Role of curdlan sulfate in the binding of HIV-1 gp120 to CD4 molecules and the production of gp120-mediated TNF-alpha

In this paper the costs and benefits associated with DNA diagnosis of subjects who are at risk of having a child with a monogenic disease and who seek genetic counselling because of their reproductive plans are predicted under various assumptions using a mathematical model. Four monogenic diseases have been considered: cystic fibrosis, Duchenne muscular dystrophy, myotonic dystrophy, and fragile X syndrome. Counselling (triggered by previous information) on the basis of DNA diagnosis is compared to the situation that only risk evaluation based on pedigree analysis is possible. The results show for each disease that with DNA diagnosis, couples can be more confident in choosing (further) offspring leading to the birth of more healthy children while the number of affected children is reduced. The costs minus savings within the health care sector depend on the prior risks and on the future burden of the monogenic illness under consideration. DNA diagnosis of relative "low" prior risks of a child with CF (for example, 1:180, 1:240 and 1:480) leads to costs instead of savings. For higher prior risks of CF and for the three other diseases, DNA diagnosis produces considerable savings. This result remains valid when assumptions regarding behaviour, reproduction, and receiving DNA diagnosis under different circumstances are varied.     

Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring

OBJECTIVE: To assess the relationship between the GCT repeat number in the myotonic dystrophy gene and the clinical phenotype and examine its predictive utility in prenatal testing. DESIGN: DNA from patients was examined for the length of the myotonic dystrophy GCT repeat region, using both Southern blot analysis and polymerase chain reaction. The results were compared with the clinical onset of disease, as well as with pregnancy outcomes. SETTING: Patient samples were referred to the Kleberg DNA Diagnostic Laboratory at the Baylor College of Medicine for DNA analysis by geneticists and genetic counselors (84%), neurologists (10%), and obstetricians and other specialists (6%). Clinical features including onset of disease and family pedigrees were determined by the referring centers. PATIENTS: A total of 241 patient samples from 118 families referred from primarily genetic or neurological centers for genetic linkage analysis or mutation analysis for myotonic dystrophy. This included 44 families referred for prenatal diagnosis. MAIN OUTCOME MEASURES: A relationship between myotonic dystrophy disease onset and length of the GCT repeat allele, parental origin of the disease allele, and results of prenatal diagnosis predictions of disease status were measured. RESULTS: There is a relationship between increasing repeat length and earlier clinical onset of disease. Essentially all (> 99%) myotonic mutations causing myotonic dystrophy are accounted for by GCT repeat amplification. Congenital myotonic dystrophy occurs with as few as 730 GCT repeats but only with alleles of maternal origin. Maternal GCT repeats were found as low as 75 (asymptomatic) that were amplified to result in a child with congenital myotonic dystrophy. Application of DNA diagnosis to 32 pregnancies provided an accurate method for identification of at-risk fetuses and allele enlargement. CONCLUSIONS: The GCT repeat in myotonic dystrophy is highly mutable. The triplet repeat amplification is highly specific for mutations involving the myotonin protein kinase gene accounting for myotonic dystrophy. The quantitation of triplet repeats can be more sensitive than physical, ophthalmologic, and electromyography examinations since the mutation can be detected in patients without evidence of myotonic dystrophy clinical findings. The length of the triplet expansion is influenced by the sex of the transmitting parent and is related to the clinical onset of disease features. Prenatal measurement of the GCT triplet repeat has utility for families with myotonic dystrophy risk since mutant and normal repeats are distinguishable and the length of mutant repeat alleles is associated with clinical severity. Thus, GCT triplet measurement provides a highly accurate means of detecting the myotonic dystrophy mutation in patients and offers a new reproductive option for families at risk for myotonic dystrophy.     

