Publications by authors named "Janusz Zimowski"

36 Publications

Evaluation of the Frequency of RETN c.62G>A and RETN c.-180C>G Polymorphisms in the Resistin Coding Gene in Girls with Anorexia Nervosa.

Endokrynol Pol 2021 Jul 22. Epub 2021 Jul 22.

Department of Adult Psychiatry, University of Medical Sciences in Poznań, Poland.

Introduction: Anorexia nervosa (AN) is a serious psychosomatic syndrome, classified as an eating disorder. AN patients strive to lose weight below normal limits defined for a specific age and height, achieving their goal even at the expense of extreme emaciation. AN has a multifactorial etiology. Genetic factors are believed to be significant in the predisposition to the development of AN. In girls suffering from AN significantly lower levels of resistin (RES) in blood serum are observed as compared to healthy girls. These differences may lead to a thesis that functional genetic polymorphisms in RES coding genes can be responsible for this phenomenon. In our pilot study we demonstrated significant differences in the distribution of genotypes in the loci RETN c.-180C>G of the RES gene in 67 girls with AN and 38 healthy girls. It seems reasonable to compare the frequency of polymorphisms of RETN c.62G>A and RETN c.-180C>G in the RES gene in girls with AN and in healthy subjects in a bigger cohort and to analyse correlations between individual variants of the polymorphisms referred to above and the RES levels in blood plasma.

Material And Methods: The study covered 308 girls with the restrictive form of AN (AN) and 164 healthy girls (C) (aged 11-19). The RES levels in blood serum were determined by means of the ELISA method on Bio-Vendor, LLC (Asheville, North Carolina, USA). The DNA isolation was carried out by means of Genomic Mini AX BLOOD (SPIN). The PCR reaction was carried out in the thermocycler ThermoCycle T100. 80-150 ng of the studied DNA and relevant starters F and R were added to the reaction mixture. The reaction products were subjected to digestion by restriction enzymes and separated on agarose gels (RFLP).

Results: The average RES level in blood serum in the AN group was significantly lower (p< 0.0001) than in the C group. The distribution of genotypes in the loci RETN c.62 of the RES gene was similar in both groups. A significant difference was demonstrated in the distribution of genotypes in the polymorphic site RETN c.-180 of the RES gene between AN and C (p=0.0145) and in the distribution of the C and G alleles in the loci RETN c.-180 (p< 0.0001). The C allele occurred significantly more frequently than the G allele in the C group as compared to the AN group. In all the study subjects jointly (AN and C) a significant positive correlation between the blood RES levels on one hand and the body mass (r= 0.42; p< 0.0001) and BMI (r= 0.61; p< 0.0001) on the other hand was observed. There was no correlation between the concentration of RES in blood serum and the distribution of genotypes in the loci of the resistin gene referred to above.

Conclusions: The CG genotype in the loci RETN c.-180 C>G of the RES gene may constitute one of the factors predisposing to the development of AN in girls. The genotype in the loci RETN c.62 G>A and RETN c.-180 C>G of the resistin gene has no influence on the levels of this hormone in blood in AN patients.
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http://dx.doi.org/10.5603/EP.a2021.0065DOI Listing
July 2021

Evaluation of the Frequency of ADIPOQ c.45 T>G and ADIPOQ c.276 G>T Polymorphisms in the Adiponectin Coding Gene in Girls with Anorexia Nervosa.

Endokrynol Pol 2021 Jul 22. Epub 2021 Jul 22.

Department of Adult Psychiatry, University of Medical Sciences in Poznań, Poland.

Introduction: Anorexia nervosa (AN) is a serious chronic psychosomatic disorder, the essence of which are attempts to obtain a slim silhouette by deliberate weight loss (restrictive diet, strenuous physical exercise, provoking vomiting). The etiology of this disorder is multifactorial. Genetic factors which influence the predisposition to AN have been searched for. A broad meta-analysis points to a strong genetic correlation between AN and insulin resistance. Adiponectin (ADIPO) increases insulin sensitivity. In our pilot study we demonstrated that the TT genotype in loci ADIPOQ c.276 G>T of the ADIPO gene and a higher concentration of ADIPO in blood serum occurs significantly more frequently in 68 girls suffering from AN than in 38 healthy girls. The objective of this study is to evaluate the frequency of the occurrence of ADIPOQ c.45 T>G and ADIPOQ c.276 G>T in the ADIPO gene in a bigger cohort of girls with AN and healthy girls, as well as an analysis of correlations between variants of the aforementioned polymorphisms and the levels of ADIPO in blood serum.

Materials And Methods: The study covered 472 girls (age: 11-19): 308 with the restrictive form of AN (AN), and 164 healthy girls (C). The level of ADIPO in blood serum was determined by means of the ELISA method on Bio-Vendor, LLC (Asheville, North Carolina, USA). The DNA isolation was carried out by means of Genomic Mini AX BLOOD (SPIN). The PCR reaction was carried out in the thermocycler ThermoCycle T100. 80-150 ng of the studied DNA and relevant starters F and R were added to the reaction mixture. The reaction products were subjected to digestion by restriction enzymes and separated on agarose gels (RFLP).

