Molecular genetics of Huntington's disease]

Huntington's disease (HD) is a progressive neurodegenerative disorder which is clinically characterized by chorea, cognitive decline, and emotional disturbance; it is inherited in an autosomal dominant manner. The HD gene maps to chromosome 4p16.3. Our linkage analysis demonstrated a significant genetic linkage between Japanese HD families and the flanking markers, D4S127, D4S43. The molecular basis of the disease is an expansion of CAG repeat in the huntingtin gene. We performed molecular analysis of the repeat in Japanese HD patients and normal controls. The size of the CAG repeat ranged from 37 to 95 repeats in affected subjects and from seven to 29 in normal controls. A significant correlation was found between the age of onset and the CAG expansion. The length of the expanded repeat is unstable in meiotic transmission and large increases occur in paternal transmission. At the same time the CCG repeat polymorphism adjacent to the CAG repeat was analysed and haplotypes of HD chromosomes were identified. Striking linkage disequilibrium was found between the CAG repeat expansion and an allele of (CCG)10 in Japanese HD chromosome. It is distinct from that described previously in western populations. Western HD chromosomes strongly associate with an allele of (CCG)7.     

Molecular genetics. Introduction

While sharing the same techniques as the field at large, diagnostic molecular genetics is unique among the subdisciplines of molecular pathology in many of its aspects, from sample collection to ethical implications of the test results obtained. Yet, despite its many challenges, this branch of DNA diagnostics has already pervaded the practice of medical genetics to an extent unmatched in any other clinical specialty. Genetic disease also presents the most immediately obvious opportunities for extension from DNA-based diagnosis to DNA-based therapy.     

Growth and congenital heart disease

PURPOSE: To assess the efficacy of heparin in preventing the abrupt closure after coronary angioplasty in low risk patients for this phenomenon. METHODS: In the last 4 years, 525 patients successfully dilated were randomized to receive intravenous heparin (n = 264) or not (n = 261) after the angioplasty. The excluding criteria were contraindications for heparin and risk for abrupt closure (refractory unstable angina, primary coronary angioplasty in acute myocardial infarction, evidence of intracoronary thrombus, intimal tear after the procedure and cases of chronic total occlusions). Both heparin and non heparin groups were similar in respect to female sex (15% x 17%; p = NS), age over 70 years old (7% x 9%; p = NS), previous myocardial infarction (26% x 24%; p = NS), multi-vessel procedures (4% x 7%; p = NS, stable angina (40% x 46%; p = NS), unstable angina (52% x 48%; p = NS) and angioplasty after thrombolytic therapy (8% x 6%; p = NS). RESULTS: The overall incidence of abrupt closure was 2/525 (0.4%), with one case (0.4%) in each group. The in-hospital mortality was 1/525 (0.2%), which occurred in a non-heparin patient, due to a anterior myocardial infarction. Major complications occurred similarly in heparin and non-heparin groups (0.4%). Bleeding complications were observed more frequently in the heparin group (7% x 2%; p = 0.002). All of them were in the catheterization site and none required blood transfusion. Severe systemic bleeding were not observed. CONCLUSION: In patients regarded as low risk for abrupt closure, the incidence of this complication was really low (0.4%) and heparin probably do not prevent it.     

Catheter treatment of congenital heart disease

Over the last 10 years, several advances have been made in paediatric cardiology and cardiac surgery. However, the major developments have been in non-surgical attempts at transcatheter treatment of congenital heart disease. Initially these concerned some simple defects such as pulmonary valve stenosis but lately much more high-risk and complex defects have been treated.     

Prenatal diagnosis of congenital heart disease

Owing to the widely different levels of experience of examiners, there is a large discrepancy in study results of second trimester ultrasound screening for fetal malformations, which is a result of varying levels of obstetric scanning expertise prevalent at the reporting centre. This holds particularly true for the prenatal diagnosis of congenital heart disease where detection rates ranging from 0 per cent to 60 per cent are being reported. On the other hand, congenital heart disease affects about 4-8 per 1000 live births and is a leading cause of infant mortality, whereas prenatal diagnosis could possibly prevent death and long-term morbidity in some of these neonates. Various screening concepts for more effective detection of congenital heart diseases are analysed in this article, including the more recent technique of early echocardiography between 13 and 15 weeks of gestation. High-risk groups are defined and the group of fetuses with increased thickness of nuchal translucency seems to be of particular interest.     

Absent mesosternum in congenital heart disease

The association of developmental abnormalities of the sternum with congenital heart disease is well known. These abnormalities include hypoplasia, multiple centers, and premature fusion. The absence of the sternal bodies in patients with congenital heart disease unrelated to a specific syndrome complex has not been previously described. Possible association with congenital pulmonary vascular disease was noted.     

