patients had deficiency of folic acid and four showed reduced levels of pancreatic isoamylase, but none of them had steatorrhoea. Two out of eight patients had abnormal bile acid breath tests with normal SeHCAT, indicating small bowel bacterial overgrowth and 12 displayed reduced SeHCAT retention. Duodenal biopsies were normal in eight patients and five out of nine rectal biopsies displayed slight inflammation. CONCLUSIONS: A possible mechanism of diarrhoea in MD could be identified in most of the patients. Bile acid malabsorption seems to be a frequent cause and can be treated successfully.     

Sevoflurane anesthesia for myotonic dystrophy

We successfully anesthetized a 14-year-old boy with myotonic dystrophy for orthopedic surgery using sevoflurane. Sevoflurane enabled anesthetic induction and tracheal intubation without intravenous anesthetics and muscle relaxants. Sevoflurane also provided stable anesthetic maintenance without intravenous anesthetics. The patient showed rapid anesthetic recovery and adequate spontaneous breathing. We conclude that sevoflurane is a useful anesthetic for patients with myotonic dystrophy.     

Molecular genetic study in congenital myotonic dystrophy

Congenital myotonic dystrophy (CMD) is the neonatal form of Steinert's myotonia. However, the symptoms and neuro-physiological findings are different from the classical adult form, there is a high mortality and early diagnosis of the condition is difficult. CMD occurs as a result of abnormal expansion of CTG triplets on chromosome 19. There is dominant autosomal transmission of this multi-systemic disorder, although when it occurs in children, it is the mother who is always the affected parent. Molecular genetic techniques enable unequivocal diagnosis of the condition, evaluation of anticipation and the possibility of offering genetic counselling to the families involved.     

Insulin resistance and clinical evolution in infantile myotonic dystrophy

1. Extensor digitorum longus muscles of C57 BL/10 and mdx mice were overloaded by removing the synergist tibialis anterior muscle of 9-12-day-old animals. The effect of this operation on the weight, contractile properties and force of the extensor digitorum longus muscle was examined at two different ages, i.e. at 2-3 months (young group) and at 5-8 months (old group). The changes with age in both the control and overloaded muscles of normal and mdx mice are also described. The values obtained from the overloaded muscles were always compared with those for the control, unoperated extensor digitorum longus. 2. In the normal strain of mice the weight of the overloaded extensor digitorum longus muscle in the younger group was increased and it remained higher in the older animals. In the mdx mice the overloaded extensor digitorum longus muscles weighed more in the younger animals but not in the older group of mice. 3. The twitch and tetanic tensions of the overloaded muscles were slightly, but not significantly, increased in the younger group of mdx mice, whereas in the older animals there was a significant decrease in both twitch and tetanic tensions. 4. Thus the overloaded muscles from mdx mice progressively deteriorated with age. In both strains of mice the overloaded muscles become less fatigable with time.     

Pneumoperitoneum complicating mechanical ventilation in congenital myotonic dystrophy

We have studied the train-of-four (TOF) response mechanomyographically during onset of neuromuscular block produced by subclinical doses of suxamethonium in order to follow the augmentation of the first twitch of the TOF (T1) and TOF fade compared with control TOF responses before the drug was given. In the groups given suxamethonium 0.05, 0.1, 0.2 and 0.3 mg kg-1, the increments in T1 after administration of the drug were observed before twitch depression occurred; these were mean 22.3 (SEM 8.1)%, 19.2 (3.3)%, 10.8 (2.0)% and 4.2 (2.2)%, respectively. This effect was more marked with the lower doses (P < 0.05). The degree of TOF fade was moderate during onset of neuromuscular block and depended on the dose of drug. The results of this study suggest that low doses of suxamethonium produced transient increase in muscle tension and twitch depression with significant TOF fade. We conclude that suxamethonium was associated with presynaptic effects as a consequence of brief stimulation of acetylcholine release followed by progressive diminution at the neuromuscular junction.     

Are muscle fibers denervated in myotonic dystrophy?

