Publications (18)50.9 Total impact
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Article: One Novel and One Recurrent Mutation in IGHMBP2 Gene, Causing Severe Spinal Muscular Atrophy Respiratory Distress 1 With Onset Soon After Birth.
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ABSTRACT: A family with 2 siblings with severe spinal muscular atrophy with respiratory distress 1 (SMARD1) was genetically proved to be caused by mutations in IGHMBP2 gene. Both patients developed progressive muscular weakness and respiratory distress and died before 6 months of age. One novel deletion, c.780delG;p.(Gln260Hisfs*24), inherited from the father and a nonsense mutation, c.1488C>A;p.(Cys496*), inherited from the mother were detected. An attempt was made to correlate the genetic-clinical data available in the literature. The clinical case presented in this study might be considered as the most severe form of spinal muscular atrophy respiratory distress 1 reported so far, presumably because of the total absence of IGHMBP2 enzyme activity.Journal of child neurology 02/2013; · 1.59 Impact Factor -
Article: 15q13.3 microdeletions in a prospectively recruited cohort of patients with idiopathic generalized epilepsy in Bulgaria.
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ABSTRACT: PURPOSE: The chromosome 15q13.3 region is a genomic rearrangement hotspot linked to idiopathic generalized epilepsies (IGEs) and such rearrangements remain the strongest risk factor for IGE known to date. Increasing evidence suggests that genetic variations can be highly population-specific. Therefore, we aimed to assess the frequency of 15q13.3 microdeletions in IGE patients from Bulgaria. METHODS: A cohort of 100 patients with various IGE syndromes was screened for large deletions/duplications by MLPA. All deletions and duplications were confirmed by array CGH analysis as previously described. RESULTS: In 100 prospectively recruited Bulgarian patients with IGE, we found one case with a microdeletion, which amounted to 1% frequency for this copy number variant. CONCLUSION: We confirm the frequency of 1% for the 15q13.3 microdeletion in a prospectively recruited cohort of Bulgarian epilepsy patients, demonstrating that this variation represents a significant risk factor for IGE for various populations and that it is retrospectively detected frequency is not due to selection bias.Epilepsy research 01/2013; · 2.48 Impact Factor -
Article: Different methylation patterns in BWS/SRS cases clarified by MS-MLPA.
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ABSTRACT: Molecular abnormalities in the 11p15.5 imprinted gene cluster lead to two different growth diseases: Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). They are mainly caused by epigenetic alterations in one of the two imprinting 11p15 control regions (ICR1 and ICR2). These CpG-rich regions are differentially methylated on the maternally and paternally derived chromosomes. We report four different methylation patterns along the BWS/SRS critical region, clarified by methylation-specific multiplex ligation-dependent probe amplification. The mathematical processing of the data provides information about alterations in the methylation status: from hypo- to almost complete demethylation of KvDMR, hypo- and hypermethylation of H19DMR and combined results from both regions provide information on paternal uniparental disomy (patUPD). The study concerns two BWS cases with KvDMR hypomethylation and almost complete loss of methylation, respectively; two patUPD11p15 cases with H19DMR hypermethylation/KvDMR hypomethylation, and one SRS case with H19DMR demethylation. In some cases KvDMR hypomethylation in patUPD11p15 can be difficult to assess, which requires combination with STR analysis or alternative method. The STR analysis provides also information on complete or segmental coverage and iso- or heterodisomy. Following this systematic approach, the precise diagnosis can be clarified in a few days and different methylation patterns could be detected.Molecular Biology Reports 10/2012; · 2.93 Impact Factor -
Article: A novel PCDH19 mutation inherited from an unaffected mother.
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ABSTRACT: We report on a 13-year-old girl with a negative family history who manifested drug-resistant, mostly fever-induced seizures in clusters from age 5 months. Seizure frequency was not substantially reduced by anticonvulsant treatment, but tended to decrease with age. Early behavioral changes, i.e., autistic and aggressive features, worsened with time. Molecular genetic testing for PCDH19 mutations was performed by sequencing all exons of the gene, and revealed duplication c.2705dupA (p.Asp902Lysfs*6) in exon 5, which was also present in the fully asymptomatic mother. This case is among the few reported with a pathogenic PCDH19 mutation inherited from an unaffected heterozygous female carrier. It indicates that PCDH19 mutation testing should be performed in sporadic cases with no family history that still demonstrate well-established features of peculiar X-linked epilepsy with mental retardation limited to females.Pediatric Neurology 06/2012; 46(6):397-400. · 1.52 Impact Factor -
Article: Gelastic seizures in ring chromosome 20 syndrome: a case report with video illustration.