Results: The distribution of genotypes in the polymorphic site ADP c.45 of the ADIPO gene and ADP c.276 was similar in both groups. In both groups the T allele was most frequent in loci ADIPOQ c.45 and the G allele in loci ADIPOQ c.276. In all the study subjects collectively (AN and C) a statistically significant negative correlation between the levels of ADIPO in blood serum on one hand and the body weight (r= -0.46; p< 0.0001) and BMI (r= -0.67; p< 0.0001) on the other was demonstrated. Exclusively in the AN group a significant correlation between the level of ADIPO in blood and the distribution of TG, TT, and GG alleles in loci ADIPOQ c.45 and ADIPOQ c.276 was demonstrated (p= 0.0052 and p< 0.0001; respectively).

Conclusions: The genotype in loci ADIPOQ c.45 and ADIPOQ c.276 of the ADIPO gene seems to have no effect on the predisposition to AN. Girls suffering from AN with the TT genotype in loci ADIPOQ c.45 and ADIPOQ c. 276 may demonstrate higher insulin sensitivity as they have significantly higher levels of ADIPO than girls suffering from AN with other genotypes. This may be suggestive of their better adaptation to the state of malnutrition, as well as it can have a potential effect on treatment effects.
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http://dx.doi.org/10.5603/EP.a2021.0064DOI Listing
July 2021

Triploid pregnancy-Clinical implications.

Clin Genet 2021 Oct 1;100(4):368-375. Epub 2021 Jun 1.

Department of Gynecologic Oncology and Obstetrics, Centre of Postgraduate Medical Education, Warsaw, Poland.

Triploidy is a life-limiting genetic aberration resulting from an extra haploid set of chromosomes of paternal (diandric triploidy) or maternal origin (digynic triploidy). Triploidy affects around 1%-2% of all conceptions. The majority of cases is miscarried at early developmental stages. In consequence of genomic imprinting, parental origin affects the phenotype of triploid pregnancies as well as the prevalence and spectrum of related maternal complications. Distinctive ultrasound features of both triploid phenotypes as well as characteristic patterns of biochemical markers may be useful in diagnosis. Molecular confirmation of the parental origin allows to predict the risk of complications, such as gestational trophoblastic neoplasia, hyperthyroidism, hypertension, or preeclampsia associated with the paternal origin of triploidy. Diagnosis of partial hydatidiform mole associated with diandric triploidy is challenging especially in the first trimester pregnancy loss due to the limitations of both histopathology and ultrasound. We present important clinical aspects of triploid pregnancies and indicate unresolved issues demanding further studies.
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http://dx.doi.org/10.1111/cge.14003DOI Listing
October 2021

Distribution of diandric and digynic triploidy depending on gestational age.

J Assist Reprod Genet 2021 May 13. Epub 2021 May 13.

Department of Genetics, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957, Warsaw, Poland.

Purpose: To establish the distribution of diandric and digynic triploidy depending on gestational age.

Methods: 107 triploid samples tested prospectively in a single genetic department during a four-year period were analyzed for parental origin of triploidy by Quantitative Fluorescent Polymerase Chain Reaction (QF-PCR) (n=95) with the use of matching parental samples or by MS-MLPA (n=12), when parental samples were unavailable. Tested pregnancies were divided into three subgroups with regard to the gestational age at spontaneous pregnancy loss: <11 gestational weeks, 11-14 gestational weeks, and >14 gestational weeks.

Results: Diandric triploidy constituted overall 44.9% (46.5% in samples miscarried <11 gestational weeks, 64.3% in samples miscarried between 11 and 14 gestational weeks, and 27.8% in pregnancies which survived >14 gestational weeks).

Conclusions: The distribution of diandric and digynic triploidy depends on gestational age. The majority of diandric triploid pregnancies is lost in the first trimester of pregnancy. In the second trimester, diandric cases are at least twice less frequent than digynic ones.
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http://dx.doi.org/10.1007/s10815-021-02202-4DOI Listing
May 2021

Observation of the natural course of type 3 spinal muscular atrophy: data from the polish registry of spinal muscular atrophy.

Orphanet J Rare Dis 2021 03 24;16(1):150. Epub 2021 Mar 24.

Department of Neurology, European Reference Network EURO-NMD, Medical University of Warsaw, Warsaw, Poland.

Background: Spinal muscular atrophy (SMA) is one of the most frequent and severe genetic diseases leading to premature death or severe motor disability. New therapies have been developed in recent years that change the natural history of the disease. The aim of this study is to describe patients included in the Polish Registry of SMA, with a focus on the course of type 3 SMA (SMA3) before the availability of disease-modifying treatments.

Results: 790 patients with SMA were included in the registry (173 with type 1 [SMA1], 218 with type 2 [SMA2], 393 with SMA3, and six with type 4 SMA [SMA4]), most (52%) of whom were adults. Data on SMN2 gene copy number were available for 672 (85%) patients. The mean age of onset was 5 months for SMA1, 11.5 months for SMA2, and 4.5 years for SMA3. In patients with SMA3, the first symptoms occurred earlier in those with three copies of SMN2 than in those with four copies of SMN2 (3.2 years vs. 6.7 years). The age of onset of SMA3 was younger in girls than in boys (3.1 years vs. 5.7 years), with no new cases observed in women older than 16 years. Male patients outnumbered female patients, especially among patients with SMA3b (49 female vs. 85 male patients) and among patients with SMA3 with four copies of SMN2 (30 female vs. 69 male patients). 44% of patients with SMA3 were still able to walk; in those who were not still able to walk, the mean age of immobilization was 14.0 years. Patients with SMA3a (age of onset < 3 years) and three copies of SMN2 had significantly worse prognosis for remaining ambulant than patients with SMA3b (age of onset ≥ 3 years) and four copies of SMN2.

