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Biomedical subjects

I Kremensky

Publications and source records attributed to I Kremensky.

At least 19 recordsLinked to original sources
PubMed2006

Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system. The most common genetic form accounting for about 40% of the autosomal-dominant HSP (ADHSP) cases is spastin gene, SPG4. We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups (Bulgarian, Turks and Gypsies) and found four new mutations and one already reported. The phenotype-genotype correlations in Bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice-site mutations. Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation. The clinical and genealogical findings in Bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal-dominant trait is a strong indication for spastin mutation screening.

Adenosine Triphosphatases↗
PubMed2004

C283Y gamma-sarcoglycan gene mutation in the Bulgarian Roma (Gypsy) population: prevalence study and carrier screening in a high-risk community.

Limb-girdle muscular dystrophy type 2C (LGMD2C) is caused by mutations in the gamma-sarcoglycan gene where a founder Gypsy mutation C283Y was detected. The Bulgarian Gypsy LGMD2C patients, as the Gypsy patients from other countries, were found to be homozygous for this mutation. Considering the large number of Gypsies in Bulgaria and the high percent of consanguinity and endogamy a raised carrier frequency of the C283Y mutation was expected especially in North-Eastern Bulgaria where most of the patients originate from. Here, we present the precise geographic distribution of the C283Y mutation in the general Roma population from the whole Bulgarian territory by determining the carrier frequency of the mutation in dry blood newborn samples. Our results show that the geographic distribution of this founder mutation and the disease are not geographically restricted only among Gypsies from North-Eastern Bulgaria. We stress upon the regions with detected high carrier and/or disease frequency and upon the results from the performed carrier screening on volunteers in one of these regions. The ongoing carrier-screening programs in isolated Gypsy groups would be of a great benefit for the genetic prophylaxis of the disease. Such regions should be with priority in the Bulgarian healthcare system for performing a carrier-screening program.

Bulgaria↗
PubMed2003

Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.

Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.

Adolescent↗
PubMed2001

Y-chromosomal STR haplotypes in three major population groups in Bulgaria.

A total of 280 unrelated males from the three largest population groups in Bulgaria: Bulgarians, Bulgarian Turks and Gypsies, were analyzed for seven Y-chromosome STRs (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393). Comparison of the allele frequency distributions revealed significant differences between the three ethnic groups which were confirmed with haplotype analysis. This permits us to suggest that population differentiation should be taken into account in forensic case analysis and paternity testing in Bulgaria.

Bulgaria↗
PubMed1999

C283Y mutation and other C-terminal nucleotide changes in the gamma-sarcoglycan gene in the Bulgarian Gypsy population.

Sarcoglycanopathies, affecting the dystrophin-associated sarcoglycan (SG) complex, are a heterogeneous group of neuromuscular disorders. A subgroup of these disorders, limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive disorder, clinically manifested as an early onset, severe Duchenne-like muscular dystrophy. LGMD2C is caused by mutations in the gamma-SG gene, localized on 13q12. Recently, a number of mutations have been described in that gene, among which C283Y, a "private" Gypsy mutation (eight codons before the 3' end of the gene) is detected. In this article, we report on a single-strand conformation polymorphism (SSCP) method for fast C283Y mutation detection, using direct dry blood spot amplification. The method permits a large number of samples to be easily screened. To check heterozygote carriers of C283Y mutation among Gypsy population in Bulgaria, the SSCP analysis was applied on 400 Gypsy newborns from northeast Bulgaria. Our results show 2.25% of heterozygosity, which means that 1 in 50 Gypsies carries the mutation. Moreover, new SSCP migration patterns were detected that revealed two polymorphisms still unavailable in the literature. One of these changes was 984G-->A, leading to substitution of conserved serine at position 287 with asparagine and the second one is 1049C-->G at the 3' UTR (untranslated region). The present data could help the understanding the role of these sequences for the protein function.

Base Sequence↗
PubMed1999

A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies).

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.

Adolescent↗
PubMed1998

Deletion analysis of Bulgarian SMA families.

All three types of autosomal recessive spinal muscular atrophy map to chromosome region 5q13. Recent reports suggest that they are associated with deletions of two adjacent genes: SMN and NAIP. Here we report the first deletion analysis of Bulgarian SMA families. Homozygous deletion of exons 7 and 8 of the SMN gene were found in 85% of our patients, but the NAIP gene (exons 5 and 6) was deleted in only 26% of patients. To our knowledge, these frequencies are some of the lowest reported so far. The NAIP gene was deleted predominantly in severely affected patients (type I), while in the group with milder types SMA only deletions of the SMN gene were detected. Our phenotype-genotype correlation study confirmed that larger deletions are associated with more severe clinical course. The Bulgarian data support the thesis that the telomeric SMN gene could play a major role in determining SMA, while the NAIP or the centromeric SMN copy have a modifying effect on the phenotype.