Features of the type of inheritance of myotonic dystrophy

The characteristic features of the genetics of myotonic dystrophy (MD) in the Bulgarian population were studied. Seventy-nine pedigrees were analyzed, comprising a total of 119 patients with MD. The following characteristic features of the MD genetics were revealed: (1) Different families exhibited different patterns of the disease transmission, including vertical (as in the autosomal dominant mode of inheritance), horizontal (as in the autosomal recessive mode of inheritance), and mixed (the horizontal transmission for the first generations and the vertical transmission for the subsequent ones); (2) All studied pedigrees were traced back to clinically healthy ancestors; (3) The symptoms of MD exhibited in anticipation, as well as a clinical heterogeneity in sibships with respect to the severity of the disease. The characteristic features of the revealed mode of inheritance may be explained by dynamic mutations.     

Myotonic dystrophy, syringomyelia, and 2/13 translocation in the same family

The present report describes a sibship with 2 individuals affected by myotonic dystrophy and a third with syringomyelia. The mother was affected by myotonic dystrophy. A balanced 2/13 translocation was detected in the individual with syringomyelia, in one affected by myotonic dystrophy and in their clinically normal father. The association between the phenotypic anomalies and the chromosome alteration is coincidental.     

Myotonic dystrophy is a significant cause of idiopathic polyhydramnios

OBJECTIVE: Myotonic dystrophy, the most common form of muscular dystrophy seen in pregnant women, may be a significant cause of middle trimester polyhydramnios. Our purpose was to determine the prevalence of myotonic dystrophy in women with idiopathic polyhydramnios and to characterize the ultrasonographic findings associated with cases. STUDY DESIGN: We examined the cases of 67 patients who were delivered of infants at the University of Utah between 1992 and 1996 with a diagnosis of idiopathic polyhydramnios (amniotic fluid index >25). Women with diabetes mellitus, hydrops, or fetal anomalies known to cause polyhydramnios were excluded from the study. Amniotic fluid samples or cord blood samples were obtained from 41 patients, and polymerase chain reaction amplification and Southern blot analysis were performed to detect the presence of the myotonic dystrophy mutation. Ultrasonographic findings, prenatal course, and neonatal outcomes were reviewed in all cases. RESULTS: Four of the 41 patients tested had the myotonic dystrophy mutation, yielding a prevalence in our population of 9.7%. Three of the 4 patients reported a family history of myotonic dystrophy. Ultrasonographic findings associated with a positive result included abnormal posturing of extremities (3/4) and unilateral clubbed foot (3/4). No other structural or growth abnormalities were seen. Two of the patients were delivered before term, 1 at 26 weeks and 1 at 32 weeks. Three of the 4 infants were severely affected, necessitating admission to the intensive care unit, and 1 died on day 11 after birth. One infant, whose myotonic dystrophy mutation consisted of between 800 and 900 triplet repeats, did not require admission to the intensive care unit. CONCLUSION: Myotonic dystrophy may be seen as idiopathic polyhydramnios and should be considered as part of the differential diagnosis in these cases. Women with a familial history of myotonic dystrophy or ultrasonographic evidence of hypotonia, including positional abnormalities of the extremities, should be offered deoxyribonucleic acid testing for the myotonic dystrophy mutation.     

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.     

Anterior temporal white matter lesions in myotonic dystrophy with intellectual impairment: an MRI and neuropathological study

We studied 12 patients with myotonic dystrophy using MRI and the Mini-mental state examination (MMSE), to see it specific MRI findings were associated with intellectual impairment. We also compared them with the neuropathological findings in an autopsy case of MD with intellectual impairment. Mild intellectual impairment was found in 8 of the 12 patients. On T2-weighted and proton density-weighted images, high-intensity areas were seen in cerebral white matter in 10 of the 12 patients. In seven of these, anterior temporal white-matter lesions (ATWML) were found; all seven had mild intellectual impairment (MMSE 22-26), whereas none of the four patients with normal mentation had ATWML. In only one of the eight patients with intellectual impairment were white-matter lesions not found. Pathological findings were severe loss and disordered arrangement of myelin sheaths and axons in addition to heterotopic neurons within anterior temporal white matter. Bilateral ATWML might be a factor for intellectual impairment in MD. The retrospective pathological study raised the possibility that the ATWML are compatible with focal dysplasia of white matter.     