Conclusions: The Registry of SMA is an effective tool for assessing the disease course in the real world setting. SMN2 copy number is an important prognostic factor for the age of onset and ambulation in SMA3. Sex and age of disease onset also strongly affect the course of SMA. Data supplied by this study can aid treatment decisions.
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http://dx.doi.org/10.1186/s13023-021-01771-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992780PMC
March 2021

Twin pregnancies discordant for digynic triploidy - A case series.

Taiwan J Obstet Gynecol 2021 Jan;60(1):139-141

Department of Gynecologic Oncology and Obstetrics, Centre of Postgraduate Medical Education, Warsaw, Poland.

Objective: To analyse natural course and perinatal management in twin pregnancies discordant for digynic triploidy.

Case Report: We present five cases of twins discordant for digynic triploidy. Pregnancy outcome was known for three of them. In one case, premature rupture of membranes occurred at 20 gestational weeks and both fetuses were miscarried. In two other pregnancies healthy co-twins were born at term after the triploid fetuses demise at 28 and 37 weeks. No maternal complications were observed.

Conclusion: Twin pregnancies discordant for triploidy poses a challenge for perinatal management. Expectant management should be considered in digynic triploid cases.
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http://dx.doi.org/10.1016/j.tjog.2020.11.021DOI Listing
January 2021

Small mutations in Duchenne/Becker muscular dystrophy in 164 unrelated Polish patients.

J Appl Genet 2021 May 9;62(2):289-295. Epub 2021 Jan 9.

Department of Genetics, Institute of Psychiatry and Neurology, 02-957, Sobieskiego 9, Warsaw, Poland.

In the 164 patients with Duchenne/Becker muscular dystrophy, we found 142 different small mutations including 51 novel mutations not listed in the LOVD, the UMD-DMD, the ClinVar, and the HGMD databases. Among all mutations, nonsense mutations occurred in 45.7%, frameshift mutations in 32.9%, and splicing mutations in 19.5%. Small mutations were distributed throughout the whole dystrophin gene. Splicing mutations were twice more common in BMD patients than in DMD patients. Eighty-two percent of mothers of the males affected with DMD/BMD were found to be carriers of small mutations.
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http://dx.doi.org/10.1007/s13353-020-00605-0DOI Listing
May 2021

Usefulness of methylation-specific multiplex ligation-dependent probe amplification for identification of parental origin of triploidy.

J Hum Genet 2020 Oct 1;65(10):889-894. Epub 2020 Jun 1.

Department of Genetics, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957, Warsaw, Poland.

Triploidy is a genetic aberration resulting from an extra haploid set of chromosomes of paternal (diandric) or maternal (digynic) origin. Diandric cases, opposite to digynic ones, may lead to gestational trophoblastic neoplasia (GTN) or generate maternal complications, therefore their identification is crucial, but reproducibility of traditionally used histopathological assessment is poor. The aim of the study was to analyse the usefulness of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) with probes for two differentially methylated regions (DMR) at chromosome 11p.15.5 for identification of the parental origin of triploidy. 84 triploid DNA samples were tested with MS-MLPA: 34 paternal cases (40.5%) and 50 maternal ones (59.5%) according to the reference results of QF-PCR. Methylation ratio (MR) was calculated. Reference values proposed by the MRC-Holland for diploid samples (MR 0.8-1.2) were used. The values outside these ranges were used to diagnose parental origin of triploidy-paternal (MR > 1.2) or maternal (MR < 0.8). The effectiveness of MS-MLPA was 94.0%. The mean MR in paternal triploidy was 1.7 (SD-0.25; n = 34) compared with 0.56 in maternal triploidy (SD-0.12; n = 50). MR values in paternal and maternal triploidy did not overlap. In five samples (6.0%) parental origin of triploidy could not be accurately established by MS-MLPA, probably due to the maternal cell contamination (MCC). MS-MLPA can be used as a convenient method for distinguishing between paternal and maternal triploidy without the necessity for parental samples testing. It enables adequate selection of the paternal triploid cases for follow up in order to exclude post-molar GTN.
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http://dx.doi.org/10.1038/s10038-020-0784-0DOI Listing
October 2020

Interaction between polymorphisms of the oxytocinergic system genes and emotion perception in inpatients with anorexia nervosa.

Eur Eat Disord Rev 2019 09 5;27(5):481-494. Epub 2019 Aug 5.

The Department of Genetics, The Institute of Psychiatry and Neurology, Poland.

Objective: The empirical literature describes the role of the oxytocinergic system in emotion perception (EP). Variants in the oxytocin (OXT) and oxytocin receptor genes have been associated with mental disorders, including anorexia nervosa (AN), that are characterized by difficulties in socioemotional functioning. Our study aimed to examine whether variability within the genes related to OXT pathways may play a role in facial EP in inpatients with AN.

