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1.
Anal Cell Pathol (Amst) ; 2018: 6836092, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079294

RESUMO

Idiopathic scoliosis (IS) is a common medical condition beginning in childhood and characterized by strong evidence for a genetic susceptibility to three-dimensional spinal deformity. The primary goal of the current case-control study is to examine the association between the TGFB1 (-509C/T) functional polymorphic variant and genetic predisposition to IS in the Bulgarian population and the genotype-phenotype correlations in distinct case-control subgroups based on age at onset, family history, and gender. A total of 127 patients with primary scoliosis and 254 gender-matched control subjects were recruited. The mean Cobb angle was 53.8 ± 21.2°. Genotyping of cases and controls was performed using the TaqMan real-time amplification technique. The results were processed statistically using Pearson's Chi-squared test and Fisher's exact test with a value of p less than 0.05 as statistically significant. The polymorphic T allele and TT genotype were associated with a greater incidence of IS and can be considered as predisposing factors with a moderate effect on deformity development. The current results suggested that there was a genetic predisposition in early and late onset IS and familial, sporadic, and female cases. Nevertheless, replication studies are needed to reveal the relationship between the TGFB1 locus and certain subtypes of IS in different populations.


Assuntos
Escoliose/genética , Fator de Crescimento Transformador beta1/genética , Adolescente , Alelos , Bulgária , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único/genética
2.
Case Rep Genet ; 2018: 3028145, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30147969

RESUMO

Congenital muscle dystrophies (CMD) are genetically and clinically heterogeneous hereditary myopathies mainly with autosomal recessive type of inheritance. The most common form worldwide is considered to be merosin-deficient muscle dystrophy type 1A, called MDC1A (due to laminin-α2 defects as a result of LAMA2 gene mutation), accounting for 30-40% of total cases of CMD. The exact molecular and clinical diagnoses, respectively, are a prerequisite for the most effective treatment; sometimes orphan drugs exist for some rare diseases. One of such drugs is Tarix, which was FDA approved and announced in 2016 for treatment of MDC1A. Here we present a patient diagnosed postmortem as having early-onset LAMA2-related muscular dystrophy as a result of mutations in LAMA2, identified by Sanger sequencing in his parents: a novel nonsense mutation c.4452T>A in exon 31, identified in the mother, and a known pathogenic nonsense mutation c.2901C>A in exon 21, detected in the father. The truncating nature of both nonsense mutations made the clinical presentation severe and the outcome fatal. Genetic analysis in such cases of muscle dystrophy is of utmost impact, because it makes the correct diagnosis with at least some specific options for treatment, makes the prognosis depending on the severity of mutation discovered, determines reproductive risk, and offers prophylaxis in the family by means of prenatal or preimplantation diagnostics.

3.
Eur J Med Genet ; 60(6): 321-325, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28392475

RESUMO

Renal cysts are common malformation during the prenatal and postnatal period and frequent cause of chronic kidney or ESRD. More than 70 genes have been shown to play role in their pathology. Part of them are responsible for the structure and function of the cilia, which assigns a large proportion of the renal cystic diseases in the ciliopathies. Another group of genes responsible for cystic kidneys encodes transcription factors with crucial role during organogenesis. We describe here a systematic approach for identifying the genetic cause(s) of an unusually severe form of renal cystic disease in a family with multiple affected siblings. High throughput mutations screening of the parents and one of the children was applied for identifying the genetic causes of the disease. The affected child was found to have inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4. The possibility for epistatic interaction of the NPHP mutations as well as the modifying effect of other inherited genetic variants is discussed.


Assuntos
Doenças Renais Císticas/genética , Cinesina/genética , Proteínas/genética , Adulto , Criança , Epistasia Genética , Feminino , Genes Modificadores , Humanos , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Masculino , Mutação , Linhagem
5.
PLoS One ; 11(12): e0167984, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936167

RESUMO

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.


Assuntos
Proteínas de Ciclo Celular/genética , Efeito Fundador , Mutação , Síndrome de Quebra de Nijmegen/genética , Proteínas Nucleares/genética , Reprodução/genética , Adulto , Estudos de Coortes , República Tcheca , Dano ao DNA , Reparo do DNA , Feminino , Triagem de Portadores Genéticos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Quebra de Nijmegen/etnologia , Eslováquia
6.
Biol Open ; 5(7): 908-20, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27288508

RESUMO

Charcot-Marie-Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot-Marie-Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite 'fingerprint' we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies.