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ABSTRACT: Although increasingly recognised, ring chromosome 20 (r[20]) syndrome is still diagnosed with delay, sometimes leading to inappropriate presurgical evaluation. The focal, presumed frontal, character of the seizures manifesting with fear and hypermotor behaviour and episodes of non-convulsive status epilepticus (NCSE) are most typical, as well as cognitive impairment with behavioural problems and, sometimes, dysmorphic signs. We present a girl diagnosed at the age of 13 years who suffered from an atypical clinical presentation, with minimal cognitive problems, absence of dysmorphic symptoms, and hypermotor/gelastic seizures. [Published with video sequences].Epileptic disorders: international epilepsy journal with videotape 05/2012; 14(2):181-6. · 1.50 Impact Factor -
Article: Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis.
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ABSTRACT: Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation-mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321_322insGAAG, p.(Lys107_Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584_624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2012; 734(1-2):69-72. · 2.85 Impact Factor -
Article: One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene.
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ABSTRACT: Mutations in SCN1A gene, encoding the voltage-gated sodium channel α1-subunit, are found to be associated with severe myoclonic epilepsy in infancy or Dravet syndrome (DS), but only rarely with the myoclonic astatic epilepsy (MAE, or Doose syndrome). We report on two patients with SCN1A mutations and severe epilepsy within the spectrum of generalized epilepsy with febrile seizures plus syndrome (GEFS+), the phenotypes being consistent with DS and MAE, respectively. Analysis of SCN1A revealed a heterozygous de novo frameshift mutation (c.4205_4208delGAAA) in the patient with DS, and a recurrent missense mutation (c.3521C>G) in that suffering from MAE. The missense mutation has been reported in patients with neurological diseases of various manifestations, which suggests that this variability is likely to result from the modifying effects of other genetic or environmental factors. DS phenotype has been mainly found associated with truncation mutations, while predominantly missense mutations and very few prematurely terminating substitutions have been reported in GEFS+ patients.Neuroscience Letters 03/2011; 494(2):180-3. · 2.11 Impact Factor -
Article: A unified rapid PCR method for detection of normal and expanded trinucleotide alleles of CAG repeats in huntington chorea and CGG repeats in fragile X syndrome.
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ABSTRACT: We report on a unified rapid betaine-based-PCR protocol for amplification of the (CAG)n region in Huntington disease (HD) and the (CGG)n region in Fragile X syndrome (FXS), followed by an electrophoretic separation on automated sequencer for precise determination of the triplet numbers. The high betaine concentration (2.5 M betaine) permits precise amplification of the CAG and CGG repeats. Ten HD affected patients and 10 healthy individuals from HD families were re-evaluated. For FXS the CGG region in normal individuals and premutations of about 100 repeats were precisely amplified by this protocol. Ten unrelated FXS premutation carriers and 24 mentally retarded non-FXS affected boys were re-examined by this method. The results totally coincided with the previous ones. This protocol is a good choice as a fast screening test. Within 24 h we can have preliminary information on the patient's genetic status. Normal individuals, CGG premutation carriers up to 100 repeats, as well as HD patients carrying an expansion up to 50 CAG repeats can be easily clarified. This accounts for a relatively large proportion (about 90%) of the suspected HD and FXS patients, referred to our laboratory for genetic analysis. The calculation of the repeat's number is more accurate for the correct interpretation of the results, screening tests and genetic counselling.Molecular Biotechnology 03/2010; 45(2):150-4. · 2.17 Impact Factor -
Article: Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA.
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ABSTRACT: We report on a fragile X mosaic male full mutation/normal allele detected by PCR and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). This combined analysis provides a diagnostic approach for fragile X syndrome (FXS). The method assesses the presence of expansion (full mutation), the CpG methylation status and could determine copy number changes (large deletions/duplications) along the FMR1 and FMR2 (fragile X mental retardation) genes. The method avoids detection of premutations, which makes it applicable for newborn screening. It can also be used in clarification of mosaic cases. The PCR results in our patient showed one normal allele; three repeats larger than his mother's one. The MS-MLPA showed hypermethylated full mutation pattern in the proband. Both results are compatible with FXS mosaic case full mutation/normal allele. The patient demonstrates atypical mild clinical manifestation of the disease, which correlates to the presence of a normal size allele in the patient's cells.Case Reports 01/2009; 2009. -
Article: MLPA analysis/complete sequencing of the DMD gene in a group of Bulgarian Duchenne/Becker muscular dystrophy patients.
