Wilson disease mutations associated with uncommon haplotypes in mediterranean patients

This study reports 12 novel mutations of the Wilson disease (WD) gene which have been detected by the molecular analysis of 29 patients of Mediterranean descent carrying uncommon chromosomal haplotypes at the WD locus. These mutations include two nonsense, one splice site and nine missense. The missense mutations lie in regions of the WD gene critical for its function, such as the transmembrane region, the transduction domain and the ATP loop and ATP-binding domain, indicating that they are disease-causing mutations. These new findings improve our knowledge for the role played by functional domains on the ATP7B function. Received: 20 March 1996     

Quality of life among patients with severe aortic stenosis

BackgroundThe disease burden of patients with severe aortic stenosis is not often explored, while the incidence is increasing and many patients who have an indication for aortic valve replacement are not referred for surgery. We studied the quality of life of 191 patients with severe aortic stenosis, hypothesising that symptomatic patients have a far worse quality of life than the general population, which could enforce the indication for surgery.MethodsThe SF-36v2 Health Survey was completed by 191 consecutive patients with symptomatic or asymptomatic severe aortic stenosis.ResultsAsymptomatic patients (n = 59) had health scores comparable with the general Dutch population but symptomatic patients (n = 132) scored significantly lower across different age categories. Physical functioning, general health and vitality were impaired, as well as social functioning and emotional well-being. There was no relation between degree of stenosis and physical or mental health scores.ConclusionsBoth physical and emotional problems have a major impact on normal daily life and social functioning of symptomatic patients with severe aortic stenosis, regardless of age. If the aortic stenosis is above the ‘severe’ threshold, the degree of stenosis does not predict disease burden. These results encourage to reconsider a conservative approach in symptomatic patients with severe aortic stenosis. Using the SF-36v2 Health Survey together with this study, an individual patient’s quality of life profile can be assessed and compared with the patient group or with the general population. This can assist in decision making for the individual patient.     

Analysis of mutations and haplotypes of polymorphic markers in patients with Wilson-Konovalov disease from Bashkir

Mutations of the Wilson disease (WD) gene were studied in patients from Bashkortostan. Four mutations were identified: His1069Gln, 3402delC, Glu1064Lys, and 3559 + 1G-->T. The latter mutation was described for the first time. Mutation His1069Gln was found to be the most prevalent in Bashkortostan; its frequency was 43.5%. The associations of the mutations found with the haplotypes for polymorphic loci D13S316, D13S133, and D13S228 were studied. The mutations were found to be linked with specific haplotypes, and the study of polymorphic haplotypes can therefore facilitate the search for mutations in the gene for WD. The results of the molecular genetic study of WD can be used for direct and indirect DNA diagnostics of this disease in Bashkortostan.     

Heterogeneity inHLA-DR2-relatedDR,DQ haplotypes in eight populations of Asia-Oceania

The relative distributions of 480DR2-relatedDR, DQ haplotypes have been determined in Australian Aborigines, Papua New Guinean Highlanders, coastal Melanesians, Micronesians, Polynesians, Javanese, and Southern and Northern Chinese. Using sequence-specific oligonucleotides (SSOs) for hybridization of polymerase chain reaction (PCR) products from DRBI,DRBS,DQA1, andDQBI genes, 15 differentDR2-related haplotypes were identified. The predominantDR2 haplotype in Oceania involved a novel combination ofDRBI ^* 1502,DRB5 ^* 0101 alleles; this haplotype occurred sporadically in Java, but not in China. In Southern China, the most frequent DR2 haplotype involved the unusual arrangementDRB1 ^* 1602,DRB5 ^* 0101; alternatively,DRB1 ^* 1602 was associated with a newDRB5 SSO pattern. This study has important implications for molecular HLA-typing protocols that assume particularDRB1 DRB5 orDR,DQ linkage relationships. Further, the novelDRBI,DRB5 haplotype in Oceania suggests that the mixed lymphocyte culture (MLC) determinants Dw2 and Dw12 are discriminated by codon 86 at theDRBI locus.     