Method: Single nucleotide polymorphisms (SNPs) of the following genes: oxytocin receptor (rs2254298, rs53576), OXT (rs6133010), OXT-arginine-vasopressin (rs2740204), CD38 (rs6449197, rs3796863), and human leucyl/cystinylaminopeptidase (rs4869317) were genotyped in 60 AN female inpatients and 60 healthy control females (HCs). Associations between genetic polymorphisms and EP as well as clinical symptoms were examined.

Results: The AN group showed decreased EP abilities compared with HCs. SNPs of rs2740204, rs6133010, and rs53576 were associated with differences in EP in women with AN and in HCs. The SNP of rs4869317 was associated with the level of eating disorders symptoms in HCs.

Conclusions: The OXT system may be involved in EP difficulties in AN. SNPs within genes related to OXT pathways may influence EP abilities. The leucyl/cystinylaminopeptidase rs4869317 SNP may be involved in the development of eating disorders psychopathology.
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http://dx.doi.org/10.1002/erv.2698DOI Listing
September 2019

Genetic polymorphisms and serum concentrations of adiponectin and resistin in anorexia nervosa and healthy controls - pilot study.

Neuro Endocrinol Lett 2017 Jul;38(3):215-223

Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60-572 Poznan, Poland.

Background: A possible role of adipokines in the regulation of body weight in patients with anorexia nervosa (AN) has been proposed. Polymorphisms in genes encoding adiponectin and resistin in AN have not been widely assessed, yet.

Objectives: 1) Assessment the frequency of ADIPOQ c.45T>G, ADIPOQ c.276G>T polymorphisms in adiponectin and RETN c.62G>A, RETN c.-180C>G in resistin genes in AN patients and control group (C) 2) Analysis of correlation between these polymorphisms and serum ADP or RETN.

Methods: We examined 67 AN girls and 38 C aged 11-18. Analyses of polymorphisms in ADIPOQ and RETN genes were performed using RFLP method and adiponectin and resistin serum levels - with commercially available ELISA kits.

Results: In AN subjects, TT genotype in ADIPOQ c.276 polymorphism as well as GG genotype of RETN c.-180 were significantly more frequent than in CG. In ADIPOQ c.45 polymorphic site, TT alleles were the most frequent in both examined groups. In RETN c.62 GA and GG alleles distribution did not differ between the groups and the most frequently observed genotype was GG. The mean serum adiponectin level in AN was significantly higher and resistin - lower than in controls. There were no statistically significant relationships between serum adiponectin and resistin levels and allele frequency in polymorphisms ADIPOQ c.276 as well as RETN c.-180 in the examined groups.

Conclusion: Differences in genotype frequencies of ADIPOQ c.276 and RETN c.-180 suggest a need for studies on a larger cohort of patients with AN.
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July 2017

Deletions, not duplications or small mutations, are the predominante new mutations in the dystrophin gene.

J Hum Genet 2017 Oct 6;62(10):885-888. Epub 2017 Jul 6.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Examination of the carrier state was performed in 744 unrelated mothers of the Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) probands with identified mutations in the dystrophin gene. Owing to that it was possible to assess frequency and type of new mutations in the gene. Contrary to the Japanese observations of Lee et al. published in this journal, we did not find significant differences in the carrier frequency between mothers of DMD and BMD patients. However, we found that new mutations in patients with deletions were significantly more frequent than in those with duplications and small mutations: of 564 unrelated patients with deletions, 236 (41.8%) carried new mutations, the respective values for duplications and small mutations were 21 of 95 patients (22.1%) and 18 of 85 patients (21.2%)-the differences highly significant (P<0.0001).
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http://dx.doi.org/10.1038/jhg.2017.70DOI Listing
October 2017

Prenatal diagnosis of Duchenne and Becker muscular dystrophies: Underestimated problem of the secondary prevention of monogenetic disorders.

J Obstet Gynaecol Res 2017 Jul 31;43(7):1111-1121. Epub 2017 May 31.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Aim: The aim of this study was to analyze the influence of effective preconceptional testing for carrier status in women at risk for Duchenne and Becker muscular dystrophies (D/BMD) on the prenatal diagnosis.

Methods: A retrospective analysis of 201 prenatal tests was performed in 169 Polish women at risk, in regard to time of testing for carrier status (prior to conception or during pregnancy) and carrier status of tested women, including confirmed D/BMD carriers (n = 78; 46.2%), D/BMD non-carriers - tested for germline mosaicism risk (n = 23; 13.6%), and women at risk with uncertain carrier status (n = 68; 40.2%).

Results: Only 52.7% of women were tested for D/BMD carrier status prior to conception and in these women prenatal diagnosis was carried out more frequently in the first trimester of pregnancy (64.7% vs 47.8%; P = 0.035). The results of prenatal testing in male fetuses in pregnancies of confirmed D/BMD carriers and D/BMD non-carriers - tested for germline mosaicism risk were conclusive in all cases, whereas in women with uncertain carrier status, only 60.0% of results were conclusive. Eighty-five of 103 female fetuses (82.5%) were tested prenatally and in 31.8% of them fetal carrier status was confirmed.