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ABSTRACT: Duchenne/Becker muscular dystrophy (DMD/BMD), the most common X-linked muscular dystrophy is caused by mutations in the enormously large DMD gene, encoding the protein called dystrophin. This gene was screened in a group of 27 unrelated Bulgarian DMD/BMD patients by MLPA analysis/complete sequencing. We managed to clarify the disease-causing mutation in 96.3% of the analyzed families. The MLPA analysis revealed 17 deletions (including a deletion of the very last exon 79), 6 duplications and 1 point mutation. Two additional point mutations (one of them novel) were detected after complete sequencing of the DMD gene. Altogether, 25 carriers and 11 noncarriers were detected in our families. The MLPA test proved to be a powerful tool in detecting deletions/duplications and in some cases point mutations/polymorphisms along the DMD gene. Using this approach in combination with a direct gene sequencing a number of Bulgarian DMD/BMD patients are genetically clarified and prepared for gene therapy in future.Neuromuscular Disorders 08/2008; 18(8):667-70. · 2.80 Impact Factor -
Article: A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients.
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ABSTRACT: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 (CAPN3) gene. The clinical diagnoses of these cases in Bulgaria are very complicated, no protein analysis on muscular biopsy is available in our country, and genetic tests are the only possibility to clarify the diagnoses in clinically ambiguous cases. We screened 48 unrelated Bulgarian cases with preliminary diagnoses of different types of muscular dystrophy for mutations in the CAPN3 gene. Altogether, 20 families (42%) were found to carry mutations in the CAPN3 gene. Several misdiagnosed cases were clarified. Three novel and six recurrent mutations were identified. In total, 40% of the patients are homozygous for c.550delA, and 70% carry it at least on one allele. The affected group of women in our sample shows later onset, milder clinical manifestation, slower progression, and later invalidization.Neurogenetics 09/2007; 8(3):225-9. · 3.35 Impact Factor -
Article: Problematic clinical isolates of Pseudomonas aeruginosa from the university hospitals in Sofia, Bulgaria: current status of antimicrobial resistance and prevailing resistance mechanisms.
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ABSTRACT: A total of 203 clinical isolates of Pseudomonas aeruginosa was collected during 2001-2006 from five university hospitals in Sofia, Bulgaria, to assess the current levels of antimicrobial susceptibility and to evaluate resistance mechanisms to antipseudomonal antimicrobial agents. The antibiotic resistance rates against the following antimicrobials were: carbenicillin 93.1 %, azlocillin 91.6 %, piperacillin 86.2 %, piperacillin/tazobactam 56.8 %, ceftazidime 45.8 %, cefepime 48.9 %, cefpirome 58.2 %, aztreonam 49.8 %, imipenem 42.3 %, meropenem 45.5 %, amikacin 59.1 %, gentamicin 79.7 %, tobramycin 89.6 %, netilmicin 69.6 % and ciprofloxacin 80.3 %. A total of 101 of the studied P. aeruginosa isolates (49.8 %) were multidrug resistant. Structural genes encoding class A and class D beta-lactamases showed the following frequencies: bla(VEB-1) 33.1 %, bla(PSE-1) 22.5 %, bla(PER-1) 0 %, bla(OXA-groupI) 41.3 % and bla(OXA-groupII) 8.8 %. IMP- and VIM-type carbapenemases were not detected. In conclusion, the studied clinical strains of P. aeruginosa were problematic nosocomial pathogens. VEB-1 extended-spectrum beta-lactamases appear to have a significant presence among clinical P. aeruginosa isolates from Sofia. Carbapenem resistance was related to non-enzymic mechanisms such as a deficiency of OprD proteins and active efflux.Journal of Medical Microbiology 08/2007; 56(Pt 7):956-63. · 2.50 Impact Factor -
Article: A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss.
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ABSTRACT: We sought to verify whether variation in the promoter of the gene encoding placental anticoagulant protein annexin A5 (ANXA5) represents a risk factor for recurrent pregnancy loss (RPL). Sequence analysis of 70 German RPL patients, all known to carry neither factor V Leiden nor a prothrombin mutation, revealed four consecutive nucleotide substitutions in the ANXA5 promoter, which were transmitted as a joint haplotype (M2). Reporter gene assays revealed that M2 reduces the in vitro activity of the ANXA5 promoter to 37-42% of the normal level. The possible relationship between M2 and RPL was evaluated by comparing RPL patients with two independent control groups recruited from the registry of the Institut für Humangenetik in Münster and the PopGen biobank in Kiel, respectively. Carriers of M2 were found to exhibit a > 2-fold higher RPL risk than non-carriers (odds ratio, 2.42; 95% confidence interval, 1.27-4.58) when using unselected controls (PopGen) and an almost 4-fold higher risk when using the Münster 'super-controls', i.e. women with successful pregnancies and no previous history of pregnancy losses (odds ratio, 3.88; 95% confidence interval, 1.98-7.54). This statistically significant association should facilitate the development of improved prognostic algorithms for RPL, involving a more precise assessment of individual disease risks, and provide a guide to offering adequate therapies where relevant.Human Molecular Genetics 04/2007; 16(5):573-8. · 7.64 Impact Factor -
Article: Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A.