Bulgaria↗
PubMed1997

SSCP analysis: a blind sensitivity trial.

Studies of the sensitivity of SSCP analysis usually have been performed under conditions contrary to the rules of quality control trials and have produced widely different results. We have performed a blind trial of the sensitivity of SSCP analysis for the detection of mutations in fragments up to 500 bp in length under a fixed single set of electrophoretic conditions. The mutation detection rate was 84%. In addition, we have identified a second mutation in nine samples. All these mutations are polymorphisms, including a novel polymorphism 1248 + 52T/C first reported in the present work.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed1997

A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism. It is one of the most frequent genetic metabolic disorders among Caucasian children. The G985 allele represented 90% of all the variant alleles of the MCAD gene in an extensive series of retrospective studies. To study the distribution of the G985 allele, newborn blood samples from the following countries were tested; 3000 from Germany (1/116). 1000 each from Belgium (1/77). Poland (1/98), Czech Republic (1/240). Hungary (1/168), Bulgaria (1/91), Spain (1/141). Turkey (1/216), and 500 from Japan (none). The frequency is shown in parentheses. The haplotype of G985 alleles in 1 homozygote and 57 heterozygote samples were then analyzed using two intragenic MCAD gene polymorphisms (Iaq1 and GT-repeat). The result indicated that only 1 of the 10 known haplotypes was associated with the G985 mutation, suggesting that G985 was derived originally from a single ancestral source. We made a compilation of the G985 frequencies in these countries and those in nine other European countries studied previously. The G985 distribution was high in the area stretching from Russia to Bulgaria in the east and in all northern countries in western and middle Europe, but low in the southern part of western and middle Europe. The incidence among ethnic Basques appeared to be low. This distribution pattern and the fact that all G985 alleles belong to a single haplotype suggest that G985 mutation occurred later than the delta F508 mutation of the CFTR, possibly in the neolithic or in a later period, and was brought into Europe by IndoEuropean-speaking people. The panEuropean distribution of the G985 allele, including Slavic countries from which patients with MCAD deficiency have rarely been detected, indicates the importance of raising the level of awareness of this disease.

Acyl-CoA Dehydrogenases↗
PubMed1997

Optimization of single-strand conformation polymorphism analysis in the presence of polyethylene glycol.

We report optimization of single-strand conformation polymorphism (SSCP) analysis in the presence of polyethylene glycol. The protocol developed separates single-strand conformers in a much shorter time (1-3 h) than conventional SSCP protocols and broadens the applicability of SSCP analysis from 150 to as much as 500 bp of DNA by different percentages of GC content present. We conclude that addition of polyethylene glycol helps improve the differential separation of conformers and, in combination with high-resolution polyacrylamide gel electrophoresis, offers an alternative to previous SSCP analysis protocols. This protocol should be very useful for clinical applications in routine detection of mutations as well as for research purposes.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed1996

Mutation analysis in Duchenne and Becker muscular dystrophy patients from Bulgaria shows a peculiar distribution of breakpoints by intron.

For the first time in Bulgaria, a deletion/duplication screening was performed on a group of 84 unrelated Duchenne/Becker muscular dystrophy patients, and the breakpoint distribution in the dystrophin gene was analyzed. Intragenic deletions were detected in 67.8% of patients, and intragenic duplications in 2.4%. A peculiar distribution of deletion breakpoints was found. Only 13.2% of the deletion breakpoints fell in the "classical" hot spot in intron 44, whereas the majority (> 54%) were located within the segment encompassing introns 45-51, which includes intron 50, the richest in breakpoints (16%) in the Bulgarian sample. Comparison with data from Greece and Turkey points at the probable existence of a deletion hot spot within intron 50, which might be a characteristic of populations of the Balkan region.

Bulgaria↗
PubMed1992

Heterogeneity of mutations in Bulgarian phenylketonuria haplotype 1 and 4 alleles.

A study of Bulgarian patients with classical PKU demonstrated that haplotypes 1 and 4 carry a significant number of rare molecular defects resulting from independent mutational events. Differences in mutations associated with these common haplotypes exist even between populations which share a common major PKU mutation. Some amino acid substitutions, previously reported to lead to mild phenylalanine hydroxylase deficiency, were detected in the present study in compound heterozygotes with severe PKU. These findings preclude carrier testing and hyperphenylalaninemia typing by genomic analysis at least in the heterogeneous Bulgarian population.

Base Sequence↗
PubMed1992

Screening for phenylketonuria in a totalitarian state.

Living under a totalitarian regime has many effects on the structure, way of thinking, and relations in a society. However, it is the impact on neonatal genetic screening that we discuss in this paper. Genetic screening functions at the interface between health services and society at large. Being involved for over a decade in setting up the Bulgarian PKU screening programme, we have had to deal with ways and attitudes which may be difficult for the western mind to grasp. Yet comprehension is very much needed in the new world we are trying to create.

Academies and Institutes↗