A Human Case of Hymenolepis diminuta in a Child from Eastern Sicily

We report a case of Hymenolepis diminuta infection in a 2-year-old child living in a suburban area of Catania, Italy. This case was initially referred to us as Dipylidium caninum infection, which was not cured after being treated twice with mebendazole. However, by analyzing the clinical presentation and stool samples we arrived to the diagnosis of H. diminuta infection. The case presented with atypical allergic manifestations which had never been reported as clinical features of symptomatic H. diminuta infection; remittent fever with abdominal pain, diffuse cutaneous itching, transient thoracic rash, and arthromyalgias. The patient was treated with a 7-day cycle of oral niclosamide, which proved to be safe and effective. This case report emphasizes that a correct parasitological diagnosis requires adequate district laboratories and trained personnel. In addition, we recommend the importance of reporting all H. diminuta infection cases, in order to improve knowledge on epidemiology, clinical presentation, and treatment protocols.     

Heterogeneity of lipidomic profiles among lung cancer subtypes of patients

Lung cancer is a leading cause of cancer‐related deaths with an increasing incidence and poor prognoses. To further understand the regulatory mechanisms of lipidomic profiles in lung cancer subtypes, we measure the profiles of plasma lipidome between health and patients with lung cancer or among patients with squamous cell carcinomas, adenocarcinoma or small cell lung cancer and to correct lipidomic and genomic profiles of lipid‐associated enzymes and proteins by integrating the data of large‐scale genome screening. Our studies demonstrated that circulating levels of PS and lysoPS significantly increased, while lysoPE and PE decreased in patients with lung cancer. Our data indicate that lung cancer‐specific and subtype‐specific lipidomics in the circulation are important to understand mechanisms of systemic metabolisms and identify diagnostic biomarkers and therapeutic targets. The carbon atoms, dual bonds or isomerism in the lipid molecule may play important roles in lung cancer cell differentiations and development. This is the first try to integrate lipidomic data with lipid protein‐associated genomic expression among lung cancer subtypes as the part of clinical trans‐omics. We found that a large number of lipid protein‐associated genes significantly change among cancer subtypes, with correlations with altered species and spatial structures of lipid metabolites.     

Heterogeneity among zymodemes of Leishmania infantum from HIV-positive patients with visceral leishmaniasis in south Italy

Abstract Eleven zymodemes of Leishmania infantum were identified among 38 parasite stocks isolated from Italian HIV-positive patients with visceral leishmaniasis (VL). Only one zymodeme is a common agent of Mediterranean VL in HIV-negative individuals, five zymodemes usually cause simple, self-resolving cutaneous leishmaniasis (CL), and five belong to unique genotypes which have not been previously reported from either VL or CL cases in immunocompetent individuals. This last group of parasites showed reassortaient patterns within electromorphs frequently observed in dermotropic L. infantum zymodemes. The highest zymodeme heterogeneity was found in south Italy (Sicily), with six zymodemes identified among 12 HIV-positive patients surveyed.     

Geographical distribution of haplotypes in Swedish families with Huntington's disease

This study was planned to determine the number of origins of the mutation underlying Huntington's disease (HD) in Sweden. Haplotypes were constructed for 23 different HD families, using six different polymorphisms [(CCG) _n , GT70, 674, BS1, E2 and 4.2], including two within the gene. In addition, extensive genealogical investigations were performed, and the geographical origin of the haplotypes was studied. Ten different haplotypes were observed suggesting multiple origins for the HD mutation in Sweden. Analysis of the two polymorphic markers within the HD gene (the CCG repeat and GT70) indicates that there are at least three origins for the HD mutation in Sweden. One of these haplotypes (7/A) accounts for 89% of the families, suggesting that the majority of the Swedish HD families are related through a single HD mutation of ancient origin. Furthermore, three of the families that were previously considered to be unrelated could be traced to a common ancestor in the 15th century, a finding that is consistent with this hypothesis.     

Heterogeneity in disease associations

Associations between polymorphisms and disease are usually detected by comparing phenotype frequencies in affected individuals and controls, usually by the method of Woolf, which also allows assessment of heterogeneity between studies. The risk of reporting a chance spurious association could be reduced if family studies, such as sib comparisons, were carried out at the same time as the original survey, rather than after many surveys have been conducted.     

Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients

Gaucher disease is inherited in an autosomal recessive manner and is the most prevalent lysosomal storage disease. Gaucher disease has marked phenotypic variation and molecular heterogeneity, and several simple and complex alleles of the acid beta-glucosidase gene have been identified as causal to this disease. Certain combinations of alleles have been shown to correlate well with the severity of the disease, but many Gaucher disease patients exist whose disease is not explained by any of the published mutations. This study was undertaken to identify mutant alleles in such incompletely characterized Gaucher disease, in an attempt to find further correlations between clinical phenotype and the presence of acid beta-glucosidase alleles. RNA was isolated from Gaucher cell lines and converted to cDNA, the cDNA was amplified by PCR and cloned, and several clones for each allele were sequenced. Several new singly mutated and multiply mutated alleles were identified, and sequence-specific oligonucleotide hybridization was used to verify the presence of these mutations in the genome of these patients. All newly identified mutations occurred only rarely in the Gaucher disease population, making it difficult to determine whether inheritance of a particular combination of alleles always correlates with the clinical manifestations seen in the test patients. Three of the newly described alleles were single missense mutations in exon 8, one was a single missense mutation in exon 5, and the fifth was a complex allele, comprising a series of different point mutations scattered throughout exons 5 and 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gallstone disease is associated with more severe liver damage in patients with non-alcoholic Fatty liver disease

Background

Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and associated with obesity and insulin resistance. We aimed to evaluate the prevalence of GD in a cross sectional study of NAFLD patients and to define whether the presence of GD is associated with diabetes and predicts more severe liver disease.

Methodology/Principal Findings

We merged databases of four Liver Units, comprising 524 consecutive biopsy-proven NAFLD (373 males) observed between January 2003 and June 2010. GD was diagnosed in 108 (20%), and 313 cases (60%) were classified by liver biopsy as nonalcoholic steatohepatitis (NASH). The GD subgroup was characterized by a significantly higher prevalence of females, prediabetes/diabetes, abdominal obesity and metabolic syndrome, older age, higher BMI, fasting glucose, HOMA-IR and lower ALT. The prevalence of GD progressively increased with advancing fibrosis and with the severity of necroinflammatory activity (p for trend  = 0.0001 and  = 0.01, respectively), without differences in the severity of steatosis. At multivariate analysis GD was associated with female gender (OR 1.37, 95% CI 1.04–1.8), age (OR 1.027, 95% CI1.003–1.05), fasting glucose (OR 1.21, 95% CI 1.10–1.33) and NASH (OR 1.40,95% CI 1.06–1.89), whereas ALT levels were associated with a lower GD risk (OR 0.98, 95% CI 0.97–0.99). When subjects with cirrhosis were excluded from analysis, the association between GD and fasting glucose, female gender, and NASH was maintained.

Conclusion

Patients with NAFLD have a high prevalence of GD, which characterizes subjects with altered glucose regulation and more advanced liver disease.     

Sharing of MHC haplotypes among apparently unrelated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

From the study of HLA, complement, and glyoxalase I alleles in 82 Venezuelan individuals belonging to 19 families of mixed ethnic origin having 20 affected newborns with salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency, a total of 38 disease haplotypes and 53 nondisease haplotypes were found. Of the pathological haplotypes 47 % were found to share the HLA-B39 or -Bw62 specificities, 55 % of them in combination with the BFS, C2C, C4A4, C4B2 (SC42) complotype. The frequencies of HLA-B39 and -Bw62 among the affected haplotypes were 29 and 18% as compared with 6 and 0 % among the nondisease haplotypes of the same families. Statistical associations (P < 0.01) with salt-wasting adrenal hyperplasia were found with the SC42 complotype and with the combination SC42, HLA-B39. These results are markedly different from those reported in the literature which show an association at the population level among many Caucasoid samples of HLA-Bw47 and the extended haplotype (HLA-Bw47, DR7, FC91, 0) with the salt-wasting form of the disease. Furthermore, four of the unrelated patients reported here were homozygous for all the major histocompatibility complex loci tested, while three others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicated clustering of the deficiency carrier HLA haplotypes. This observation, together with the fact that there is an excess of homozygotes among the patients in Venezuela, strongly suggests that salt-wasting 21-OH deficiency congenital adrenal hyperplasia is mostly the result of a founder effect of relatively few independent mutations and, thus, of identity by descent of a few abnormal alleles at the 21-OHB locus in most cases. The mutation marked by HLA-Bw47 was not observed in this population.     