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ABSTRACT: The amount of residual F8 (FVIII:C) determines the clinical severity of hemophilia A. Recently, we showed that the mutation detection rate in severely affected male patients (FVIII:C<1% of normal) is virtually 100% when testing for the common intron 22-/intron 1- inversions and big deletions, followed by genomic sequencing of the F8 gene. Here we report on the spectrum of mutations and their distribution throughout the F8 gene sequence in 135 patients with moderate (n=23) or mild (n=112) hemophilia A. In contrast to the severe form of the disorder, analysis on the genomic level failed to detect the molecular defect in approximately 4% of the moderately and in approximately 12% of the mildly affected patients. A total of 36 of the mutations identified in this study are novel. The vast majority of the detected changes were missense. The newly detected amino acid substitutions were scored for potential distant or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling. Two molecular changes in the promoter region of the factor VIII gene (c.-112G>A and -219C>T), affecting the core segment (minimal promoter) were detected in two patients with mild hemophilia A. To our knowledge this is the first report on promoter mutations in the F8 gene.Human Mutation 02/2007; 28(1):54-60. · 5.69 Impact Factor -
Article: Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A.
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ABSTRACT: Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 males worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.Human Mutation 10/2005; 26(3):249-54. · 5.69 Impact Factor -
Article: 550delA mutation in the calpain 3 (CAPN3) gene: DMD/BMD, SMA, or LGMD2A--clinically misdiagnosed cases.
American Journal of Medical Genetics Part A 09/2005; 136A(4):399-400. · 2.39 Impact Factor -
Article: Dilated cardiomyopathy and new 16 bp deletion in exon 44 of the Dystrophin gene: the possible role of repeated motifs in mutation generation.
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ABSTRACT: Here we report a boy with dilated cardiomyopathy and severe Duchenne muscular dystrophy (DMD). The disease-causing mutation was a new 16 bp deletion in exon 44 of the dystrophin gene, which led to frameshifting and premature translation termination. This deletion in exon 44 was associated with dilated cardiomyopathy. The dystrophin region in exon 44 might be considered as one of the high-risk regions in which mutations could lead to myocardial damage, dilated cardiomyopathy, and early death. The abundance of repeated motifs was detected within the deleted segment and in the region. These sequence motifs might be involved in secondary structure formation and thus they could participate in the mutation generation.American Journal of Medical Genetics Part A 08/2003; 120A(1):5-7. · 2.39 Impact Factor -
Article: Screening for C283Y gamma-sarcoglycan mutation in a high-risk group of Bulgarian Gypsies: evidence for a geographical localization and a non-random distribution among Gypsy subgroups.
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ABSTRACT: Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive disorder caused by mutations in the gamma-sarcoglycan gene. A 'private' Gypsy C283Y mutation was detected in this gene. Recently, a number of LGMD2C-affected families belonging to a Xoroxane Gypsy group have been detected in eastern Bulgaria and all of these cases were due to the same mutation. We have screened 300 unrelated individuals of reproductive age from this high-risk Xoroxane Gypsy group, settled in Sliven. The genetic test by PCR-SSCP analysis for the C283Y mutation revealed a carrier frequency of 7.7%. The screened sample was ethnically not homogeneous. It was divided in ethnonym groups on the basis of social and economic status, language characteristics and trades. We found that the C283Y was not randomly distributed among the Gypsy subgroups. The disease seemed to be limited to the Xoroxane Gypsy group and geographically localized in eastern Bulgaria.Community Genetics 02/2002; 5(4):217-21. · 1.32 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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University Hospital "St. Anna", Sofia, Bulgaria
Sofia, Oblast Sofiya-Grad, Bulgaria
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2002–2012
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Medical University of Sofia
- • Department of Chemistry and Biochemistry
- • Laboratory of Molecular Pathology
Sofia, Oblast Sofiya-Grad, Bulgaria
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2007
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Universitätsklinikum Münster
- Institut für Humangenetik
Münster, North Rhine-Westphalia, Germany
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