Search PubMed⌕ Search

Biomedical subjects

L Kalaydjieva

Publications and source records attributed to L Kalaydjieva.

At least 37 records · Page 2Linked to original sources
PubMed1999

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred.

Members of a Roma (Gypsy) family with hereditary motor and sensory peripheral neuropathy (HMSN) and concomitant auditory and vestibular cranial neuropathies were identified in Kocevje, Slovenia. The illness begins in childhood with a severe and progressive motor disability and the deafness is delayed until the second decade. There are no symptoms of vestibular dysfunction. The family structure is consistent with an autosomal recessive pattern of inheritance and the genetic locus for the disorder is linked to the same region of chromosome 8q24 as other Roma families with HMSN and deafness from Lom, Bulgaria (HMSN-Lom). The present study shows that the deafness is caused by a neuropathy of the auditory nerve with preserved measures of cochlear outer hair cell function (otoacoustic emissions and cochlear microphonics) but absent neural components of auditory brainstem potentials. The hearing loss affects speech comprehension out of proportion to the pure tone loss. Vestibular testing showed absence of caloric responses. Physiological and neuropathological studies of peripheral nerves were compatible with the nerve disorder contemporaneously affecting Schwann cells and axons resulting in both slowed nerve conduction and axonal loss. Genetic linkage studies suggest a refinement of the 8q24 critical region containing the HMSN-Lom locus that affects peripheral motor and sensory nerves as well as the cranial auditory and vestibular nerves.

Acoustic Stimulation↗
PubMed1999

Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome.

Observations have been made on the peripheral nerve changes in four patients, ranging in age from 4 to 32 years, with the congenital cataracts facial dysmorphism neuropathy syndrome. Myelinated fibre density was within normal limits. The salient abnormality was diffuse hypomyelination which, in the older patients, was associated with demyelination and then axonal degeneration. These findings could be correlated with the relative preservation of sensory action potential amplitude despite markedly reduced nerve conduction velocity. Unmyelinated axon density was preserved. The morphological observations suggest the operation of a developmental process affecting myelination with a later superimposed degenerative disorder.

Adult↗
PubMed1999

Exclusion of linkage to the HLA region in ninety multiplex sibships with autism.

Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.

Adolescent↗
PubMed1999

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel developmental disorder in Gypsies maps to 18qter.

We have identified a novel developmental disorder with complex phenotypic characteristics involving primarily the nervous system, which appears to be common in a specific Gypsy group in Bulgaria. We propose to refer to the syndrome as congenital cataracts facial dysmorphism neuropathy (CCFDN). We have assigned the disease locus to the telomeric region of chromosome 18q. Linkage disequilibrium and highly conserved haplotypes suggest genetic homogeneity and founder effect. CCFDN co-localises with an EST which shows high homology to a conserved Drosophila gene involved in the regulation of nervous system development in vertebrates.

Adolescent↗
PubMed1999

Ultrastructural changes in peripheral nerve in hereditary motor and sensory neuropathy-Lom.

Ultrastructural observations have been made on nerve biopsy specimens from five cases of hereditary motor and sensory neuropathy-Lom (HMSNL). A number of features that distinguish it from other hereditary demyelinating neuropathies were identified. Teased fibre studies were not feasible but examination of longitudinal sections by electron microscopy demonstrated demyelination/remyelination. Severe progressive axonal loss was a conspicuous feature. There was no indication of axonal atrophy. Hypertrophic onion bulb changes were present in the younger patients which later regressed, probably secondary to axonal loss. Myelin thickness was generally reduced in relation to axon diameter, indicating hypomyelination, and partial ensheathment of axons by Schwann cells was observed. The Schmidt-Lanterman incisures were atypical in extending for long lengths along the internode. Uncompacted myelin with a periodicity greater than that observed in other neuropathies in which it occurs was a feature, as was the accumulation of pleomorphic material in the adaxonal Schwann cell cytoplasm. An unusual finding was the presence of intra-axonal accumulations of irregularly arranged curvilinear profiles. These resemble those that have been described in experimental vitamin E deficiency. The amount of endoneurial collagen was markedly increased and some endoneurial blood vessels showed a non-specific basal laminal reduplication.

Adolescent↗
PubMed1999

A genomic screen of autism: evidence for a multilocus etiology.

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.

Adolescent↗
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↗
PubMed1999

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations.

During a study of hereditary motor and sensory neuropathy-Lom in Bulgaria, a previously unrecognized neurological disorder was encountered, mainly in Wallachian Gypsies, who represent a relatively recent genetic isolate. The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features. Fifty individuals from 19 extended pedigrees were identified and examined clinically and electrophysiologically. At least 1 patient from each family was admitted to the hospital in Sofia for full investigation. Pedigree analysis indicates autosomal recessive inheritance. The disorder is recognized in infancy by the presence of congenital cataracts and microcorneas. A predominantly motor neuropathy beginning in the lower limbs and later affecting the upper limbs develops during childhood and leads to severe disability by the third decade. Associated neurological features are a moderate nonprogressive cognitive deficit in most affected individuals together with pyramidal signs and mild chorea in some. Accompanying nonneurological features include short stature, characteristic facial dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. The CCFDN syndrome is thus a pleomorphic autosomal recessive disorder displaying a combination of neurological and nonneurological features.

Adolescent↗
PubMed1998

Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects.