Conclusion: Carrier status testing in women prior to conception has a positive impact on the frequency of first-trimester prenatal diagnosis and known D/BMD carrier status on the effectiveness of prenatal diagnosis. Due to the low percentage of women tested effectively prior to conception, carrier status testing in the families at risk should be propagated (including possibility of prenatal diagnosis of female fetuses).
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http://dx.doi.org/10.1111/jog.13344DOI Listing
July 2017

A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene.

J Appl Genet 2017 Aug 28;58(3):343-347. Epub 2017 Feb 28.

Department of Genetics, Institute of Psychiatry and Neurology, ul. Sobieskiego 9, 02-957, Warszawa, Poland.

In the material of 227 families with Becker muscular dystrophy (BMD), we found nine non-consanguineous families with 17 male individuals carrying a rare mutation-a single exon 48 deletion of the dystrophin gene-who were affected with a very mild or subclinical form of BMD. They were usually detected thanks to accidental findings of elevated serum creatine phosphokinase (sCPK). A thorough clinical analysis of the carriers, both children (12) and adults (5), revealed in some of them muscle hypotonia (10/17) and/or very mild muscle weakness (9/17), as well as decreased tendon reflexes (6/17). Adults, apart from very mild muscle weakness and calf hypertrophy in some, had no significant abnormalities on neurological assessments and had good exercise tolerance. Parents of the children carriers of the exon 48 deletion are usually unaware of their children being affected, and possibly at risk of developing life-threatening cardiomyopathy. The same concerns the adult male carriers. Therefore, the authors postulate undertaking preventive measures such as cascade screening of the relatives of the probands. Newborn screening programmes of Duchenne muscular dystrophy (DMD)/BMD based on sCPK marked increase may be considered.
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http://dx.doi.org/10.1007/s13353-017-0391-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509810PMC
August 2017

Co-incidence of Turner syndrome and Duchenne muscular dystrophy - an important problem for the clinician.

Dev Period Med 2016;20(4):273-278

Department of Biology and Genetics, Medical University of Gdańsk.

Introduction: Turner syndrome is a relatively common chromosomal disorder which affects about one in 2000 live born females. Duchenne muscular dystrophy is an X-linked recessive disorder affecting 1:3600 live born males. Considering the above, the coexistence of these two diseases may occur only anecdotally.

Case Presentation: Here, we report a 4 ½ year-old female with classical 45,X Turner syndrome who also had Duchenne muscular dystrophy caused by a point mutation in the dystrophin gene (c.9055delG). The patient showed the typical phenotype of Turner syndrome including distinctive dysmorphic features (short neck, low posterior hairline, wide position of nipples), aortic coarctation and feet lymphedema. Besides, she presented with an unusually early beginning of muscular dystrophy symptoms with infantile-onset motor developmental delay, intellectual disability and early calf muscular hypertrophy.

Conclusion: The coexistence of an X-linked recessive disorder should be considered in women affected by Turner syndrome presenting with additional atypical clinical features.
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September 2017

First trimester pregnancy loss: Clinical implications of genetic testing.

J Obstet Gynaecol Res 2017 Jan 8;43(1):23-29. Epub 2016 Dec 8.

I Department of Obstetrics and Gynecology, Professor Witold Orlowski Clinical Hospital, Centre of Postgraduate Medical Education, Warsaw, Poland.

Around 10-15% of pregnancies result in a spontaneous first trimester miscarriage, which is most frequently caused by chromosomal abnormalities, mainly aneuploidies. Genetic analysis of pregnancy loss includes conventional G-banding karyotyping and various molecular methods. Apart from variable methodological limitations, the effectiveness of genetic analysis depends on the type and quality of the tested sample. To improve the reliability of genetic testing, we present methods of appropriate collection and pre-laboratory preparation of chorionic villi from first trimester miscarriage. We also discuss issues of maternal cell contamination, placental mosaicism and reciprocal and Robertsonian translocations in the context of interpretation of the results and genetic counseling.
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http://dx.doi.org/10.1111/jog.13179DOI Listing
January 2017

Impaired social cognition processes in Asperger syndrome and anorexia nervosa. In search for endophenotypes of social cognition.

Psychiatr Pol 2016 ;50(3):533-42

Klinika Psychiatrii Dzieci i Młodzieży IPiN w Warszawie.

A growing number of publications indicates presence of significant deficits in social cognition in patients with anorexia nervosa (AN). These deficits appear to be comparable in qualitative and quantitative dimension with impairment of the same functions among people with Asperger syndrome (AS). The aim of this study is to identify subject areas in the field of impairment of social cognition processes among people with Asperger syndrome and anorexia nervosa taking into consideration the potential contribution of genetic pathways of oxytocin and vasopressin in the pathogenesis of these diseases. In the first part of the paper a systematic analysis of studies aimed at the evaluation of the processes of social cognition among patients with AN and AS has been carried out. The results of a significant number of studies confirm the presence of deficits in social cognition in AN and AS. In addition, among patients with AN and AS there exists a similar structure and distribution of the brain functions in regions responsible for social cognition. The second part of the paper describes the role of the oxytocin-vasopressin system (OT-AVP) in the processes of social cognition in AN and AS. Its genetic basis and the possible importance of single nucleotide polymorphisms within the genes: OXT, AVP, CD38, OXTR, AVPR1A and LNPEP have also been presented.
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http://dx.doi.org/10.12740/PP/OnlineFirst/33485DOI Listing
April 2017

No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction.

