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The authors present more than 20 years' experience with coeliac disease, with a summary of their published studies. Hair shaft characteristics were determined by scanning electron microscopy. Hair diameter was significantly lower and cuticular erosion scores higher in those who were not on gluten-free diets as compared to controls, showing a tendency towards normal values following start of gluten-free diets. Proton-induced X-ray emission showed significantly lower zinc content of the hair shaft in the group with acute coeliac disease and after a short-term diet, which approached the normal range only after a year-long diet. The serum prolactin levels in healthy controls and in coeliac patients on the diet were within normal limits, whereas in children with coeliac disease taking gluten in their meals, a significant hyperprolactinaemia was found. The erythrocyte glutathione content of coeliac children was elevated, and the glutathione disulfide level was significantly decreased, as compared to values in normal controls. The erythrocyte glutathione disulfide level and glutathione disulfide/erythrocyte glutathione ratio in coeliac children also differed from those in children with iron deficiency. With genotyping, the DQB1*0201/2 (p < 0.00001) and DR3 (p < 0.00001), DR7 (p < 0.01) alleles showed significant positive association with the disease. [ABSTRACT FROM AUTHOR]

The article focuses on the human leucocyte antigen (HLA) class II allele polymorphisms involved in the development of primary Sjögren's syndrome (pSS). This study was observed in 48 Hungarian pSS patients DRB1∗0301-DQA1∗05011-DQB1∗0201 proved to be the haplotype of susceptibility. The DRB1∗03 allele exhibited a positive correlation with anti-SSB autobody production, the presence of renal tubular acidosis, and the development of malignant lymphoma.

An abstract of the study "An Unusual Long Deletion Mutation in the Dystrophin Gene in a Patient With X-Linked Dilated Cardiomyopathy and Muscular Dystrophy," by R. Sepp and colleagues is presented.

Autism is a neurodevelopmental disorder of unknown etiology. Genetic and environmental factors, such as subacute exposure to OPs during critical periods of prenatal neurodevelopment, contribute to autism pathogenesis. Human serum paraoxonase (PON1) is a calcium-dependent HDL-associated ester hydrolase, which in addition to hydrolyzing organophosphates (OPs), aromatic carboxylic acid esters and aliphatic lactones, physiologically reduces LDL and HDL oxidation. The gene encoding for this enzyme shows two functional polymorphisms: L55M and Q192R. These polymorphisms influence the concentration and the activity of PON1 towards different substrates, including OPs. The gene-environment interaction is tested in the present study by assessing the distribution and frequency of the 55L/M and 192Q/R functional single nucleotide polymorphisms of PON1 (by RT-PCR & melting curve analysis) in 35 autistic children and 35 controls. The distribution of the 192 Q/R genotypes were QQ 54.3%, QR 40%, RR 5.7% in the autistic group and 51.4%, 40% and 8.6% in the control group, respectively. The distribution of the 55L/M genotypes were LL 25.7%, ML 65.7%, MM 8.6%, in the autistic group and 31.4%, 57.1%, 11.4% in control group, respectively. By using Χ² test we found no significant differences neither between genotypes distribution in autistic patients and controls, for both PON 192 and 55 polymorphisms (P>0.05), nor for R and Q allele frequencies (P> 0.05). These results suggest that, for this groups, genetic polymorphisms of PON1 and environmental OPs exposure have no influence on the etiopathogenesis of autism. [ABSTRACT FROM AUTHOR]

