Human cytomegalovirus DNA detection in a recurrent glioblastoma multiforme tumour,but not in whole blood: a case report and discussion about the HCMV latency and therapy perspectives

Journal of NeuroVirology - In the current study, a 58-year-old male patient presented with recurrent glioblastoma multiforme (GBM). The patient underwent surgical resection, 4 months...     

Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene

Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. Purpose: To study five patients with clinically suspected Von Hippel-Lindau syndrome, who were referred for molecular genetic testing. Methods: Sanger sequencing of the coding regions of the VHL gene. Results: Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). Conclusion: Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies.     

Novel Mutations in the DYNC1H1 Tail Domain Refine the Genetic and Clinical Spectrum of Dyneinopathies

The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole‐exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.     

MBL2 polymorphisms – manifestations in Bulgarian patients with adult dermatomyositis and systemic lupus erythematosus

Deficiency in some complement factors is known to cause both systemic lupus erythematosus (SLE) and dermatomyositis (DM). Mannose‐binding lectin (MBL) is a recognition molecule of the lectin pathway, and its low levels are reported to influence some autoimmune diseases. Furthermore, MBL2 polymorphisms have been described associated with low MBL serum levels due to impaired MBL structure and function. This is a pilot study to investigate the role of MBL2‐550G/C (H/L), ‐221G/C (Y/X), Arg52Cys (D), Gly54Asp (B), Gly57Glu (C) polymorphisms and MBL serum levels as a risk factor for a development of adult DM and SLE in Bulgarian patients. None of the studied MBL2 polymorphisms appeared associated with the diseases investigated. However, we have found an increased OR of MBL2‐221XY genotype in the patients with SLE (OR 1.64, 95%CI 0.77–3.52). MBL2 polymorphisms seemed to affect MBL serum levels and to be associated with the clinical features although none of the associations remained statistically significant after Bonferroni correction. The‐550L allele showed an association with electromyography findings in patients with DM. The‐221XY genotype was associated with photosensitivity in patients with SLE. The 54AB genotype showed an association with malar rash in patients with SLE, but it appeared decreased among SLE patients with ANA. In conclusion, our results suggest that the MBL2 polymorphisms have rather a disease modifying role and they are not associated with the disease susceptibility in adult DM and SLE among Bulgarian patients.     

Association of TNF‐α polymorphisms with adult dermatomyositis and systemic lupus erythematosus in Bulgarian patients

Background Single‐nucleotide polymorphisms (SNPs) of tumor necrosis factor‐alpha (TNF‐α) have been implicated in various autoimmune diseases; however, the results are quite controversial, and there is still no widely accepted opinion about their role in the pathology of the autoimmune diseases. This is a pilot study to investigate the association of six SNPs of the TNF‐α gene with the risk of adult dermatomyositis (DM) and systemic lupus erythematosus (SLE) in Bulgarian patients. Materials and methods Twenty‐seven patients with DM and 27 with SLE were included in this study. Genomic DNA was extracted from the peripheral blood, and six SNPs (?1031T/C, ?863C/A, ?857C/T, ?308G/A, ?238G/A, +489G/A) were selected for investigation by polymerase chain reaction‐restriction fragment length polymorphism analysis. Results We found association between the TNF‐α?1031CC genotype and SLE (P = 0.025) and tendency for association with DM (P = 0.0876). The association appeared even stronger in the female patients with SLE (P = 0.024) and DM (P = 0.067). The TNF‐α?857GG genotype shows weak association with SLE (P = 0.097, OR 2.06, 95% CI 0.81–5.29) when analyzed for the whole group, but it appeared significantly associated with SLE in women (P = 0.048, OR 3.23, 95% CI 0.93–11.14). The ?863C allele showed association with arthritis in patients with SLE (P = 0.008). The haplotype analysis revealed a significant association between TNF ?1031C/?863C/?857C/?308G/+489G haplotype with both DM (P = 0.022) and SLE (P = 0.007) in women. Conclusions The TNF‐α polymorphisms are associated with increased relative risk mainly for SLE, particularly in women, while their role for DM is less evident and needs further analysis in an enlarged sample cohort.     

The 6th heart sound]

The author describes a new sound in systole which he calls the V1th heart sound. This sound can be recorded in patients with pure aortic incompetence, but also in healthy subjects. It is not sufficiently loud to be heard on auscultation. It is visible only on the low frequency bands at 35 Hz, and rarely at 70 Hz. It is maximal at the apex and the endapex. It is characterised by 1 or 2 oscillations at the end of mesosystole and at the beginning or middle of end-systole. This sound may be physiological: it will then be of low amplitude, and further from the 2nd sound than in cases of pure aortic incompetence, in which it is pathological, and closer to the 2nd sound. The author puts forward two hypotheses for the origin of the VIth sound.