7.
J Biomark ; 2016: 5318239, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27293961

RESUMO

The concept of disease-modifier genes as an element of genetic heterogeneity has been widely accepted and reported. The aim of the current study is to investigate the association between the promoter polymorphism TPH1 (rs10488682) and progression of idiopathic scoliosis (IS) in Eastern European population sample. A total of 105 patients and 210 healthy gender-matched controls were enrolled in this study. The TPH1 promoter polymorphism was genotyped by amplification followed by restriction. The statistical analysis was performed by Fisher's Exact Test. The results indicated that the genotypes and alleles of TPH1 (rs10488682) are not correlated with curve severity, curve pattern, or bracing. Therefore, the examined polymorphic variant could not be considered as a genetic factor with modifying effect of IS. In conclusion, this case-control study revealed no statistically significant association between TPH1 (rs10488682) and progression of IS in Eastern European population sample. These preliminary results should be replicated in extended population studies including larger sample sizes. The identification of molecular markers for IS could be useful for a more accurate prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures.

8.
Hum Pathol ; 47(1): 144-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26603346

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant congenital disorder (prevalence, 1:125000-720000) characterized by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa, and short stature. The purpose of this study was to use targeted exome sequencing to identify the genetic cause of RSTS in a 6.5-year-old girl presenting typical features of this condition. Targeted exome sequencing of the patient DNA revealed de novo transition c.1066C>T corresponding to a novel nonsense mutation p.Q356X in the CREB-binding protein gene, CREBBP, whose haploinsufficiency is responsible for 50% to 60% of the RSTS cases. Based on comparing the clinical manifestations of our patient with those of patients carrying similar mutations, we supposed that haploinsufficiency is the possible functional consequence of p.Q356X mutation by creation of a loss-of-function CREBBP allele due to a premature stop codon and RSTS phenotype. Our findings expand the spectrum of mutations associated with this condition.


Assuntos
Proteína de Ligação a CREB/genética , Códon sem Sentido , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Rubinstein-Taybi/genética , Criança , Exoma , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Fenótipo , Valor Preditivo dos Testes , Síndrome de Rubinstein-Taybi/diagnóstico
9.
Spine (Phila Pa 1976) ; 41(9): 785-91, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26656061

RESUMO

STUDY DESIGN: A case-control study was performed on 105 patients with idiopathic scoliosis (IS) and 210 unrelated gender-matched controls from Bulgarian population. OBJECTIVE: Investigation of the association between common genetic polymorphisms of IL-6 and MMP3 genes and the etiology and progression of IS among Bulgarian patients. SUMMARY OF BACKGROUND DATA: The IL-6 and MMP3 genes have been considered as candidate genes of IS in Caucasian population. METHODS: Molecular detection of the promoter polymorphisms of IL-6 and MMP3 was performed by polymerase chain reaction followed by restriction fragment length polymorphism. The statistical analysis was performed by χ test with a value of P < 0.05 as statistically significant. The combinatorial effect of the candidate genes was also examined. RESULTS: This case-control study revealed statistically significant association between the IL-6 (rs1800795) functional polymorphism and susceptibility to IS (χ = 16.055; P < 0.0001). In addition, a significant association between IL-6 (rs1800795) and curve severity was detected (χ = 16.87; P < 0.0001). No genotype or allele of MMP3 (rs3025058) was found to be correlated to the onset or progression of IS (P > 0.05). One IL-6-MMP3 genotype combination was associated with the susceptibility to IS. CONCLUSION: IL-6 gene could be considered as a susceptibility and modifying factor of IS. The identification of molecular markers with diagnostic and prognostic value could be useful for early detection of children at risk for the development of IS and for prognosis of the risk for a rapid deformity progression. That would facilitate the therapy decisions and early stage treatment of the patient with the least invasive procedures. LEVEL OF EVIDENCE: 4.


Assuntos
Estudos de Associação Genética/métodos , Interleucina-6/genética , Metaloproteinase 3 da Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Escoliose/diagnóstico , Escoliose/genética , Adolescente , Bulgária/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Escoliose/epidemiologia
10.
Genet Res Int ; 2015: 852196, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26380113

RESUMO

Idiopathic scoliosis (IS) is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine with unknown etiology. For the aims of the current study we selected 3 single nucleotide polymorphisms with a low incidence of the polymorphic allele in Bulgarian population, AMPD1 (rs17602729), VDR (rs2228670), and IGF-1 (rs5742612), trying to investigate the association between these genetic polymorphisms and susceptibility to and progression of IS. The polymorphic regions of the genes were amplified by polymerase chain reaction (PCR). The PCR products were cleaved with the appropriate restriction enzymes. The statistical analysis was performed by Pearson's chi-squared test. A value of p < 0.05 was considered to be statistically significant. In conclusion, this case-control study revealed no statistically significant association between the VDR, IGF-1, and AMPD1 polymorphisms and the susceptibility to IS or curve severity in Bulgarian patients. Replication case-control studies will be needed to examine the association between these candidate-genes and IS in different populations. The identification of molecular markers for IS could be useful for early detection and prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures.