Dynamic three-dimensional echocardiographic reconstruction of congenital cardiac septation defects

DNA and FISH (fluorescence in situ hybridization) analysis were carried out in 12 patients with stigmata of Turner syndrome to determine whether the Supernumerary Marker Chromosome (SMC) found cytogenetically in each of these patients was derived from the Y chromosome. The presence of a Y chromosome in these patients may predispose them to develop gonadoblastoma. PCR-Southern blot analysis, followed by FISH, was used to detect the presence of Y chromosome material. The Sex determining Region Y (SRY), Testis Specific Protein Y-encoded (TSPY) and Y-chromosome RNA Recognition Motif (YRRM) genes, which map at Yp11.31, Yp11.1-11.2 and Yp11.2/Yq11.21-11.23, respectively, were selected as markers, because they span the whole Y chromosome, and more importantly, they are considered to be involved in the development of gonadoblastoma. It was shown that in 12 patients, all of whom had an SMC, the SMC of 11 was derived from the Y chromosome. Furthermore, the presence of the SRY, TSPY and YRRM gene sequences was determined and FISH analysis confirmed the Y origin of the SMCs. The methodology described in this report is a rapid, reliable and sensitive approach which may be easily applied to determine the Y origin of an SMC carried in Turner syndrome. The identification of an SMC is important for the clinical management and prognostic counseling of these patients with Turner syndrome.     

Endovascular stents in congenital heart disease

Acquired or de novo vascular obstructions can adversely affect the outcomes of management algorithms for children with congenital heart lesions. Although surgical repair is frequently feasible, some acquired or congenital obstructions are difficult to address in the operating theater. Presented is the recent experience with endovascular stents to relieve such stenoses, and their impact on patient care.     

Radioactive tracers in congenital heart disease

Radionuclide angiocardiography is a useful method in the evaluation of patients with congenital heart disease, safely and nontraumatically. Physiologic variables such as transit times, cardiac output, left ventricular ejection fraction, stroke volume, end-diastolic volume can be measured accurately with this technique. An important application of radionuclide angiocardiography in children with congenital heart disease is in the detection, localization and quantification (pulmonary to systemic flow ratio) of intracardiac shunts and shunts between the great vessels. This technique has been found useful in the evaluation of the newborn infant with cyanosis, the patient with a cardiac murmur and the patient who has had cardiovascular surgery. Newer mobile gamma camera-computer systems permit the performance of radionuclide angiocardiography in several ill premature and newborn infants and patients during the early postoperative period. Specially designed magnifying collimators and the development of ultrashort-lived radionuclides should result in an overall improvement in the diagnostic capabilities of this technique and in a further reduction in the radiation dose.     

Platelet kinetics in congenital heart disease

The survival of 111indium labelled platelets has been determined in a series of 47 subjects comprising nine with cyanotic congenital disease (Eisenmenger's syndrome), seven with congenital heart disease associated with left to right shunts, six with primary pulmonary hypertension, six with peripheral vascular disease, 11 with cardiac disorder associated with low cardiac output and eight normal volunteers. Compared with the value in the normals of 9.5 days, mean survival was significantly shortened in those with Eisenmenger's syndrome (8.4 days) and with peripheral vascular disease (8.5 days). It was normal in patients with left to right shunts (9.5 days). Gamma camera imaging in selected patients failed to reveal any abnormal sites of deposition of labelled platelets except in one patient with peripheral vascular disease who had bilateral abnormal activity in his lower limbs and a shortened platelet survival (8.0 days). From theoretical considerations, it was concluded that the reduction in platelet survival in Eisenmenger's syndrome was such that, had it been the result of pulmonary intravascular platelet deposition, abnormal activity should have been visible on chest scanning with the gamma camera. The absence of scintigraphic evidence of abnormal platelet deposition in the lungs of these patients, combined with the linear configuration of their platelet survival curves, suggests that the accelerated platelet destruction is in the reticuloendothelial (RE) system rather than intravascular. Indirect evidence in favour of increased RE destruction of platelets in Eisenmenger's syndrome was the finding of an approximate doubling of intrasplenic platelet transit time, indicating abnormal platelet pooling within the spleen.     

Brain abscess and congenital heart disease

The clinical features and management of 18 patients with congenital heart disease and a brain abscess are reviewed. Except for one patient all had cyanosis. All abscesses were large, containing at least 50-60 ml of pus, and mostly unilocular. Bilocular and multilocular abscesses were also encountered. The organisms cultured from the pus had little relation to the mortality. Tapping may be the final investigation, and is also the treatment of choice. The high mortality (50%) is attributed to the delay in referral of these patients to a neurosurgical unit.     

