A novel mutation of congenital nephrotic syndrome in a Slovenian child eventually receiving a renal transplant

Congenital nephrotic syndrome (CNS) is a rare disease defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema presenting in the first three months of life. It is most commonly caused by mutations in the NPHS1 gene associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner. Symptomatic treatment with intravenous albumins, vitamins, minerals, nutritional, and hormonal supplementation and treatment of complications are mandatory. Children refractory to the symptomatic treatment are recommended to undergo nephrectomy and renal replacement therapy, preferably renal transplantation. We report on a child with Finnish type CNS with a NPHS1 mutation, which is the first case confirmed by genetic study in Slovenia. We showed for the first time that homozygous mutation c.2928-3del in the NPHS1 gene caused exon 22 skipping, leading to a truncated protein and Fin-minor phenotype

Microduplication in the 2p16.1p15 chromosomal region linked to developmental delay and intellectual disability

Abstract Background Several patients with the 2p16.1p15 microdeletion syndrome have been reported. However, microduplication in the 2p16.1p15 chromosomal region has only been reported in one case, and milder clinical features were present compared to those attributed to 2p16.1p15 microdeletion syndrome. Some additional cases were deposited in DECIPHER database. Case presentation In this report we describe four further cases of 2p16.1p15 microduplication in four unrelated probands. They presented with mild gross motor delay, delayed speech and language development, and mild dysmorphic features. In addition, two probands have macrocephaly and one a congenital heart anomaly. Newly described cases share several phenotype characteristics with those detailed in one previously reported microduplication case. Conclusion The common features among patients are developmental delay, speech delay, mild to moderate intellectual disability and unspecific dysmorphic features. Two patients have bilateral clinodactyly of the 5th finger and two have bilateral 2nd-3rd toes syndactyly. Interestingly, as opposed to the deletion phenotype with some cases of microcephaly, 2 patients are reported with macrocephaly. The reported cases suggest that microduplication in 2p16.1p15 chromosomal region might be causally linked to developmental delay, speech delay, and mild intellectual disability

Molecular Characterization of Escherichia coli Strains Isolated from Different Food Sources

Hrana predstavlja mogući izvor patogenih i na antibiotik otpornih sojeva bakterije Escherichia coli, pa je u radu analizirano 84 izolata iz uzoraka hrane identificiranih 2007. i 2008. godine na Nacionalnom institutu za javno zdravstvo u Sloveniji. Pomoću metode PCR (lančana reakcija polimeraze) prema Clermontu izolati su razvrstani u filogenetske skupine i podskupine. Četrdeset i dva (50 %) su izolata svrstana u filogenetsku skupinu A, a njih trideset (35,7 %) u skupinu B1. Te dvije skupine uglavnom obuhvaćaju komenzale crijevne mikroflore. Deset je izolata (11,9 %) svrstano u skupinu D, a samo njih dva (2,4 %) u skupinu B2. U tim se skupinama uglavnom nalaze ekstraintestinalni patogeni sojevi E. coli. Sojevi su zatim analizirani ne bi li se utvrdila prisutnost različitih virulentnih gena i plazmidnih gena otpornosti na kinolone (qnr). U jednom je izolatu (1,2 %) otkriven virulentni gen stx1, kod njih pet (6 %) gen stx2, a u sljedećih pet izolata (6 %) oba gena, stx1 i stx2. U osam je izolata (9,5 %) pronađen gen ehxA, a u njih tri (3,7 %) gen eae. Svi su ti geni karakteristični za patotip STEC, koji proizvodi Shiga toksin. Gen fimH pronađen je u sedamdeset i četiri (88,1 %) izolata. Od virulentnih gena tipičnih za ekstraintestinalne patogene sojeve E. coli, gen hra je pronađen u devet (11 %), gen ompTAPEC u osam (9,5 %), a gen iha u šest (7 %) izolata. U jednom su izolatu otkriveni geni kpsMTII, sfa, usp i vat, dok geni hlyA, bmaE, cnf, hpb, sat i plazmidni geni otpornosti na kinolone qnr nisu pronađeni u ispitanim izolatima. Rezultati pokazuju da razni prehrambeni proizvodi zaista predstavljaju izvor intestinalnih, te u manjoj mjeri ekstraintestinalnih patogenih sojeva E. coli.Since food represents a possible source of pathogenic and antibiotic-resistant Escherichia coli strains, we analyzed 84 isolates from food samples identified in 2007 and 2008 at the National Institute of Public Health in Slovenia. Using polymerase chain reaction (PCR), the isolates were classified into phylogenetic groups and subgroups following the Clermont method. Forty-two (50 %) and thirty (35.7 %) isolates were classified into commensal gut phylogenetic groups A and B1, respectively. Only ten (11.9 %) and two (2.4 %) isolates were assigned to the phylogenetic groups D and B2, which include mainly extraintestinal pathogenic E. coli strains. The strains were further analyzed for the presence of various virulence genes and plasmid-mediated quinolone resistance qnr genes. Virulence genes stx1, stx2, both stx1 and stx2, ehxA and eae associated with Shiga-toxin producing E. coli were detected in one (1.2 %), five (6 %), five (6 %), eight (9.5 %) and three (3.7 %) isolates, respectively. Seventy-four (88.1 %) isolates carried the gene fimH, whereas virulence genes characteristic of extraintestinal pathogenic E. coli, hra, ompTAPEC and iha, were detected in nine (11 %), eight (9.5 %) and six (7 %) isolates, respectively. Genes kpsMTII, sfa, usp and vat were discovered in single isolates, whereas hlyA, bmaE, cnf, hbp and sat, as well as plasmid- mediated quinolone resistance genes qnr, were not detected in the analyzed strains. Our results show that various food items are indeed a source of intestinal and, albeit to a lesser extent, of extraintestinal pathogenic E. coli strains