11.
J Biomark ; 2015: 425310, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26317037

RESUMO

Idiopathic scoliosis (IS) is the most common spinal disorder in children and adolescents. The current consensus on IS maintains that it has a multifactorial etiology with genetic predisposition factors. In the present study the association of two functional polymorphisms of leptin (rs7799039) and BMP4 (rs4898820) with susceptibility to IS and curve severity was investigated in a Bulgarian population sample. The molecular detection of the genotypes was performed by amplification followed by restriction technology. The statistical analysis was performed by Pearson's chi-squared test. This case-control study revealed no statistically significant association between the functional polymorphisms of leptin and BMP4 and susceptibility to IS or curve progression (p > 0.05). On the basis of these results the examined polymorphic variants of leptin and BMP4 could not be considered as genetic variants with predisposition effect or as risk factors for the progression of the curve. In addition, these results do not exclude a synergistic effect of the promoter polymorphisms of leptin and BMP4 in the etiology and pathogenesis of IS. The identification of molecular markers for IS could be useful for early detection and prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures.

12.
BMC Cancer ; 15: 523, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26183948

RESUMO

BACKGROUND: About 3885 women are diagnosed with breast cancer and 1285 die from the disease each year in Bulgaria. However no genetic testing to identify the mutations in high-risk families has been provided so far. METHODS: We evaluated 200 Bulgarian women with primary invasive breast cancer and with personal/ family history of breast cancer for the presence of unequivocally damaging germline mutations in BRCA1/2 using Sanger sequencing. RESULTS: Of the 200 patients, 39 (19.5 %) carried a disease predisposing mutation, including 28 (14 %) with a BRCA1 mutation and 11 (5.5 %) with a BRCA2 mutation. At BRCA1, 6 different mutations were identified, including 2 frameshifts, 1 nonsense and 1 missense that had been previously reported (c.5030_5033delCTAA, c.5263_5264insC, c.4603G > T, c.181 T > G), and 2 frameshifts, which were novel to this study (c.464delA, c.5397_5403delCCCTTGG). At BRCA2, 7 different frameshift mutations were identified, including 5 previously reported (5851_5854delAGTT, c.5946delT, c.5718_5719delCT, c.7910_7914delCCTTT,c.9098_9099insA) and 2 novel (c.8532_8533delAA, c.9682delA). A BRCA1 mutation was found in 18.4 % of women diagnosed with breast cancer at/or under the age of 40 compared to 11.2 % of women diagnosed at a later age; a BRCA2 mutation was found in 4 % of women diagnosed at/or under the age of 40 compared to 6.5 % of women diagnosed at a later age. A mutation was present in 26.8 % patients with a positive family history and in 14.4 % of women with a negative family history. The most prevalent mutation observed in 22 patients (11 %) was BRCA1 c.5263_5264insC, a known Slavic mutation with founder effect in Eastern European and AJ communities. Other recurrent mutations were BRCA2 c.9098-9099insA (2 %), BRCA1 c.181T > G (1 %) and BRCA2 c.5851_5854delAGTT (1 %). Notably, BRCA1 c.5263_5264insC represented 56 % of all mutations identified in this series. Of the 22 patients with BRCA1 c.5263_5264insC, 9 were diagnosed with early onset breast cancer, 11 with TNBCs, 4 with bilateral breast cancer, and 6 with both breast and ovarian cancer. CONCLUSIONS: This is the first comprehensive study of the BRCA1/2 mutation spectrum in Bulgaria and will assist the establishment of efficient protocols for genetic testing and individualized risk assessment for Bulgarian breast/ovarian cancer patients and healthy individuals at a high-risk.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Mutação , Adulto , Idoso , Neoplasias da Mama/etnologia , Bulgária/etnologia , Feminino , Efeito Fundador , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Medicina de Precisão , Análise de Sequência de DNA
13.
Anal Cell Pathol (Amst) ; 2015: 621893, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26199858

