Evoked Potentials in Patients With Wilson Disease.

INTRODUCTION: Wilson disease (WD) is an inherited disorder of copper metabolism presenting with a variety of symptoms but commonly as a liver or neuropsychiatric disease. Abnormal evoked responses are constantly found among patients with neurologic manifestations and sometimes in patients with hepatic presentation or in presymptomatic siblings. The aim of our study was to assess visual and brainstem auditory evoked potentials (BAEP) in patients with various presentation of WD. METHODS: Visual evoked potentials (VEP) were performed in 36 WD patients and BAEP were done in 37 WD patients. RESULTS: Brainstem auditory evoked potentials were normal in patients with isolated hepatic presentation, whereas they were abnormal in 93.5% of patients with neurologic symptoms. There was significant prolongation of the latencies of the III and V waves and of the interpeak III-V and I-V latencies in comparison with the healthy controls (T-test P = 0). Abnormal VEP were observed in 81% of the patients including six of seven neurologically asymptomatic patients. The values of N75, P100, and N145 latencies were significantly longer in all patients than in healthy controls (T-test). CONCLUSIONS: The data showed that VEP and BAEP are more frequently abnormal in WD than previously reported. The abnormal VEP and BAEP even without clinical signs and brain MRI abnormalities point to subclinical involvement of visual and auditory pathways caused by copper toxicity. Because VEP and BAEP are noninvasive and widely available, they should be performed in all patents with WD.

No evidence of association between 118A>G OPRM1 polymorphism and heroin dependence in a large Bulgarian case-control sample.

The µ-opioid receptor is the primary site of action of most opioids. The 118A>G (rs1799971) polymorphism in exon 1 of the µ-opioid receptor gene (OPRM1) leads to an Asn40Asp amino acid change that affects a putative N-glycosylation site. It has been widely investigated for association with alcohol and drug dependence and pain sensitivity, with mixed results. The aim of the current study was to examine whether this polymorphism was associated with heroin dependence in a large Bulgarian cohort of 1842 active users and 1451 population controls. SNP genotyping was done using Real-Time PCR TaqMan technology. Association analyses were conducted, separately for Roma and non-Roma participants. Our results suggest that there is no direct effect of 118A>G genotype on the risk for heroin dependence among active heroin users.

CHEK2 I157T and endometrial cancer.

Endometrial cancer (EC) is the most common malignancy of the female reproductive system in the industrialized world. Similar to other common diseases, gene variations are believed to be able to alter an individual's predisposition to developing the disease. The CHEK2 gene encodes a tumor suppressor that takes part in various cell processes, including cell cycle regulation, DNA repair, and apoptosis. The polymorphic variant Ile157Thr in exon 3 of the gene has been demonstrated to enhance the risk of several types of cancer and at the same time to reduce the risk for developing other cancer types. To study the significance of CHEK2 I157T for EC, we have genotyped 268 patients and 449 female controls. We found carriers of I157T more often among controls than we did among patients (2.45% vs. 1.75%), but the difference was not statistically significant. Case-only analysis revealed that the variant is overrepresented in patients diagnosed at 75 or more years of age (9.09%, p = 0.05) and in those with deep myometrial invasion (3.85%, p = 0.06). The highest frequency was observed in patients with both the aforementioned characteristics (20%, p = 0.01). Tumors of I157T carriers showed endometrioid, clear cell, and mucinous morphology, which suggested that the variant may not be restricted to a certain histotype of the disease and could even be overrepresented in rare ones. This study is the first to explore the association between germline CHEK2 I157T and EC. It suggests the need for further large-scale evaluation of the role this variant plays in endometrial carcinogenesis.

Frequency and application of the hot spot BRAF gene mutation (p.V600E) in the diagnostic strategy for Hereditary Nonpolyposis Colorectal Cancer.

BACKGROUND: BRAF somatic mutations were reported with high frequency in sporadic colorectal cancers (CRCs) with microsatellite instability (MSI). The hot spot c. 1799 T>A, p.V600E gene mutation is very rarely involved in the tumorigenesis of CRC linked to Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These data suggested that the screening of mismatch repair (MMR) genes could be avoided in cases positive for p.V600E. The aim of our study was to analyze the frequency of this hotspot mutation in a group of 140 CRC patients and the applicability of BRAF 15 exon mutation screening in the diagnosis of HNPCC. METHODS: Exon 15 of the BRAF gene was PCR amplified and subjected to single-strand conformation polymorphism (SSCP) analysis. Samples showing an altered mobility pattern were then subjected to direct sequencing. Associations between BRAF mutation and clinical, pathological or molecular features were evaluated using Fisher's exact chi-squared tests as appropriate. RESULTS: The mutation was detected in eight of 140 (5.7%) CRC samples with common characteristic features such as MSI, proximal tumor location, moderate differentiation, mucinous production and early Dukes' stage. CONCLUSIONS: We conclude that screening for this mutation is an efficient tool in the diagnostic strategy for HNPCC.

Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22.

Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.