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

14noopenopenCini, Giulia; Mezzavilla, Massimo; Della Puppa, Lara; Cupelli, Elisa; Fornasin, Alessio; D'Elia, Angela Valentina; Dolcetti, Riccardo; Damante, Giuseppe; Bertok, Sara; Miolo, Gianmaria; Maestro, Roberta; de Paoli, Paolo; Amoroso, Antonio; Viel, AlessandraCini, Giulia; Mezzavilla, Massimo; Della Puppa, Lara; Cupelli, Elisa; Fornasin, Alessio; D'Elia, Angela Valentina; Dolcetti, Riccardo; Damante, Giuseppe; Bertok, Sara; Miolo, Gianmaria; Maestro, Roberta; de Paoli, Paolo; Amoroso, Antonio; Viel, Alessandr

Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review

BackgroundFamilial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder usually caused by variants in the APOB gene that frequently interferes with protein length. Clinical manifestations include malabsorption, non-alcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction.MethodsGenomic DNA was isolated from the blood samples of the pediatric patient with hypocholesterolemia and his parents and brother. Next-generation sequencing (NGS) was performed, and an expanded dyslipidemia panel was employed for genetic analysis. In addition, a systematic review of the literature on FHBL heterozygous patients was performed.Case reportGenetic investigation revealed the presence of a heterozygous variant in the APOB (NM_000384.3) gene c.6624dup[=], which changes the open reading frame and leads to early termination of translation into the p.Leu2209IlefsTer5 protein (NP_000375.3). The identified variant was not previously reported. Familial segregation analysis confirmed the variant in the mother of the subject, who also has a low level of low-density lipoprotein and non-alcoholic fatty liver disease. We have introduced therapy that includes limiting fats in the diet and adding lipid-soluble vitamins E, A, K, and D and calcium carbonate. We reported 35 individuals with APOB gene variations linked to FHBL in the systematic review.ConclusionWe have identified a novel pathogenic variant in the APOB gene causing FHBL in pediatric patients with hypocholesterolemia and fatty liver disease. This case illustrates the importance of genetic testing for dyslipidemias in patients with significant decreases in plasma cholesterol as we can avoid damaging neurological and ophthalmological effects by sufficient vitamin supplementation and regular follow-ups