RESUMO

Scoliotic human nuclei pulposi can respond to exogenous proinflammatory stimuli by secreting increased amounts of interleukin-6 (IL-6). The G/C polymorphism of the promoter region of IL-6 gene influences levels and functional activity of the IL-6 protein. We conducted a case-control study of eighty patients with idiopathic scoliosis (IS) and one hundred sixty healthy unrelated gender-matched controls trying to investigate the association between IS and the IL-6 promoter polymorphism at -174 position (rs1800795 G/C) in Bulgarian population. Molecular detection of the IL-6 genotypes was performed by amplification followed by restriction technology. The statistical analysis was performed by Pearson's chi-squared test. Our case-control study revealed a statistically significant association between the IL-6 (-174 G/C) functional polymorphism and susceptibility to IS. In addition, a significant association between the IL-6 (-174 G/C) polymorphism and curve severity was detected. IL-6 gene could be considered as susceptibility and modifying factor of idiopathic scoliosis. The identification of molecular markers with diagnostic and prognostic value could be useful for early detection of children at risk for the development of scoliosis and for prognosis of the risk for a rapid deformity progression. That would facilitate the therapy decisions and early stage treatment of the patient with the least invasive procedures.


Assuntos
Predisposição Genética para Doença , Interleucina-6/genética , Escoliose/genética , Alelos , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene/genética , Humanos , Masculino , Razão de Chances
14.
Open Access Maced J Med Sci ; 3(2): 278-82, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27275235

RESUMO

BACKGROUND: The current consensus on idiopathic scoliosis maintains that it has a multifactorial etiology with genetic predisposing factors. AIM: Estrogen receptor alpha gene has been considered as candidate gene of idiopathic scoliosis. MATERIAL AND METHODS: We conducted a case-control study of Bulgarian population samples (eighty patients with idiopathic scoliosis and one hundred-sixty healthy unrelated gender-matched controls) trying to investigate the association between common genetic polymorphisms of estrogen receptor alpha and the susceptibility to idiopathic scoliosis. Molecular detection of the restriction polymorphisms XbaI and PvuII was performed by polymerase chain reaction following by restriction fragment length polymorphism. The statistical analysis was performed by Pearson's chi-squared test. RESULTS: Our case-control study showed statistically significant association between the PvuII polymorphism and susceptibility to idiopathic scoliosis and curve progression. No genotype or allele of XbaI polymorphism was found to be correlated with the onset or severity of the disease. CONCLUSIONS: The identification of molecular markers with diagnostic and prognostic value could be useful for early detection of children at risk for the development of scoliosis and for prognosis of the risk for a rapid deformity progression. That would facilitate the therapy decisions and early stage treatment of the patient with the least invasive procedures.

15.
Mol Genet Metab ; 113(1-2): 76-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25087164

RESUMO

Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.


Assuntos
Acidose Láctica/genética , Efeito Fundador , Mutação , Complexo Piruvato Desidrogenase/genética , Acidose Láctica/diagnóstico , Adolescente , Criança , Pré-Escolar , Códon , Consanguinidade , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Romênia , Eslováquia
18.
Eur J Hum Genet ; 21(3): 338-42, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22929024

RESUMO

Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single-nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree.


Assuntos
Cromossomos Humanos Par 10 , Genes Dominantes , Retinite Pigmentosa/genética , Feminino , Ligação Genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Polimorfismo de Nucleotídeo Único , Romênia/etnologia
19.
J Inherit Metab Dis ; 34(4): 917-21, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21499719

RESUMO

EXT1/EXT2-CDG (Multiple cartilagineous exostoses, hereditary multiple osteochondroma (MO); OMIM 133700/133701) are common defects of O-xylosylglycan glycosylation. The diagnostic criteria are at least two osteochondromas of the juxta-epiphyseal region of long bones with in the majority of cases a positive family history and/or mutation in one of the EXT genes. The authors report data on clinical symptoms and complications of 23 patients (from 16 families), discussing the family history, age of diagnosis, new clinical and molecular data. Fifteen mutations and large deletions, of which nine are new, were detected in the EXT1 and EXT2 gene by sequence analysis, FISH and MLPA analysis.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Adolescente , Adulto , Bulgária , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/genética , Análise Mutacional de DNA/métodos , Exostose Múltipla Hereditária/complicações , Exostose Múltipla Hereditária/diagnóstico , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases/fisiologia , Adulto Jovem
20.
Neurosci Lett ; 494(2): 180-3, 2011 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-21396429

RESUMO

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.


Assuntos
Epilepsias Mioclônicas/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Idade de Início , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/fisiopatologia , Feminino , Mutação da Fase de Leitura , Humanos , Lactente , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1 , Fenótipo
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