Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs), which due to paradoxical embolization may cause cerebral abscess.
To estimate the risk of cerebral abscess among patients with HHT.
All patients with HHT included in the Danish HHT data base, between January 1995 and October 2012, have been clinically evaluated for the presence of neurological symptoms and history of previous cerebral abscess.
A total of 337 patients with HHT have been included in the Danish database. Of these, 264 were screened for the presence of PAVM. In 117 patients, a PAVM was diagnosed; among these, we identified nine patients with a history of cerebral abscess. The prevalence of cerebral abscess among patients with HHT and PAVM was therefore 7.8%. The patients with a history of cerebral abscess were genetically evaluated, and seven had ENG mutations, one had an ALK1 mutation, and in one case, a mutation could not be identified.
Patients with untreated PAVM have a considerable risk of sustaining cerebral abscesses. A cerebral abscess may be the first symptom leading to an HHT diagnosis. Patients with unexplained cerebral abscess should be evaluated for HHT and PAVM.
We performed a screening of exon 9 of the low density lipoprotein receptor (LDLR) gene in 14 Danish families with familial hypercholesterolemia (FH) using the denaturing gradient gel electrophoresis (DGGE) technique. In one of the probands from these families an abnormal band pattern in the gradient gel was detected. Subsequent DGGE analysis of the family of this index patient revealed that the DGGE pattern cosegregated with the disease in this family. Sequencing of the exon showed a deletion of a C in codon 424 of the LDLR gene resulting in a frame shift with the introduction of a stop codon 5 codons further downstream. The mutation is referred to as FH-Odense. The predicted truncated receptor protein consists of the 428 amino terminal amino acids. Consequently, the cytosolic and membrane spanning parts of the mature LDL receptor, which normally secure the receptor in the plasma membrane, are missing. The FH-Odense mutation results in severe premature coronary atherosclerosis as shown by the clinical expression in 5 generations of the affected family.
Development of a high-resolution melting genotyping assay for the angiotensin I converting enzyme insertion/deletion polymorphism and establishment of genotype-specific reference intervals in a Danish population.
The serum-angiotensin I converting enzyme (s-ACE) activity is influenced by a genetic insertion/deletion (I/D) polymorphism in the ACE gene, and the resulting large interindividual variation in s-ACE limits the use of normal reference intervals in the evaluation of sarcoidosis. In this study, we developed a new method for genotyping the I/D polymorphism in ACE and established genotype-specific reference intervals in order to improve the diagnostic accuracy and the value for treatment of sarcoidosis.
The new genotyping assay is based on high-resolution melting (HRM) using LCGreen?+?and was used to genotype 400 healthy Danish individuals. The assay was compared to a real-time polymerase chain reaction (RT-PCR) assay in a validation set of 86 samples. Enzyme activity in serum was measured using the Infinity™ ACE Liquid Stable Reagent from Thermo adapted for the ABX Pentra analyzer.
There was full concordance between genotyping assays. The three genotypes II, ID and DD were present with a frequency of 0.23, 0.51 and 0.26. The distribution of s-ACE values in the total population was non-Gaussian (non-parametric 95% reference interval 12.0-60.0 U/L). The median activities of the genotypes differed significantly (P
In a population of 930,000 inhabitants all records of native valve infective endocarditis diagnosed in the decade 1980-89 were reviewed. One hundred and thirty-two cases were found, of whom 23 were not diagnosed until postmortem. Median prehospital duration of symptoms was 20 days (range 0-180) and median in-hospital diagnostic delay five days (range 0-54). Known cardiac disease was found in 42%, possible portal of entry in 33%, but in 36% no predisposing factors were found. During the clinical course 55% experienced cardiac failure and 17% embolic episodes. Surgery was required in 19 patients. Of 111 culture positive cases, streptococci were found in 61 and staphylococci in 45 cases. Overall mortality was 33% with a mortality of clinically diagnosed cases of 18%. Native valve endocarditis is thus associated with a significant mortality in part due to significant diagnostic delays and a large number of post-mortem diagnosed cases. Only by securing a high level of alertness towards endocarditis can we expect a reduced mortality.
Familial hypercholesterolaemia (FH) is an autosomal co-dominantly inherited condition resulting from mutations of the low-density lipoprotein (LDL) receptor which occur in heterozygous form in approximately one in 500 individuals. Clinically, FH is characterized by 2-3-fold elevation of serum LDL cholesterol levels, accelerated development of atherosclerotic vascular disease, and, if untreated, shortened lifespan. The Finnish population, which represents a genetic isolate, offers exceptional possibilities for genetic-epidemiological studies on FH, as a handful of founder gene mutations account for the majority of FH cases in Finland. This review summarizes data from our FH studies carried out since 1985. We wish to emphasize the continuum of genotype-phenotype relationships, the importance of molecular diagnosis, the detection of novel risk factors of vascular disease, and innovations inhibiting cholesterol absorption for the modern treatment of FH.