Human papillomavirus investigation of patients with cervical intraepithelial neoplasia 3, some of whom progressed to invasive cancer

Unstable expansion of the CTG repeats in the 3' untranslated region encoding a member of the protein kinase family in the q13.3 band on chromosome 19 is a mutation specific for myotonic dystrophy. To examine the correlation between clinical expression and CTG trinucleotide repeat length, we carried out Southern blot analysis in a family with myotonic dystrophy. In this pedigree, the expanded CTG repeats were transmitted maternally. The mother had three female children. The mother had about 200 CTG repeats, and the number of repeats for each child was about 800, 1500 and 1600 in birth order. The mother and the patient with 800 repeats were unaware of muscle weakness or myotonia. Symptoms were present from age 3 years in the patient with 1500 repeats and from birth in the one with 1600 repeats. Although the mother menstruated regularly, the patients with 800 and 1500 repeats both menstruated irregularly, and the one with 1600 repeats has never menstruated. The age of onset and severity of the disease were correlated with the size of the expanded repeats. Endocrinological studies revealed that the basal levels of the gonadotropins, PRL and E2 were within normal range, and a pituitary response to LHRH was observed. These data suggest that the amenorrhea and menstrual irregularities were caused by a suprahypophyseal dysfunction. When expanded CTG repeats are transmitted maternally, abnormal products resulting from the metabolic disturbance in the affected mother may harm the fetus in utero. A heterozygous fetus, who has more CTG repeats, may be unable to metabolize the pathologic products sufficiently and therefore may become more severely affected. This may explain the exclusive maternal transmission of congenital myotonic dystrophy.     

Angioarchitectural comparison of the filiform papillae of the cat and rabbit using scanning electron microscopic specimens

Women undergoing prenatal diagnosis (PND) for psychological reasons constitute a considerable proportion (10-20 per cent) of tests carried out on pregnant women. In these cases, the couple is below the lower limit for parental age, and there is no increased genetic risk. The aim of the present study was to describe the psychosocial background of women asking for PND on psychological grounds and to evaluate their wish for PND. A consecutive series of 51 women were interviewed in the 12th-15th week of gestation before attending for the test. Forty-five per cent were close to the limit for advanced maternal age (35-37 years). Most of them were educated and had stable partners; more than half of the women worked in nursing. Almost half (23/51) of them had previous psychic problems and 29/51 showed depressive mood. During childhood, 21 women had experienced severe disease or handicap. One-third (17/51) of them had been a consolidating member in their family. More than half (33/51) described considerable problems in relation to their mother or to motherhood and 10/51 in their relation to their father. Half of the women described at least three and only three women none of the following six identified predisposing factors: previous or present psychic insufficiency, experience of disability in childhood, role as a significant supporter in childhood, problems in relation to own mother, problems in relation to own father. These women's anxiety was understandable when their psychological history and current mental status were recognized. More than half of the women (29/51) were considered to have strong and 22 moderately strong psychological reasons for their desire to have prenatal diagnosis.     

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.     

A retrospective radiographic survey of embedded primary molar roots in Saudi adult patients

We compared the fluid-attenuated inversion recovery (FLAIR) sequence with conventional spin-echo (SE) imaging for detection of involvement of the central nervous system in five patients with myotonic dystrophy (MD). The diagnosis was made based on clinical features and DNA analysis. All patients showed abnormal high-intensity lesions in the white matter on T2-weighted images, although these were more clearly visible using FLAIR.     