Polycystin-1 and polycystin-2 are the products of PKD1 and PKD2, genes that are mutated in most cases of autosomal dominant polycystic kidney disease. Polycystin-2 shares approximately 46% homology with pore-forming domains of a number of cation channels. It has been suggested that polycystin-2 may function as a subunit of an ion channel whose activity is regulated by polycystin-1. Here we report the identification of a human gene, PKDL, which encodes a new member of the polycystin protein family designated polycystin-L. Polycystin-L has 50% amino acid sequence identity and 71% homology to polycystin-2 and has striking sequence and structural resemblance to the pore-forming alpha1 subunits of Ca2+ channels, suggesting that polycystin-L may function as a subunit of an ion channel. The full-length transcript of PKDL is expressed at high levels in fetal tissues, including kidney and liver, and down-regulated in adult tissues. PKDL was assigned to 10q24 by fluorescence in situ hybridization and is linked to D10S603 by radiation hybrid mapping. There is no evidence of linkage to PKDL in six ADPKD families that are unlinked to PKD1 or PKD2. The mouse homologue of PKDL is deleted in Krd mice, a deletion mutant with defects in the kidney and eye. We propose that PKDL is an excellent candidate for as yet unmapped cystic diseases in man and animals.

Amino Acid Sequence↗
PubMed1998

The gene for the human Src-like adaptor protein (hSLAP) is located within the 64-kb intron of the thyroglobulin gene.

In this study, we describe the molecular cloning and characterization of a Src-like adaptor protein gene embedded within the genomic organization of the human thyroglobulin (Tg) gene. This gene was identified by exon trapping on overlapping cosmids encompassing the largest Tg intron. A 2.6-kb transcript, with the highest levels of expression in fetal brain and lung, was detected on Northern blots. Two full-length cDNAs (one alternatively spliced) were isolated from a fetal brain library, both containing an open reading frame of 276 amino acids, but lacking a catalytic tyrosine kinase domain. The gene shows a high degree of cross-species similarity and appears to be transcribed in the direction opposite to Tg. This gene, designated hslap, appears to be the human ortholog of the recently described gene for the murine Src-like adaptor protein (mSLAP), a candidate intermediate in the signal-transduction pathway of the Eck receptor tyrosine kinase. Human slap is located in the candidate region for a recessive demyelinating neuropathy on chromosome 8q24, but sequence analysis failed to identify mutations, suggesting that it is not the gene for this disease.

Adaptor Proteins, Signal Transducing↗
PubMed1998

HMSNL in a 13-year-old Bulgarian girl.

We present a 13-year-old Bulgarian girl with a new form of demyelinating neuropathy with hearing loss. The clinical and neuropathological features of the patient were similar to those of the recently described hereditary motor and sensory neuropathy type Lom (HMSNL), first identified in a large Bulgarian Gypsy population. Neuropathological examination of a peripheral nerve biopsy revealed an excess of nerve fibres with inappropriately thin myelin sheaths compared with the axon diameter, surrounded by concentric Schwann cells without typical onion-bulb formation. The parents of our patient are unaware of Gypsy ancestry and are not in a consanguineous marriage. Genetic analyses showed that the patient was homozygous for the predominant HMSNL haplotype on 8q24. Our findings indicate that HMSNL should be considered in the differential diagnosis of any patient presenting with the symptoms of demyelinating neuropathy with hearing loss, even if no Gypsy ethnic background is reported.

Adolescent↗
PubMed1998

Hereditary motor and sensory neuropathy Lom type in an Italian Gypsy family.

We describe a form of hereditary motor and sensory neuropathy (HMSN) affecting four siblings in an Italian family of Gypsy ethnic origin with both clinical and pathological findings very reminiscent of the HMSN Lom type (HMSNL), recently described in a group of Bulgarian Gypsies. Genetic analysis demonstrated linkage to chromosome 8q24 and conserved haplotypes in the HMSNL region, thus confirming that this is the first Gypsy family outside the Balkans suffering from the same disorder.

Adolescent↗
PubMed1998

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings.

A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait disorder followed by upper limb weakness in the second decade and, in most subjects, by deafness which is most often first noticed in the third decade. Sensory loss affecting all modalities is present, both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformity, is frequent. Severely reduced motor nerve conduction velocity indicates a demyelinating basis, which was confirmed by nerve biopsy. The three younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The hypertrophic changes were not evident in the oldest individual biopsied and it is likely that they had regressed secondarily to axon loss. In the eight cases in which brainstem auditory evoked potentials could be recorded, the results suggested demyelination in the eighth cranial nerve and also abnormal conduction in the central auditory pathways in the brainstem. As no myelin genes are known to be located at chromosome 8q24, the disorder may involve a gene for a novel myelin protein or be due to an abnormality of axon-Schwann cell signalling.

Adolescent↗
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

Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study.

We present data on the population genetics of cystic fibrosis (CF) in Bulgaria, obtained by comprehensive mutation analysis and the construction of intragenic microsatellite haplotypes. The sample of 262 CF alleles analysed is representative of the patients diagnosed during the period of referral and of the three main ethnic groups in the country. deltaF508 accounted for 100% of Gypsy CF alleles, which thus differed significantly from both Bulgarians and ethnic Turks. In Bulgarian and Turkish CF patients, 92% of the mutant alleles were identified, yielding a total of 25 different mutations, of which only 7 occurred at frequencies higher than 1%. The findings were compared to other European populations and to the distribution of phenylketonuria mutations. Genetic distances and population trees demonstrated that in the south-eastern tip of Europe, the overall distribution of CF mutations and polymorphic haplotypes is very close to that of Mediterranean populations, with a high frequency of N1303K and G542X, a large number of rare mutations and a prevalence of the 23 31 13 haplotype in association with deltaF508. These findings are consistent with a main role for the Neolithic expansion in the shaping of the CF mutation spectrum in Bulgaria and southern Europe.

Bulgaria↗
PubMed1996

Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

Adolescent↗