Human α-fucosidase (EC 3.2.1.51) is an enzyme (hydrolase) of particular biological and medical interest, as the inherited deficiency in its activity leads to fucosidosis, a pathology belonging to severe glycoprotein lysosomal storage disorders. Although its importance has increased in latest years, data about its plasma level in children with inflammatory disorders are still lacking. In the present study, plasma activity of α-L-fucosidase-1 (FUCA-1) and its potential association with chronic inflammatory pathologies was evaluated in hospitalized individuals, both pediatric and adult ones. A number of 201 Hungarian hospitalized patients, 144 children (1-13 years) and 57 adults (31-88 years), were enrolled in the study and underwent plasma assay of FUCA-1 activity, following the normal routine analytical run in the hospital service. Regression and Pearson tests were evaluated to investigate the relationship between FUCA-1 plasma levels and inflammatory disorders diagnosed with subjects recruited in the study. No correlation of FUCA-1 activity was observed in the pediatric patients with immune (p = 0.9677) or metabolic (p = 0.6974) disorders, but a correlation was reported when comparing clusters of chronic inflammatory and autoimmune disease vs. controls (p < 0.05). Furthermore, a relationship was found between FUCA-1 activity in plasma and inflammatory disorders and autoimmunity both in adults and in the pediatric cohort of patients (Pearson test, p = 0.000148). Alterations in plasma levels of FUCA-1 were significantly associated with chronic inflammatory and autoimmune disorders, both in children and adults. The result of the present study should encourage further research on FUCA-1 as a marker of chronic inflammation and autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10 -8 ), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Autism research continues to receive considerable attention as the options for successful management are limited. The understanding of the autism spectrum disorder (ASD) etiology has now progressed to encompass genetic, epigenetic, neurological, hormonal, and environmental factors that affect outcomes for patients with ASD. Glycosaminoglycans (GAGs) are a family of linear, sulfated polysaccharides that are associated with central nervous system (CNS) development, maintenance, and disorders. Proteoglycans (PG) regulate diverse functions in the central nervous system. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major GAGs present in the PGs of the CNS. As neuroscience advances, biochemical treatments to correct brain chemistry become better defined. Nutrient therapy can be very potent and has minimal to no side effects, since no molecules foreign to the body are needed. Given GAGs are involved in several neurological functions, and that its level can be somewhat modulated by the diet, the present study aimed to evaluate the role of GAGs levels in ASD symptoms. Both tGAG and its different fractions were evaluated in the urine of ASD and healthy control childrens. As levels differed between groups, a second trial was conduted evaluating if diet could reduce tGAG levels and if this in turn decrease ASD symptoms. The present study found that tGAG concentration was significantly higher in the urine of children with ASD compared to healthy control children and this was also evident in all GAG fractions. Within groups (controls and ASD), no gender differences in GAG excretion were found. The use of a 90 days elimination diet (casein-free, special carbohydrates, multivitamin/mineral supplement), had major effects in reducing urinary tGAG excretion in children with ASD.

Alport syndrome (AS) is an inherited type IV collagen nephropathies characterized by microscopic hematuria during early childhood, the development of proteinuria and progression to end-stage renal disease. Since choosing the right therapy, even before the onset of proteinuria, can delay the onset of end-stage renal failure and improve life expectancy, the earliest possible differential diagnosis is desired. Practically, this means the identification of mutation(s) in COL4A3-A4-A5 genes. We used an efficient, next generation sequencing based workflow for simultaneous analysis of all three COL4A genes in three individuals and fourteen families involved by AS or showing different level of Alport-related symptoms. We successfully identified mutations in all investigated cases, including 14 unpublished mutations in our Hungarian cohort. We present an easy to use unified clinical/diagnostic terminology and workflow not only for X-linked but for autosomal AS, but also for Alport-related diseases. In families where a diagnosis has been established by molecular genetic analysis, the renal biopsy may be rendered unnecessary.

Background: Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL., Procedure: We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols., Results: DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively)., Conclusions: Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity., (© 2015 Wiley Periodicals, Inc.)

Objectives: To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease., Methods: Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs., Results: Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans., Conclusions: These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Hypotonia in the neonatal period and early infancy is a common clinical finding. It can be caused by various heterogeneous disorders of different origin which might lead to diagnostic difficulties. Disorders of the neuromuscular junction, such as congenital myasthenic syndromes and neonatal transient myasthenia gravis are among the aetiologies. We report on a case of congenital myasthenia caused by mutation in the long cytoplasmic loop of the epsilon subunit of the acetylcholine receptor and a neonate of a myasthenic mother diagnosed with transient myasthenia gravis.

Aim: Oxidative stress, observed in the asthmatic airways, is not localized only to the bronchial system. It would be a great advantage to monitor the oxidative stress markers from blood especially in childhood asthma following the inflammation. Our aim was to measure the levels of antioxidants and the oxidatively damaged biomolecules. We were also interested in the gene expression alterations of the free radical source gp91(phox) subunit (CYBB) of the NADPH oxidase system, and the antioxidant heme oxygenase-1 (HMOX-1) isoenzyme in the blood. Our findings were also examined in the context of medical treatment., Main Methods: Oxidative stress parameters via photometric methods, CYBB and HMOX-1 expressions via real-time PCR were measured in 58 asthmatic and 30 healthy children., Key Findings: Higher blood thiobarbituric acid reactive substances (TBARS) (p<0.03) and carbonylated protein (p<0.05) levels were found in the asthmatic children than in the controls. The relative expression of CYBB was significantly lower (p<0.05) in patients treated with a low daily dose of inhaled corticosteroid (ICS), than in asthmatics not receiving ICS therapy. Higher ICS doses alone or combined with long acting β2-receptor agonists did not influence the expression significantly. No similar tendency was found as regards to HMOX-1 expression., Significance: Elevated levels of damaged lipid (TBARS) and protein (carbonylated) products corroborate the presence of oxidative stress in the blood during bronchial asthma and suggest the presence of chronic oxidative overload. Our findings also suggest that ICS treatment can influence the relative CYBB mRNA expression in circulating leukocytes in a dose dependent manner., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE)., Methods: Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding., Results: Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life., Conclusions: These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.