Primary suprarenal insufficiency and multiglandular atrophy in a patient affected by myotonic dystrophy

We present the case of a 27 year old man diagnosed as having myotonic dystrophy (MD) who showed two novelties with respect to those endocrinopathies hitherto described as being associated with MD: primary suprarenal failure and pluriglandular atrophy (thyroid and suprarenal, in addition to the already known testicular type). We describe here the results of a clonic, hormonal and genetic study of the proband and his family (a carrier father and an affected brother). We discuss the possible etiopathogenesis of the picture which, in our opinion, could consist of an abnormality of the AMPc dependent protein-kinase, related to the MD gene (PKMD). Consequently intracellular signaling was altered after the union of peptide hormones (in our case ACTH, LH and TSH) to their receptor leading, through the lack of trophic stimulus, to glandular atrophy. We conclude that before diagnosing MD, it is convenient to add suprarenal study to the traditional evaluations of possible associated endocrinopathies.     

Transfusion malaria in sick neonates

A 45-year-old woman was incidentally suspected to have megacolon. Chest X-rays showed elevated left diaphragm due to colonic gas, and the heart was deviated to the midline. Barium enema revealed marked dilation of the sigmoid colon, confirming the diagnosis of megacolon. Maximal diameter of the sigmoid colon was 23 cm, but she had no gastrointestinal symptoms. During the work up for megacolon, the presence of myotonic dystrophy was suspected. She had hatchet face, but was not bald. Muscles of the neck and extremities were slightly atrophic. There was percussion myotonia of the tongue and both hands, and grip myotonia of the hands. Laboratory examinations showed impaired glucose tolerance and low level of serum IgG. EMG showed myotonic discharges and myopathic units in the limbs. Brain CT imaging revealed a thick skull. Cases of myotonic dystrophy associated with marked megacolon are rare in Japan. Megacolon presents a high risk for ileus, volvulus, and rupture, and myotonic dystrophy is associated with a high operative and anesthesic risk. Megacolon, therefore, is an important complication to look for in the management of myotonic dystrophy.     

Clinical manifestations of myotonic dystrophy: epidemiologic survey

BACKGROUND: The presence of a local aggregation of cases of myotonic dystrophy (MD) allows the evaluation of clinical symptoms of the disease in a sample in which the influence of a possible genetic heterogeneity is decreased. METHODS: The degree of global neuromuscular handicap and the incidence and severity of four of the most characteristic symptoms (cataracts, myotonia, muscular weakness and neuropsycologic disturbances) were studied in 183 patients with MD (146 typical adult forms, 19 neonatal, and 18 partial syndromes) in relation with the age of onset of the symptomatology or length of disease. RESULTS: Only 8.3% of the patients (excluding the neonatal forms) were severely handicapped, and the degree of neuromuscular handicap depended fundamentally on the age of onset of the disease. Cataracts and myotonia were present in 87 and 89% of the patients, respectively. Almost all the patients above the age of 40 presented cataracts. No clinical or subclinical evidence of neuromuscular involvement was present in 11% of the patients with MD. These patients principally corresponded to the group in whom the disease initiated over the age of 50. CONCLUSIONS: The age of onset of the symptomatology appears to be the determining factor to establish both the global prognosis of neuromuscular incapacity of patients with myotonic dystrophy and the explanation of the chronology of the appearance of the most characteristic symptoms of the disease. The presence of carriers without neuromuscular symptomatology is of note, this fact reinforcing the need to incorporate DNA examination in the evaluation of asymptomatic relatives or with exclusive ocular symptomatology.     

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.     

Instability of normal (CTG)n alleles in the DM kinase gene

We report on a myotonic dystrophy (DM) family exhibiting instability of normal sized (CTG)n alleles in the DM kinase gene on the non-DM chromosome. At least two mutational events involving normal DM alleles must have occurred in this family; one was characterised as a 34-35 (CTG)n repeat mutation. These findings represent a dissociation between (CTG)n repeat instability and myotonic dystrophy. Furthermore, this family highlights genetic counselling issues relating to the pathogenicity of alleles at the upper end of the normal size range and the risk of further expansion into the disease range.     