Pharmacogenetics antiepileptic drugs in children and youngsters with epilepsy

Uvod in namen dela: Cilj zdravljenja epilepsije je popolna kontrola napadov in omejitev pojava neželenih učinkov, kar je pri otrocih in mladostnikih, kjer je zdravljenje s protiepileptičnimi zdravili večinoma dolgotrajno, še posebno pomembno. Genetske variante v genih, ki sodelujejo v presnovi in transportu protiepileptičnih zdravil, pomembno vplivajo na učinkovitost zdravljenja epilepsije in pojavljanje neželenih učinkov. V doktorski nalogi smo opredelili tiste genetske označevalce pri otrocih in mladostnikih z epilepsijo, ki vplivajo na učinkovitost zdravljenja s tremi pogosteje uporabljenimi zdravili in na pojav neželenih učinkov. Metode: Vključeno je bilo 165 otrok in mladostnikov z epilepsijo, ki se zdravijo na Kliničnem oddelku za otroško, mladostniško in razvojno nevrologijo Pediatrične klinike Univerzitetnega kliničnega centra v Ljubljani. Pridobili smo klinične podatke ter smo preiskovancem, z molekularno genetskimi preiskavami, določili izbrane polimorfizme v genih CYP3A4, CYP2C9, CYP2C19, ABCB1, ABCC2, ABCG2 in SCN1A. S statistično analizo s programom SPSS smo preverili povezave genetskih in kliničnih podatkov. Vključili smo tudi 95 zdravih kontrolnih preiskovancev. Raziskavo je odobrila Komisija za medicinsko etiko. Rezultati in razprava: Pri bolnikih zdravljenih z valproatom in genotipom TT polimorfizma ABCB1 rs1128503 se 4-krat pogosteje pojavlja neželeni učinek kognitivnih motenj v primerjavi z genotipom CT. Ta povezava v literaturi še ni bila opisana. Pri bolnikih z genotipom AG polimorfizma ABCC2 rs2273697 se 3-krat pogosteje pojavlja neželeni učinek kognitivnih motenj v primerjavi z genotipom GG, kar je v skladu z znanimi podatki o tem da je koncentracija valproata pri bolnikih z genotipom AA višja kot pri bolnikih z genotipom GG. Pri bolnikih z genotipom GG polimorfizma CYP2C19 rs4244285 se 2,6-krat pogosteje pojavljajo vedenjske težave kot neželeni učinek v primerjavi z genotipom AA, medtem ko se za genotip AA 2,8-krat pogosteje pojavljajo vedenjske težave kot neželeni učinek v primerjavi s kognitivnimi motnjami. Ta varianta je že bila povezana s pojavom drugih neželenih učinkov, kot sta porast telesne teže in hiperinzulinizem pri bolnicah z epilepsijo, ki so bile zdravljenje z valproatom, ni pa bila opisana v povezavi z vedenjskimi težavami. Pri bolnikih zdravljenih s karbamazepinom oz. okskarbazepinom in genotipom AG polimorfizma ABCC2 rs717620 se 3-krat pogosteje pojavljajo vedenjske težave kot neželeni učinek v primerjavi z genotipom GG, kar še ni bilo opisano v literaturi. Prvič smo dokazali, da je alel G polimorfizma SCN1A rs2298771, predvsem v homozigotni obliki, povezan z večjo učinkovitostjo protiepileptičnega zdravljenja. Hkrati je ta alel povezan tudi z dovzetnostjo za epilepsijo, ki je že bila opisana v azijskih populacijah. Zaključki: Rezultati naše in podobnih raziskav bodo lahko v prihodnosti osnova za določitev priporočil za individualizirano izbiro najprimernejšega protiepileptičnega zdravila, ki bo učinkovitejše in bo imelo čim manjšo možnost pojava neželenih učinkov zdravljenja.Introduction: The goal of the antiepileptic therapy is the complete control of seizures with adverse drug reactions as limited as possible. This becomes even more important in children and adolescents with longstanding therapy, where the effectiveness of the treatment and the possible manifestation of adverse drug reactions are even more crucial. Polymorphisms of genes involved in the metabolism and transport of antiepileptic drugs influence the effect of therapy and in the manifestation of collateral effects. In this dissertation, we evaluated genetic markers in children and adolescents with epilepsy, which may be associated with the effectiveness of therapy and the manifestation of collateral effects. Methods: We included 165 children and adolescents with epilepsy treated at the Department of Child, Adolescent and Developmental Neurology, Children\u27s Hospital, University Medical Centre Ljubljana, Slovenia. Family and personal history were taken. Molecular genetics analysis with qPCR to test for known polymorphisms of the genes CYP3A4, CYP2C9, CYP2C19, ABCB1, ABCC2, ABCG2 and SCN1A were performed. Statistical analysis with genetics and clinical data were performed. A control group of 95 presumably healthy participants was used. Results: Patients treated with valproic acid with genotype TT of the polymorphism ABCB1 rs1128503 have 4 times more frequently present cognitive impairment compared to patients with genotype CT. The association of this variant with cognitive impairment due to valproic acid treatment has not been previously reported. Patients treated with valproic acid with genotype AG of polymorphism ABCC2 rs2273697 have 3 times more frequently present cognitive impairment compared to those with genotype GG. This corroborated the reported higher valproic acid concentrations in patients with AA genotype in comparison to GG genotype. Patients with genotype GG of the polymorphism CYP2C19 rs4244285 have 2.6 times more frequently present adverse drug reactions behavioural disorder compared to genotype AA, while patients with genotype AA have 2.8 times more frequently behavioural disorder compared with cognitive impairment. This variant has been previously reported in correlation with other adverse drug reactions of the valproic acid treatment, such as obesity and hypeinsulinism in female patients with epilepsy, but not in association with behavioural disorders. Patients treated with carbamazepine or oxcarbazepine with genotype AG of the polymorphism ABCC2 rs717620 have 3 times more frequently behavioural disorders compared to genotype GG which has not been previously reported. We have shown that in patients with G allele of the polymorphism SCN1A rs2298771, mainly at the homozygous state, the antiepileptic treatment is more efficient, which has not been previously reported. At the same time, it is associated with predisposition to develop epilepsy, already reported in Asian populations. Conclusions: The results of our and similar studies could be the foundation of the future recommendations for the individualised treatment of the epilepsy that will have sufficient efficiency and limited adverse drug reactions