Psychopathology in young adults with congenital heart disease. Follow-up results

Non-steroidal anti-inflammatory drugs inhibit constitutive (COX-1) and induced cyclooxygenase (COX-2), blocking prostaglandin production. We have compared the effects on nociceptive reflexes of meloxicam, which is COX-2 selective, with indomethacin, which is non-selective, using an in vitro spinal cord preparation. Cords were taken from naive rats, and from rats with carrageenan-induced hyperalgesia of one hindpaw. Reflex thresholds were lower in carrageenan preparations. Superfusion with meloxicam (10-100 microM) dose-dependently inhibited baseline reflexes and wind-up in normal and carrageenan preparations, whereas indomethacin (100-300 microM) had no effect. Thus meloxicam inhibits spinal reflexes, whereas indomethacin does not, despite its high affinity for both COX isoforms. We conclude that meloxicam has spinal antinociceptive actions which cannot be explained by the current concept of COX inhibition.     

Palmoplantar keratoderma associated with congenital heart disease

We report the case of a 14-month-old boy suffering from total anomalous pulmonary venous connection (TAPVC) associated with congenital diffuse palmoplantar keratoderma (PPK). An association between TAPVC and PPK has not been described previously, but PPK has been reported in association with a variety of cardiac abnormalities. Given the low frequency of both conditions, a genetic link seems likely. It is therefore advisable for dermatologists to check for heart abnormalities in children with congenital PPK.     

Combined heart and single-lung transplantation in complex congenital heart disease

We present a patient with a history of tricuspid and pulmonary atresia who underwent a classic Glenn shunt and a Potts shunt during childhood, resulting in different right and left pulmonary physiology. Because of progression of cardiopulmonary disease and the fact that the right lung was "protected," the patient underwent combined heart-left single-lung transplantation. The postoperative course was uneventful. Potential early and late advantages of this approach include simplifying of the operative procedure and mitigating the potential effects of obliterative bronchiolitis.     

The haematological management of patients with cyanotic congenital heart disease. A time for consensus?

AIMS: Recurrent venesection of patients with cyanotic congenital heart disease may be detrimental, with an increased risk of cerebrovascular events and symptomatic iron-deficiency. The aim of this study was to determine the venesection policies as practised in hospitals within a U.K. region and to determine if these policies followed current recommendations. METHODS AND RESULTS: Fifty-eight consultants (56% response rate) in cardiac specialties completed self-assessment questionnaires regarding the indications for and practice of venesection. Sixty-one percent of those responding were involved directly in the care of patients with cyanotic congenital heart disease and of these clinicians 97% used venesection. Indications for venesection varied, with 51% of those responding using an elevated haemoglobin per se (6.5-21.0 g. dl-1); 78% an elevated haematocrit (0.55-0.75) and 83% symptoms. Desired maintenance haemoglobin and haematocrit levels also varied greatly. Fifty percent of the consultants responding routinely screened their patients for iron deficiency and 23% felt there was no indication for investigating a low mean corpuscular volume. Only 18% of the policies described followed any evidence based principles. CONCLUSIONS: The practice of venesecting patients with congenital cyanotic heart disease varies greatly. Policies in many hospitals do not reflect the minimal benefits and considerable risks associated with recurrent venesection.     

Molecular genetics (HLA) of Beh?et's disease

Beh?et's disease (BD) has been known to be strongly associated with the human leukocyte antigen (HLA) B51. This B51 association has been confirmed in many different ethnic groups between the Middle East and Japan, and it has been proposed that BD is prevalent in those ethnic groups along the old Silk Route. The hypothesis could be made that B51 molecules are primarily involved in BD development through specific antigen presentation. However, polymorphic analyses of the TNFB gene and Tau-a microsatellite between the HLA-B and TNF genes indicate that the pathogenic gene of BD is not the HLA-B51 gene itself but another gene located around the HLA-B gene. HLA-C genotyping by the PCR-SSP method also suggests that the BD pathogenic gene is not the HLA-C gene itself but other gene located near the HLA-B gene. Recently we sequenced a single contig of 236,822 bp from the MICA gene (58.2 kb centromeric of HLA-B) to 90.8 kb telomeric of HLA-C and identified 8 novel genes designated NOB1-8 (NOB: new organization associated with HLA-B). During the course of the genomic sequence analysis we clarified the genetic structure of the MICA (MHC class I chain-related gene A) gene and found a triplet repeat microsatellite polymorphism of (GCT/AGC)n in the transmebrane (TM) region. Furthermore, the microsatellite allele consisting of 6 repetitions of GCT/AGC (MICA A6 allele) was present at a significantly higher frequency in the BD patient group than in the control group and a significant fraction of B51-negative patients were positive for this MICA A6 allele. These results suggest the possibility of a primary association of BD with MICA rather than HLA-B.