Ryszard Ślęzak

Metabolic dysregulation in first-episode schizophrenia patients with respect to genetic variation in one-carbon metabolism.

The aim of this study was to investigate the prevalence of metabolic disturbances in patients with first-episode schizophrenia (FES) and test the hypothesis that genetic variation in one-carbon metabolism may account for metabolic dysregulation in early psychosis. We measured fasting glucose, lipid profile parameters, homocysteine, folate and vitamin B12 in 135 patients with FES and 146 healthy controls (HCs). Polymorphisms in the following genes were determined: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G) and BHMT (G742A). Serum levels of folate and high-density lipoproteins (HDL) were significantly lower in patients with FES compared to HCs. In turn, serum levels of homocysteine and triglycerides were significantly higher in patients with FES than in HCs. Prevalence of hyperhomocysteinemia, low folate and HDL levels together with dyslipidemia was significantly higher in patients with FES compared to HCs. Higher homocysteine levels, lower vitamin B12 levels and the presence of metabolic syndrome were associated with higher severity of negative symptoms. None of studied polymorphisms was associated with schizophrenia risk. Several associations between studied polymorphisms and cardio-metabolic parameters were found. None of them remained significant after Bonferroni correction. Our results indicate that metabolic dysregulation in patients with FES is not associated with genetic variation in one-carbon metabolism.

Ten new ATM alterations in Polish patients with ataxia‐telangiectasia

Inherited biallelic mutations of the ATM gene are responsible for the development of ataxia telangiectasia (AT). The objective of the present study was to conduct molecular analysis of the ATM gene in a cohort of 24 Polish patients with ataxia‐telangiectasia with aim being to provide an updated mutational spectrum in Polish AT patients. As a result of molecular analysis, the status of recurrent mutation was confirmed and ten new ATM variants were detected. Application of MLPA analysis allowed the detection of large genomic deletion. Previously, this type of mutation had never been seen in our population. Finally, in silico analysis was carried out for newly detected ATM alterations. In addition, functional analysis was performed to evaluate the effects of intronic variants: c.3402+30_3402+32delATC.

DNA methylation analysis of ade novo balanced X;13 translocation in a girl with abnormal phenotype: evidence for functional duplication of the whole short arm of the X chromosome

We report on a 13-month-old girl showing dysmorphic features and a delay in psychomotor development. She was diagnosed with a balancedde novo translocation 46, X, t(X;13)(p11. 2;p13) and non-random inactivation of the X chromosome. FISH analysis, employing the X chromosome centromere andXIST-region-specific probes, showed that theXIST locus was not involved in the translocation. Selective inactivation of paternal X, which was involved in translocation, was revealed by the HUMARA assay. The pattern of methylation of 5 genes located within Xp, which are normally silenced on an inactive X chromosome, corresponded to an active (unmethylated) X chromosome. These results revealed that in our proband the X chromosome involved in translocation (Xt) was preferentially inactivated. However, genes located on the translocated Xp did not includeXIST. This resulted in functional Xp disomy, which most probably accounts for the abnormal phenotype in our patient.

Genetic variation in one-carbon metabolism and changes in metabolic parameters in first-episode schizophrenia patients

Abstract Background: In this study, we aimed to investigate the effects of polymorphisms in genes encoding 1-carbon metabolism enzymes on differential development of metabolic parameters during 12 weeks of treatment with second-generation antipsychotics in first-episode schizophrenia patients. Methods: The following polymorphisms in 1-carbon metabolism genes were genotyped: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G), and BHMT (G742A). A broad panel of metabolic parameters including body mass index, waist circumference, total cholesterol low and high density lipoproteins, triglycerides, homocysteine, folate, and vitamin B12 was determined. Results: There was a significant effect of the interaction between the MTHFR C677T polymorphism and time on body mass index and waist circumference in the allelic and genotype analyses. Indeed, patients with the MTHFR 677CC genotype had higher increase in body mass index and waist circumference compared with other corresponding genotypes or the MTHFR 677T allele carriers (CT and TT genotypes). In addition, patients with the MTHFR 677TT genotype had higher waist circumference in all time points. Similarly, patients with the MTHFR 677TT genotype had higher body mass index in all time points, but this effect was not significant after correction for multiple testing. Conclusions: Our results indicate that the MTHFR C677T polymorphism may predict antipsychotic-induced weight gain. Effects of the MTHFR C677T polymorphism might be different in initial exposure to antipsychotics compared with long-term perspective.