INFANTILE CORTICAL HYPEROSTOSIS

Infantile cortical hyperostosis or Caffey disease is a rare genetic disorder caused by a mutation in the collagen 1 gene. The mechanism of the disease has not yet been fully elucidated, but the most important factor in the pathogenesis and the consequence of the mutation is periosteal inflammation. The disease becomes clinically evident during the first months of life with asymmetrical bone thickening, most commonly in the mandible, clavicle, scapula, ribs, and long bones. Non-specific systemic inflammatory symptoms can also be present. X-ray imaging with demonstration of bone hyperostosis is essential for the diagnosis, which is confirmed by genetic testing. Treatment is symptomatic. The prognosis of the disease depends on the mode of inheritance. The autosomal recessive form, known as the prenatal form, has a poor prognosis. The autosomal dominant form or infantile Caffey disease usually resolves spontaneously without consequences before the age of two years. We present a case of a neonate with Caffey disease with proven COL1A1 gene mutation

A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study

Abstract Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G>T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen- activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis

Childhood Osteoporosis and Presentation of Two Cases with Osteogenesis Imperfecta Type V / Osteoporoza V Otroški Dobi in Predstavitev Dveh Bolnikov Z Osteogenesis Imperfecta Tipa V

Uvod. Osteogenesis imperfecta (OI) je vzročno heterogena bolezen, katere značilnost je osteoporoza v otroštvu. Pri vseh opisanih bolnikih s podtipom OI tipa V je vzrok bolezni ista mutacija c.-14C>T gena IFITM5. Kljub temu med bolniki obstaja izrazita fenotipska variabilnost v klinični sliki, toda opisan je le dober odgovor na zdravljenje z bisfosfonati