JIMD Rep 2016 2;27:63-8. Epub 2015 Oct 2.

Department of Medical Genetics, The Children's Memorial Health Institute, 04-730, Warsaw, Poland.

SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44-2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45-1.04).Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice.
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http://dx.doi.org/10.1007/8904_2015_468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864719PMC
May 2016

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Hum Mutat 2015 Apr 17;36(4):395-402. Epub 2015 Mar 17.

The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine, University of Newcastle, Central Parkway, Newcastle upon Tyne, UK.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
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http://dx.doi.org/10.1002/humu.22758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405042PMC
April 2015

MLPA based detection of mutations in the dystrophin gene of 180 Polish families with Duchenne/Becker muscular dystrophy.

Neurol Neurochir Pol 2014 24;48(6):416-22. Epub 2014 Oct 24.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Duchenne/Becker muscular dystrophy (DMD/BMD) is a recessive, X-linked disorder caused by a mutation in the dystrophin gene. Deletions account for approximately 60-65% of mutations, duplications for 5-10%. The remaining cases are mainly point mutations. According to Monaco theory clinical form of the disease depends on maintaining or disrupting the reading frame. The purpose of the study was to determine frequency and location of deletions and duplications in the dystrophin gene, to determine the compliance between maintaining/disrupting the reading frame and clinical form of the disease and to check the effectiveness of MLPA (multiplex ligation-dependent probe amplification) in the detection of these mutations in hemizygous patients and heterozygous female carriers. The material is composed of combined results of molecular diagnosis carried out in years 2009-2012 in 180 unrelated patients referred with the diagnosis of DMD/BMD tested by use of MLPA. We identified 110 deletions, 22 duplication (in one patient two different duplications were detected) and 2 point mutations. Deletions involved mainly exons 45-54 and 3-21, whereas most duplications involved exons 3-18. The compliance with Monaco theory was 95% for deletions and 76% for duplications. Most of mutations in the dystrophin gene were localized in the hot spots - different for deletions and duplications. MLPA enabled their quick identification, exact localization and determination whether or not they maintained or disrupted the reading frame. MLPA was also effective in detection of deletions and duplications in female carriers.
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http://dx.doi.org/10.1016/j.pjnns.2014.10.004DOI Listing
March 2015

Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients.

Neuromuscul Disord 2014 Jul 24;24(7):617-23. Epub 2014 Apr 24.

Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.

The aim of our study was to identify point mutations in a group of 606 patients diagnosed for spinal muscular atrophy with excluded biallelic loss of the SMN1 gene. Point missense mutations or small deletions in the SMN1 gene were ultimately identified in 18 patients. Six patients were found to have small deletions, the c.429_435del mutation in 3 cases, the c.431delC mutation in 2 and c.722delC in one. Those mutations, not described previously, were characteristic of patients presenting a severe phenotype. The most frequent missense mutation - p.Thr274Ile, was identified in 9 patients presenting a rather mild phenotype. Three other missense mutations, i.e., p.Ser230Leu, p.Ala111Gly and p.Pro244Leu, were identified in a further 3 SMA3 patients. Mutation p.Pro244Leu, not described so far, was identified in a patient with a mild form of SMA and more distal distribution of muscle weakness. Our results suggest a specific point mutation spectrum in the Polish population. The existence of small deletions not identified thus far could suggest a possible founder effect. In patients with preserved one SMN1 allele without common exon 7 deletion, presenting a mild form of SMA, a special consideration should be given to the p.Thr274Ile mutation.
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http://dx.doi.org/10.1016/j.nmd.2014.04.003DOI Listing
July 2014

[Non-invasive prenatal diagnosis of the most common aneuploidies with cell-free fetal DNA in maternal serum--preliminary results].

Ginekol Pol 2014 Mar;85(3):208-13

Objectives: The aim of the study was to present initial results of non-invasive prenatal diagnosis of common aneuploidies of chromosomes 21, 18 and 13 based on cell-free fetal DNA in maternal serum in high-risk patients, and to compare the results with routine karyotyping.

Material And Methods: Before the invasive procedure, 10 ml of peripheral blood from 10 patients was collected to isolate cell-free fetal DNA and to perform a non-invasive fetal trisomy test (NIFTY provided by Beijing Genomics Institute, BGI, Shenzen, China).

Results: Three out of 10 samples showed an abnormal karyotype in traditional karyotyping. There were 9 conclusive NIFTY results. NIFTY detected 1 out of 2 trisomies 18. The quantity of cell-free fetal DNA in maternal plasma in the second probe with trisomy 18 was unsatisfactory fora conclusive NIFTY result. In 1 case traditional karyotyping revealed mosaicism impossible to detect with NIFTY
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http://dx.doi.org/10.17772/gp/1715DOI Listing
March 2014

[Noninvasive prenatal diagnosis of trisomy 21, 18 and 13 using cell-free fetal DNA].