An underlying neurogenic abnormality has recently been postulated in the muscular dystrophies. To test this hypothesis, we applied a widely accepted criterion of denervation-ie, and increase in extrajunctional acetyicholine (ACh) receptor sites--to muscles biopsy specimens from nine patients with myotonic dystrophy and three with amyotrophic lateral scierosis (ALS). The ACh receptor sites were determined by means of iodine 125-labeled alpha-bungarotoxin binding, measured by scintillation counting and autoradiography. None of the myotonic dystrophy muscles showed increased extrajunctiona ACh receptor sites, even in the smallest fibers. By contrast, muscle biopsy specimens from patients with ALS showed notably increased extrajunctional ACh receptor sites, especially in the small fibers. Our findings do not support the hypothesis of a neurogenic defect in myotonic dystrophy.     

Steinert''s congenital myotonic dystrophy. Genetic aspects

The study of the air contamination was carried out in six fruit farms located in the region of Grójec and Warka. The measurements were carried out during the application of "Fastac 10EC" insecticide (alphamethrin) in fruit growing at work sites of tractor drivers operating the sprayers. The mean concentrations of alphamethrin at individual work sites were low and ranged between 0.001 and 0.0039 mg/m3 of the air. Due to the lack of maximum allowable concentration (MAC), the inhalation toxicity of alphamethrin of 320 mg/m3 (4-h), toxicity class of alphamethrin (III) and MAC of natural pyrethrum were considered. In this context the determined concentrations seem to be safe.     

Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy

We studied 134 patients with Steinert's myotonic dystrophy (MD) in order to determine the prevalence of chronic hypercapnia, the level of muscle weakness and forced expiratory volume at which hypercapnic respiratory failure is likely to occur, and how clinical assessment might help predict hypercapnic respiratory failure. Subjects were divided into five classes with a muscular disability rating scale (MDRS): 0 = no clinical impairment (n = 9), I = minimal signs of impairment (n = 11), II = distal weakness (n = 41), III = moderate proximal weakness (n = 62), and IV = nonambulatory (n = 11). The prevalence of hypercapnia (PaCO2 > or = 43 mm Hg) was found to be 0%, 27%, 29%, 45% and 55% for MDRS 0 to 4, respectively (p = 0.03). A multiple regression analysis limited to clinical data showed that daytime hypersomnolence was a significant cofactor with the MDRS (p = 0.01) in predicting PaCO2 (r = 0.40). Among respiratory parameters, FVC, respiratory muscle strength (RMS), and maximal inspiratory pressure against occluded airways (PImax) were found to be predictors of nearly equal strength, explaining 16%, 15%, and 14% of the PaCO2 variance, respectively. In multiple regression analysis, sex, daytime sleepiness, and the expected/observed FVC ratio for a given RMS were found to be significant cofactors with PImax in predicting PaCO2 (r = 0.51). It is concluded that respiratory insufficiency should be suspected in MD patients with proximal weakness or daytime sleepiness. The likelihood of hypercapnia also increases with volume restriction and respiratory muscle weakness. Our study suggests that the combination of inspiratory muscle weakness and loading plays a predominant role in the pathogenesis of chronic alveolar hypoventilation in MD patients. The occurrence of daytime hypersomnolence suggests that other factors, such as low central ventilatory drive or sleep apnea, might play an additional role.     

Contrasts in clinical presentation and genetic transmission of myotonic dystrophy

Myotonic dystrophy, the most common inherited neuromuscular disease, is an autosomal dominant muscular dystrophy characterized by myotonia and distal muscle weakness. It is caused by an increase in the number of cytosine-thymine-guanine (CTG) nucleotide repeats present on the long arm of chromosome 19. Two patients were evaluated, one with classic adult-onset myotonic dystrophy and the other with congenital myotonic dystrophy. Contrasts in the clinical features and genetic transmission of this disease and clinical management are reviewed.     

Electron microscopic study of extraocular muscles in myotonic dystrophy

A study was made of the effect of morphine on electrical activity within single ganglia of Auerbach's plexus of guinea pig longitudinal muscle-myenteric plexus as monitored by means of external electrodes. Morphine produces a concentration dependent block of single spike activity. This effect is competitively antagonized by naloxone. The ED50 for morphine effect is about 7 X 10(-7) M. Naloxone and dextrorphan have no effect on electrical activity. Acetylcholine in the concentration range of 10(-7)--10(-5) M augments electrical activity of ganglia. Morphine has little if any effect on the enhanced stimulation produced by acetylcholine thus indicating that the drug does not act directly upon the ganglion. Our results suggest that a specific opiate receptor is present on the preganglionic nerve terminals and that morphine and other opiates block ganglionic transmission by inhibiting the release of preganglionic acetylcholine.