The stretch reflex in the Eaton Lambert syndrome, myasthenia gravis and myotonic dystrophy

The stretch reflex at rest and after muscle work was studied in three cases of Eaton Lambert syndrome. After muscle work a potentiation of the stretch reflex was demonstrated clinically and electrophysiologically. The presence of muscle stretch reflexes and their potentiation after muscle work was correlated with the clinical stage of the disease. The enhancement of the stretch reflex after voluntary effort was absent in normal subjects, myasthenia gravis and myotonic dystrophy.     

Buffy coat platelets stored in apyrase, aprotinin, and ascorbic acid in a suspended bag: combined strategies for reducing platelet activation during storage

The aim of the study was to compare the masticatory pattern and the activity of the masticatory muscles of a group of myotonic dystrophy patients with those of a group of healthy individuals. The electromyographic (EMG) activity of the temporal and the masseter muscles was measured in the resting position, during maximal clenching, and while the patient was chewing five peanuts until swallowing. It was found that the patients had approximately 3 times less EMG activity in the masticatory muscles during maximal clenching. During chewing the patients had approximately half the activity in the anterior temporal and the masseter muscles, while the activity of the posterior temporal muscle did not differ significantly from that in healthy individuals. No differences were found in the muscle activity in the resting position or in the speed of chewing between the groups. The patients needed more time and more chewing cycles to bring the five peanuts to the swallowing threshold, but possibly this was an effect of the lower number of antagonizing teeth. Myotonic dystrophy thus influences the masticatory muscles, reducing their activity both at a maximal and a functional level.     

Effects of orthotopic liver transplantation on body composition

The aim of this prospective noninvasive follow-up study was (1) to assess the progression of cardiac involvement (CI) in patients with myotonic dystrophy (MD), Becker's muscular dystrophy (BMD) and mitochondrial myopathy (MMP), (2) to find out if CI and neurologic impairment are related and (3) to determine how often cardiac investigations should be performed. Clinical, electrocardiographic, echocardiographic and 24-hour ambulatory electrocardiographic examinations were performed at yearly intervals. CI was assessed qualitatively by the presence of pathologic examinations and quantitatively by the number of pathologic examinations. Qualitatively, CI was present at baseline in 36 of the 38 cases (18-68 years) and the number of cases did not change. Quantitatively, CI progressed after 1 (2) year in 50% (50%) of patients with MD (n = 16), 0% (43%) of patients with BMD (n = 7) and 27% (27%) of patients with MMP (n = 15). CI and neurologic impairment were not related (p = 0.54). Cardiac investigations should be repeated at yearly intervals irrespective of whether there is neurologic deterioration or not.     

Intellectual impairment and brain MRI findings in myotonic dystrophy: with a special reference to hippocampal atrophy and white matter lesions

We performed a correlative study between intellectual impairment, CTG repeat expansion and magnetic resonance imaging (MRI) abnormalities, including hippocampal atrophy, white matter lesions and ventricular dilatation in 15 patients with myotonic dystrophy (MD). They included 4 males and 11 females aged from 20 to 66 years, averaging 43 years of age and 15 years of duration of illness. Nine patients had intellectual impairment (WAIS-R<80). Negative correlations were found between full scale IQ (FSIQ), duration of illness (p<0.05) and CTG repeat expansion (p<0.05). Compared with normal controls, the patients with MD showed a significant reduction in size of the hippocampal head (p<0.01), which was positively correlated to FSIQ, verbal IQ and performance IQ levels (p<0.05). Ten patients had white matter lesions. Severer white matter lesions tended to be recognized in patients with longer duration of illness and with decreased FSIQ level. These results suggest that hippocampal atrophy and white matter lesions are related to intellectual impairment in patients with MD.