Unlabelled: AIM was to detect the mutations of alpha-galactosidase A gene in two Hungarian Fabry patients., Methods: Mutation analysis was performed by polymerase chain reaction (PCR) sequencing of the seven exons and adjacent introns of the alpha-galactosidase A gene., Results: Case 1. (19 y. male patient) Mutation analysis was done for alpha-galactosidase gene, a missence mutation has been identified in the 5th exon, the aspartic acid at codon 266 has been substituted by a tyrosine (notation D266Y) due to a G-T transversion at position 10287 of the alpha GAL-A gene. Case 2. (28 y. male Fabry patient) The GAL-A mutation has been proven to be R220X mutation in exon 5 of the alpha-galactosidase A gene.

Introduction: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question., Methods: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication., Results: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr) =0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci., Conclusion: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.

The relationship between renal disease progression and genetic polymorphism of enzymes influencing endothelial function remains incompletely understood. We genotyped three cohorts of elderly Hungarian patients: 245 patients with end-stage renal disease (ESRD) on chronic hemodialysis (HD), 88 patients with mild chronic kidney disease (CKD), and 200 healthy controls. The underlying diagnoses of renal diseases were primary glomerulonephritis, interstitial nephritis, hypertension, diabetic nephropathy, and hereditary diseases. We examined genetic polymorphisms of eight candidate genes associated with endothelial function: endothelial constitutive nitric oxide synthase (ecNOS) T-786C, endothelin-1 G5727T, methylenetetrahydrofolate reductase (MTHFR) C677T, paraoxonase-1 Q192R and M55L, angiotensinogen M235T, angiotensin-converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C gene. Six gene polymorphisms were detected by real-time polymerase chain reaction with melting-point analysis, and two via allele-specific amplification and gel electrophoresis. Control group patients were in Hardy-Weinberg equilibrium for all tested genotypes. In ESRD patients attributed to hypertension, the endothelin gene G5727T GG genotype occurred significantly less but GT genotype more frequently (P < 0.01 for both). In ESRD patients attributed to primary glomerulonephritis, more ACE DD and less ID genotypes were found (P < 0.02 for both) than in the controls. The underlying diagnosis may modify the association of genetic polymorphism and dialysis-dependent ESRD., (© 2011 The Authors; Hemodialysis International © 2011 International Society for Hemodialysis.)

The Col4A3, Col4A4 and Col4A5 collagen type IV genes are found to be mutated in Col IV nephropathy. In males with a mutation in the Col4A5 gene (X-linked Alport syndrome: XL-AS), progressive renal disease always develops. Female carriers with a mutation in the Col4A5 gene can develop thin basement membrane nephropathy (TBMN). Males and females who carry 1 Col4A3 or Col4A4 mutation usually manifest TBMN with nonprogressive hematuria. In the event of 2 Col4A3 or Col4A4 gene mutations, the autosomal recessive AS will develop. We examined the cosegregation pattern of hematuria in 20 families. The renal biopsies led to diagnoses of AS in 7 families, and of TBMN in 6 families. In 7 others, the diagnosis of familial hematuria (FHU) was based on the clinical symptoms. Markers of the ColA3/Col4A4 and Col4A5 loci (Col4A3: CA11 and D2S401; Col4A4: HaeIII/RFLP; and Col4A5: DXS456, 2B6 and 2B20) were used to assess their linkage to the clinical symptoms and morphological alterations. Maximum likelihood and the FASTLINK version of the linkage program were applied to compute logarithm of the odds (LOD) scores. A linkage to the Col4A3/Col4A4 genes was identified in 5 families (FHU in 3, AS in 2 families, 25%, LOD score range: 0.20-3.51). The XL-AS pattern of inheritance seemed likely with Col4A5 in 9 families (45%, LOD: 0.43-4.20); we found 4 disease-causative mutations by high-resolution melting curve analysis (LC480) and sequencing in this group. In 2 FHU families, the linkage to chromosomes 2 and X was precluded. Knowledge of the genetic background of Col IV nephropathy is essential to avoid the misdiagnosis of FHU and early AS. The allele frequencies, heterozygosity content and polymorphism information content of the applied STR markers on unrelated Hungarian normal and affected chromosomes 2 and X were also calculated., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: Costimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association., Methods: Twelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3'-untranslated region (3'-UTR) of the gene were prepared and used in transfection experiments., Results: A 3-variant haplotype, rs763361;rs34794968;rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 × 10(-4) , odds ratio 1.24, 95% confidence interval 1.11-1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts., Conclusion: This study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3'-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells., (Copyright © 2010 by the American College of Rheumatology.)