Familial hypercholesterolemia is a human monogenic disease caused by population-specific mutations in the low density lipoprotein (LDL) receptor gene. Despite thirteen different mutations of the LDL receptor gene were reported from Russia prior to 2003, the whole spectrum of disease-causing gene alterations in this country is poorly known and requires further investigation provided by the current study.
Forty-five patients with clinical diagnosis of FH were tested for the apolipoprotein B (apoB) mutation R3500Q by restriction fragment length analysis. After exclusion of R3500Q mutation high-sensitive fluorescent single-strand conformation polymorphism (SSCP) analysis and automatic DNA sequencing were used to search for mutations in the LDL receptor gene.
We found twenty one rare sequence variations of the LDL receptor gene. Nineteen were probably pathogenic mutations, and two (P518P, T705I) were considered as neutral ones. Among the mutations likely to be pathogenic, eight were novel (c.670-671insG, C249X, c.936-940del5, c.1291-1331del41, W422X, c.1855-1856insA, D601N, C646S), and eleven (Q12X, IVS3+1G>A, c.651-653del3, E207X, c.925-931del7, C308Y, L380H, c.1302delG, IVS9+1G>A, V776M, V806I) have already been described in other populations. None of the patients had the R3500Q mutation in the apoB gene.
Nineteen pathogenic mutations in the LDL receptor gene in 23 probands were identified. Two mutations c.925-931del7 and L380H are shared by St.-Petersburg population with neighbouring Finland and several other mutations with Norway, Sweden or Denmark, i.e. countries from the Baltic Sea region. Only four mutations (c.313+1G>A, c.651-653del3, C308Y and W422X) were recurrent as all those were found in two unrelated families. By this study the number of known mutations in the LDL receptor gene in St.-Petersburg area was increased nearly threefold. Analysis of all 34 low density lipoprotein receptor gene mutations found in St.-Petersburg argues against strong founder effect in Russian familial hypercholesterolemia.
Familial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR). Deletions and other major structural rearrangements of the LDLR gene account for approximately 5% of the mutations in many populations.
Five genomic deletions in the LDLR gene were characterized by amplification of mutated alleles and sequencing to identify genomic breakpoints. A diagnostic assay based on duplex PCR for the exon 7-8 deletion was developed to discriminate between heterozygotes and normals, and bioinformatic analyses were used to identify interspersed repeats flanking the deletions.
In one case 15 bp had been inserted at the site of the deleted DNA, and, in all five cases, Alu elements flanked the sites where deletions had occurred. An assay developed to discriminate the wildtype and the deletion allele in a simple duplex PCR detected three FH patients as heterozygotes, and two individuals with normal lipid values were detected as normal homozygotes.
The identification of the breakpoints should make it possible to develop specific tests for these mutations, and the data provide further evidence for the role of Alu repeats in intragenic deletions.
The aim of the study was to evaluate the results from the prevalence round of the mammography screening programme in the Municipality of Copenhagen. All women who by 1 April 1991 were 50-69 years old, and who lived in the Municipality of Copenhagen, were during the period 1 April 1991-24 April 1993 offered a mammography. Those with suspect findings were recalled for further examination and possible biopsy. Women with breast cancer were offered treatment according to the standard national protocols (DBCCG). The participation rate was 71% (30,416/43,087). Among these 2043 (6.7%) were re-examined and 592 (1.9%) underwent surgical biopsy. Breast cancer was revealed in 359 (1.2%) women, of whom 88% had an invasive breast cancer. Prevalence of breast cancer increased significantly with increasing age. The positive predictive value for breast cancer among those re-examined was 18% and for those who had a surgical biopsy 61%. Among women with an invasive breast cancer 41% had a tumour of 10 mm or less, 80% had negative lymph node status and 56% had breast conserving surgery. During the following 12 months 14 women with a normal mammogram at the screening round developed breast cancer giving a sensitivity of 96%. It is concluded that the first mammography screening in Denmark showed the highest breast cancer prevalence published so far. A possible explanation could be a high sensitivity of the screening method, indicated by a relatively high frequency of small cancers. The screening programme was fully comparable with international standards.
Comment On: Ugeskr Laeger. 1996 Feb 26;158(9):1218-218644426
Measurements of nitrogen dioxide using the Palmes diffusion tubes in Uummannaq, Aasiaat, and Nuuk. all located along the west-coast of Greenland, have demonstrated that the levels of pollution at the most heavily impacted sites are comparable to levels in much larger towns in Denmark. The highest concentrations were, in general, observed near sites influenced by car traffic (peak concentrations of up to 16 ppbv), medium concentrations were observed in the residential areas (2 6 ppbv), and very low levels were found at the background locations in the town outskirts (1-2 ppbv). Observations of nitrogen dioxide concentrations less than 0.1 ppbv at a remote site, Akia, 25 km from Nuuk, indicate that, compared to local sources, long-range transport of nitrogen dioxide is not important in western Greenland.