Both viremia and cytokine levels associate with the lack of severe disease in secondary dengue 1 infection among adult Chinese patients

Secondary dengue infections are frequently associated with increased risk for dengue hemorrhagic fever and dengue shock syndrome. Surprisingly, we observed no dengue hemorrhagic fever cases among 353 hospitalized dengue-infected patients including 212 with primary, and 141 with secondary dengue 1 infection in China. To explore virological and immunological mechanisms which may account for this unexpected clinical observation, we assessed dengue viremia, type I interferon and inflammatory cytokine levels in these patients. While the levels of viremia and inflammatory cytokines are indistinguishable between primary and secondary infections, IFNα levels are significantly higher in primary than that in secondary infection. However, IFNα levels are positively correlated with dengue viremia levels (p<0.0001), but negatively correlated with the platelet counts (p<0.0001) and serum ALT levels (p = 0.0003). These results provide direct in vivo evidence that clinical dengue disease severity is affected by both viral and human immune factors.     

Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia

Autonomic dysfunction is frequent in patients with fibromyalgia (FM). Heart rate variability analyses have demonstrated signs of ongoing sympathetic hyperactivity. Catecholamines are sympathetic neurotransmitters. Catechol-O-methyltransferase (COMT), an enzyme, is the major catecholamine-clearing pathway. There are several single-nucleotide polymorphisms (SNPs) in the COMT gene associated with the different catecholamine-clearing abilities of the COMT enzyme. These SNPs are in linkage disequilibrium and segregate as 'haplotypes'. Healthy females with a particular COMT gene haplotype (ACCG) producing a defective enzyme are more sensitive to painful stimuli. The objective of our study was to define whether women with FM, from two different countries (Mexico and Spain), have the COMT gene haplotypes that have been previously associated with greater sensitivity to pain. All the individuals in the study were female. Fifty-seven Mexican patients and 78 Spanish patients were compared with their respective healthy control groups. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Six COMT SNPs (rs2097903, rs6269, rs4633, rs4818, rs4680, and rs165599) were genotyped from peripheral blood DNA. In Spanish patients, there was a significant association between three SNPs (rs6269, rs4818, and rs4680) and the presence of FM when compared with healthy controls. Moreover, in Spanish patients with the 'high pain sensitivity' haplotype (ACCG), the disease, as assessed by the FIQ, was more severe. By contrast, Mexican patients displayed only a weak association between rs6269 and rs165599, and some FIQ subscales. In our group of Spanish patients, there was an association between FM and the COMT haplotype previously associated with high pain sensitivity. This association was not observed in Mexican patients. Studies with a larger sample size are needed in order to verify or amend these preliminary results.     

Gene polymorphism among hypertensive patients with coronary artery disease

The obstruction of the coronary arteries causes Coronary Artery Disease (CAD). It has been reported that interleukin-6 gene is related to the development of cardiovascular diseases such as atherosclerosis and coronary artery disease. This was due to the large variability and short half-life of interleukin 6 (IL-6). There are few studies on the link between interleukin 6 and CAD on the patients with hypertension. Therefore, goal of this study was to see if there is a link between IL-6 gene polymorphisms and coronary artery disease with hypertension patients. The polymorphisms were carried out by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The data was determined for statistical significance using chi-square analysis. A significant difference was found in the GG genotype of IL-6 -174, which was more frequent in cases of CAD (48.67 %) than in controls (8%) and 95% CI was 0.473455 - 0.500326; P<0.010620511. The GG genotype of IL-6-572C/G polymorphism was more frequent in cases of CAD (42.6%) compared with controls (8%) and 95% CI 0.386724 - 0.480945; P<0.017939631). likewise, significant association of variant allele G with CAD patients was reported. Hypertension was significantly higher among patients as compared to controls (P<0.022847535). Our findings indicated that both gene polymorphisms may be associated with development of CAD.