Assessment of the FTO gene polymorphismsinmale patients with metabolic syndrome

BACKGROUND Accumulating evidence indicates the potential involvement of the FTO gene polymorphisms in the etiology of metabolic syndrome (MetS) and related disorders. OBJECTIVES In this study, we aimed to investigate whether the FTO gene polymorphisms are associated with the risk of MetS and its simple components in a homogeneous sample of males. MATERIAL AND METHODS Anthropometric and biochemical parameters were assessed in 192 males. A total of 100 males met the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria for a diagnosis of MetS. The following FTO gene polymorphisms were genotyped: rs1421085, rs17817449, rs1558902, and rs9939609. RESULTS There were significant differences between participants with distinct rs9939609 genotypes with respect to waist-to-hip ratio (WHR) and the levels of total cholesterol. Individuals with the rs1421085 CC genotype had significantly higher levels of triglycerides compared to those with other corresponding genotypes. Participants with the rs1558902 AA genotype had significantly higher body mass index (BMI), WHR, as well as the levels of total cholesterol and triglycerides. There were no significant differences in genotype distribution allelic frequencies of all tested polymorphisms between individuals with MetS and control subjects. CONCLUSIONS Our results indicate that the genetic variation in the FTO gene might be related to single metabolic disturbances. However, the FTO gene polymorphisms are not associated with the risk of MetS.

Uncommon constellation of multiglandular deficiency with 2 mutations in AIRE gene in an 18-year-old girl — 12 years of observation

Autoimmune polyglandular syndromes (APS) consist of a variety of endocrine and non-endocrine disorders. The syndromes are complex and their occurrence in life does not follow any pattern. Early detection of such disorders may prevent many serious clinical consequences which are usually a result of delayed diagnosis. We present the case of a female patient whose clinical symptoms very strongly suggested APS, however neither autoimmune background except elevated anti-thyroid peroxidase and anti-thyroglobulin antibodies of multiglandular deficiency, nor critical mutations in the AIRE gene have been confirmed or detected, yet we identified five polymorphisms and two mutations in exon1 of gene AIRE during 12 years of observation and treatment.

Validation of the minisequencing method for detection of G1691A (Leiden) factor V mutation.

Abstract Introduction: The factor V (FV) plays an important role in the coagulation process and belongs to the group of factors that significantly increases the risk of thrombophilia. Our study presents a novel, rapid method for the detection of FV (R506Q) mutation using minisequencing approach. Material and methods: Samples of peripheral blood were obtained from 300 females of the Lower Silesian population. Minisequencing, as one of the polymerase chain reaction (PCR)-based methods, was used for detection the of FV (R506Q) point mutations. The allele restriction mutation system PCR (ARMS-PCR) verifying method was applied. Results: By using minisequencing reaction we examined the FV genotypes in the female group who experienced at least one unexplained spontaneous miscarriage. The results of the ARMS-PCR, as a verifying test, were fully consistent with the results of the minisequencing technique. Discussion: One of the many factors which may cause thrombophilia is the FV gene mutation R506Q. A full validation of the minisequencing method was carried out in order to apply this method to clinical tests. The validation shows that the minisequencing technique is highly precise and may be used in routine diagnostics of the FV R506Q mutation

Niestabilność chromosomowa u dzieci z trisomią 21

Wstep Najczestsza aberracja chromosomowa, jaką jest trisomia chromosomu 21, jest związana ze zwiekszoną podatnością na powstanie nowotworow, glownie ukladu krwiotworczego. Celem pracy byla analiza czestości zlaman chromosomowych w teście bleomycynowym u dzieci z zespolem Downa w wieku do 12 miesiecy w porownaniu z grupą kontrolną zdrowych niemowląt i osob doroslych. Material i metody Grupa badana skladala sie z 93 niemowląt z zespolem Downa. Grupe kontrolną stanowilo 100 niemowląt bez aberracji chromosomowych, 13 niemowląt z innymi aberracjami liczbowymi oraz 81 zdrowych osob doroslych. U wszystkich wykonano test bleomycynowy i oceniono liczbe zlaman na komorke (b/c) oraz procent uszkodzonych metafaz (%am). Wyniki Czestośc b/c oraz %am w grupie badanej byly zblizone do wartości populacyjnych oraz nie roznily sie w porownaniu z kontrolną grupą zdrowych niemowląt i dzieci z innymi niz trisomia 21 aberracjami. Znamiennie wyzsze wartości obu czynnikow uzyskano w grupie kontrolnej osob doroslych w stosunku do wszystkich grup niemowląt. Wnioski Wyniki przeprowadzonych przez nas badan nie pozwalają wiec na proste powiązanie miedzy trisomią chromosomow pary 21 a nadwrazliwością na mutageny. Wskazują na potrzebe poszukiwania innych mechanizmow, ktore mogą byc odpowiedzialne za zwiekszoną podatnośc na zachorowania na nowotwory wśrod dzieci z zespolem Downa. Wyniki mogą tez sugerowac, ze ukryta niestabilnośc chromosomowa moze byc, wbrew dotychczasowym obserwacjom, zalezna w pewnym stopniu od dzialania czynnikow mutagennych