Ginekol Pol 2013 Aug;84(8):714-9

Klinika Ginekologii i Połoznictwa - CMKP SPSK im. prof. Orłowskiego, Warszawa, Polska.

Trisomy 21, 18 and 13 are the most common trisomies diagnosed in newborns. Screening methods consist of ultrasound and maternal serum markers. High risk for fetal aneuploidies is an indication for routine karyotyping, which requires collection of fetal tissue through amniocentesis or chorionic villous sampling. They are invasive procedures and carry a potential risk of miscarriage. The discovery of cell free fetal DNA (cffDNA) in maternal blood offered new opportunities for noninvasive prenatal diagnosis. The fraction of cell-free fetal DNA in total pool of cell-free DNA in maternal plasma is very low, therefore the analysis of cffDNA is very challenging. The introduction of massive parallel sequencing has enabled the application of noninvasive prenatal testing in the clinical practice and a variety of recent studies have proven its high efficacy in diagnosing common aneuploidies.
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http://dx.doi.org/10.17772/gp/1629DOI Listing
August 2013

Multiplex ligation-dependent probe amplification (MLPA)--new possibilities of prenatal diagnosis.

Ginekol Pol 2013 Jun;84(6):461-4

Department of Obstetrics and Gynecology of the Postgraduate Center of Medical Education, Warsaw, Poland.

Multiplex Ligation-dependent Probe Amplification (MLPA) is a relatively new method of molecular diagnosis. It enables a relative quantitative assessment of up to 50 different PCR amplicons in one reaction by the use of a very small amount of examined DNA. Nowadays MLPA is becoming a very helpful tool in prenatal diagnosis and is widely used for the detection of aneuploidies, familial single gene disorders, common microdeletion syndromes, sub-telomeric alterations and identification of marker chromosomes in fetuses. This review demonstrates possible applications of MLPA in prenatal diagnosis.
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http://dx.doi.org/10.17772/gp/1605DOI Listing
June 2013

The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation.

Mitochondrion 2013 Nov 26;13(6):810-6. Epub 2013 May 26.

Department of Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland; Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland. Electronic address:

The aim of this study was to assess the natural history of the SCO2 deficiency in relation to the genotype in a cohort of 62 patients with SCO2 mutations (36 this study, 26 previous reports). A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency. The prevalence of SCO2 deficiency in Poland is relatively high. A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate.
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http://dx.doi.org/10.1016/j.mito.2013.05.007DOI Listing
November 2013

Two mutations in one dystrophin gene.

Neurol Neurochir Pol 2013 Mar-Apr;47(2):131-7

Zakład Genetyki, Instytut Psychiatrii i Neurologii w Warszawie, Polska.

Background And Purpose: Duchenne/Becker muscular dystrophies (DMD/BMD) lead to progressive irreversible muscle deterioration caused by recessive mutations in the dystrophin encoding gene (Xp21.1). Approximately 60% of mutations are deletions, 10% are duplications and the remaining 30% are point mutations. The aim of the study is to present the rare occurrence of two pathogenic mutations (deletions or duplications) in one allele of the dystrophin gene.

Material And Methods: DNA of patients from 1364 DMD/ BMD families was tested. Two techniques - PCR-multiplex and multiplex ligation-dependent probe amplification - were used to search for mutations in the dystrophin gene.

Results: Deletion was detected in 648 families and duplication was found in 74 families (analysis in progress). In two families, presence of two mutations in one gene was documented - in the first family two deletions were found (exons 45-49 and 60-61), and in the second family two duplications were detected (exons 2-7 and 50-59). One of the deletions disrupted the reading frame, and the other deletion retained the reading frame. Both duplications also retained the reading frame of the gene but in both families the disease took a severe course (DMD). In the family with two duplications prenatal diagnosis was also carried out, and carriership of both mutations was discovered in the female fetus.

Conclusions: In the analyzed group of DMD/BMD families, the frequency of combined occurrence of two mutations in one gene was 2 per 722 (0.3%). The phenomenon of detected non-contiguous deletions and duplications is presented together with 31 similar cases published so far.
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http://dx.doi.org/10.5114/ninp.2013.34586DOI Listing
August 2013

Hereditary form of prion disease in Poland.

Neurol Neurochir Pol 2012 Nov-Dec;46(6):509-18

Zakład Genetyki, Instytut Psychiatrii i Neurologii w Warszawie, Al. Sobieskiego 9, Warszawa, Polska.

Background And Purpose: The aim of the study was to perform molecular analysis in a group of patients affected with prion disease. Diagnosis was based on results of clinical and/or histopathological examination of the brain. This is the largest investigation of this type performed so far in Poland.

Material And Methods: Analysed material contained 36 cases of prion disease, including 35 cases of Creutzfeldt-Jakob disease and one case of Gerstmann-Sträussler-Scheinker disease, as well as two familial cases initially suspected of Huntington disease and Alzheimer disease. The control group consisted of 87 subjects. The most frequent known mutations in the PRNP gene were looked for, namely those in codons 102, 117, 178, 200, 217 and OPRI; the polymorphism Met/Val in codon 129 was also analysed. The methods applied were PCR-RFLP and DNA sequencing.

Results: The following mutations were found: E200K in 5 families, P102L in one family (previously identified), D178N in one family and 6OPRI in one family. Overall, mutations were detected in 17 persons (including 8 preclinical ones) from 8 pedigrees. Highly significant difference of codon 129 Met/Val heterozygosity frequencies was found between the affected subjects and the controls. Frequency of the familial form of prion disease in the material analysed was 14%.

Conclusions: Screening for mutations in the PRNP gene should be performed in all diagnosed cases of prion disease and in cases of familial occurrence of early onset dementia of unknown aetiology. Families with identified mutations should be offered genetic counselling and informed of risks of blood and organs' donation.
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http://dx.doi.org/10.5114/ninp.2012.32353DOI Listing
April 2013

Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion).

Pediatr Endocrinol Diabetes Metab 2012 ;18(4):153-7

Klinika i Katedra Endokrynologii Wieku Rozwojowego Uniwersytetu Medycznego we Wroclawiu.

Contiguous gene syndromes are disorders caused by deletions of genes that are adjacent to one another. One of them is complex glycerol kinase deficiency. It is caused by partial deletion of Xp21, which includes the genes responsible for glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy and intellectual disability. There are no definite dysmorphic features for this syndrome. The diagnosis is based on clinical and laboratory findings. Symptoms depend on the size of deletion and appear almost exclusively in the male gender. Usually the first and most severe are the signs of adrenal hypoplasia, which, if not cured, may lead to death in a short time. The symptoms of glycerol kinase deficiency occur also early in life, but they may be masked by the deficiency of mineralocorticoids. Duchenne muscular dystrophy appears in childhood and is always accompanied by certain symptoms. Developmental retardation and intellectual disability occur often with complex glycerol kinase deficiency. The reasons for it are heterogeneous, but usually, there is a connection with the deletion of DMD or I L1R A P L genes. Due to the fact that loci of all genes responsible for complex glycerol kinase deficiency were determined, it is possible to carry out molecular examination, confirm clinical diagnosis and determine female carriers of the disorder.
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November 2013

Incidence of spinal muscular atrophy in Poland--more frequent than predicted?

Neuroepidemiology 2010 15;34(3):152-7. Epub 2010 Jan 15.

Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Background: The application of molecular methods has enhanced and enlarged the diagnostics of spinal muscular atrophy (SMA) and its carriership. It allows for reliable epidemiological studies which are of importance to demography and genetic counseling.

Methods: This study sought to evaluate the incidence of SMA in Poland, on the basis of the prevalence of the SMN1 gene deletion carrier state in the general population, as well as an analysis of all cases of SMA diagnosed in the years 1998-2005.

Results: The prevalence of the SMN1 gene deletion carrier state was estimated at 1 per 35 persons (17/600), yielding an incidence of SMA equal to 1 per 4,900. By contrast, the incidence of SMA based on the results of the meta-analysis was an estimated 1 per 7,127 in Warsaw and 1 per 9,320 persons across Poland, suggesting that some cases of SMA remain undiagnosed. SMA1 predominated among the diagnoses, accounting for 69% of all cases.

Conclusion: A high prevalence of the SMN1 deletion carrier state in the general population indicates that SMA could be a more frequent disease than is predicted by the epidemiological data regarding diagnosed cases.
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http://dx.doi.org/10.1159/000275492DOI Listing
December 2010

[Detection of rare mutations in the dystrophin gene].

Med Wieku Rozwoj 2009 Apr-Jun;13(2):140-5

Zakład Genetyki, Instytut Psychiatrii i Neurologii, Al. Sobieskiego 9, 02-957 Warszawa.

Introduction: Duchenne/Becker muscular dystrophies (DMD/BMD) are allelic X-linked, recessive proximal muscle disorders, caused by mutations in the dystrophin gene located in Xp21. DMD occurs with the incidence 1:3500, BMD with the incidence of 1:18,500 new-born males. Approximately about 60% of mutations in the dystrophin gene are deletions, 10%--duplications and 30%--point mutations.

Aim: The aim of the study was detection of the mutations: rare deletions, duplications and point mutations in the dystrophin gene in patients diagnosed as DMD/BMD in whom the presence of the most common deletions had previously been excluded.

Materials And Methods: Molecular analysis was performed using DNA samples isolated from 105 DMD and 10 BMD patients. Detection of rare deletions and duplications was carried out by Multiplex Ligation-dependent Probe Amplification (MLPA). Point mutations were identified by analysis of single strand conformation polymorphism (SSCP) and DNA sequencing.

Results: 38 Different mutations were detected: 10 rare deletions, 14 duplications and 14 point mutations and microdeletions. Majority of the detected rare deletions (7 out of 10) and point mutations (11 out of 14) are novel mutations.

Conclusions: Application of MLPA technique allows the detection of small, rare deletions and duplications. Identification of the nature and localization of the mutations may, in the future, help to apply appropriate therapeutic approaches in DMD patients.
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November 2009

Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease.

Acta Biochim Pol 2009 14;56(1):103-8. Epub 2009 Mar 14.

Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease - the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M = 0.78) and SMA3b (F/M = 0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients with SMA3a and 3b had a deletion of the NAIP gene, and a third patient with SMA2 had one copy of the SMN2 gene.
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June 2009
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