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Clinical Oncology

MAY 10, 2018

[Fusions in solid tumors]

KOPPER László

[Genetic fusions are the cosequence of genomic rearrangement including chromosomal inversion, interstitial deletion, duplication, amplifi cation, translocation. Fusions can influence tumor development and progression. Fusions fi rst discovered in hematological malignances (e.g. BCR-ABL), butlater more and more were identified dueto the higly sensitive NGS. It has been found that the oncogenic fusions are in minority in a given tumor. Today, some fusions were apprevedas targets (ALK, ROS1, PDGFB) by FDA. Asino ther targeted therapy resistance is in evitable, which is a very important challenge for newly designed drugs.]

Hypertension and nephrology

SEPTEMBER 20, 2015

[Effect of angiotensin-converting enzyme gene insertion/deletion polymorphism on survival of hemodialyzed patients]

KISS István, SZEGEDI János, KULCSÁR Imre, AMBRUS Csaba, KERKOVITS Lóránt, TISLÉR András, KISS József Zoltán

[Introduction: There are inconsistent observations regarding the earlier studies of the connection between ACE gene I/D polymorphism and the cardiovascular mortality. In the case of hemodialyzed patients suffering from chronic kidney disease the DD polymorphism connected to the elevated ACE levels was pointed out to be connected to the mortality rate primarily in patients with diabetes. The previous observations were verified by us during the analyzation of the short-term (three year period) survival data. We hypothesized that the significance of the ACE gene I / D polymorphism in chronic kidney disease would be verified and that during long-term observations (10 year period) the previous results could be validated. Method: In our non-invasive, prospective and multicentre study clinical data was collected from 746 patients whose blood samples were genotyped for ACE gene I/D single nucleotide polymorphism. Three genotype groups (I/I, I/D és D/D) were created during the analyzation of the mortality that was done using multivariate Cox proportional hazard models. Results: The mean age of the HD patients was 54.9 years, 46,8% of all patients were female. The prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before the start of the study was 23.8 months (IQR 11.2-47.1). The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. During the ten year follow- up of patients, the median follow-up was 29.8 months (IQR 12.6-63.4). The D/D genotypes showed lower survivability (I/I vs. D/D: log-rank test: p=0.04) from the group of patients without ACE inhibitor therapy. In multivarite Cox regression models D/D genotype compared with I/I genotype only showed that it significantly determines mortality in patients with no ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, p=0.03). Conclusions: There was no difference in survival among unselected patients with different genotypes. Our data suggests that hemodialyzed patients with the D/D genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup.]

Clinical Neuroscience

NOVEMBER 28, 2014

[The modifying effect a PMP22 deletion in a family with Charcot-Marie-Tooth type 1 neuropathy due to an EGR2 mutation]

REMÉNYI Viktória, INCZÉDY-FARKAS Gabriella, GÁL Anikó, BEREZNAI Benjámin, PÁL Zsuzsanna, KARCAGI Veronika, MECHLER Ferenc, MOLNÁR Mária Judit

[Background - Mutations of both the PMP22 and EGR2 genes cause Charcot-Marie-Tooth (CMT) disease type 1. Deletion of the PMP22 gene, results in hereditary neuropathy with liability to pressure palsies. More publications exist about the interaction of PMP22 duplication and other CMTcausing gene mutations. In these cases the intrafamiliar discordant phenotypes draw the attention to the possible role of modifying genes. The gene-gene interactions between the PMP22 and EGR2 genes are not well understood. Case report - We report two brothers with late onset CMT1 due to a c. 1142 G>A (Arg381His) heterozygous substitution in the EGR2 gene. Additionally, the older brother with the less severe symptoms harbored the PMP22 gene deletion also. Conclusion - The coexistence of the two genetic alterations did not aggravate the clinical symptoms. Moreover, the PMP22 deletion appeared to have a beneficial modifying effect, thus implying potential gene-gene interaction of PMP22 and EGR2. PMP22 deletion may increase Schwann cells proliferation and compensate the dominant-negative effect of the Arg381His substitution in the EGR2 gene.]

Clinical Neuroscience

SEPTEMBER 30, 2014

[Retinal ganglion cell layer and visual function in patients with progressive external ophthalmoplegia caused by common mtDNA deletion]

FARZANEH Naghizadeh, VARGA Edina Tímea, MOLNÁR Mária Judit, HOLLÓ Gábor

[Aim - Mitochondrial (mt) disorders are metabolic conditions with multiorgan involvement, which often cause neuroophtalmological symptoms. The aim of the study was to investigate the relation between progressive external ophthalmoplegia (PEO), visual pathway and mitochondrial DNA (mtDNA) mutations in patients younger than 55 years of age. Methods - Five female patients (35 to 53 years of age) with mithochondrial disease were investigated. Automated threshold perimetry (Octopus G2 test), scanning laser polarimetry (GDx-VCC and GDx-ECC) and Fourier-domain optical coherence tomography (RTVue-100 OCT) were used in addition to detailed ophthalmological examination and evaluation of visually evoked potentials (VEP). Frequent mutations of the mtDNA were investigated in the patients’ blood and muscle samples. Results - PEO of various severity levels was found in all patients, using clinical tests. Genetic testing showed “common deletion” of mtDNA in all cases. For both eyes of 4 patients functional and structural ophthalmic tests had normal results. In one patient decreased visual acuity, reduced retinal nerve fiber layer thickness and prolonged L3 VEP latency time were found without optic disc damage and visual field deterioration. Conclusion - In 4 of our 5 patients with PEO due to common deletion of mtDNA retinal ganglion cells and visual function remained normal for a long period of life.]

Clinical Neuroscience

JANUARY 30, 2014

[Sleep-EEG in dizygotic twins discordant for Williams syndrome]

BÓDIZS Róbert, GOMBOS Ferenc, SZŐCS Katalin, RÉTHELYI M. János, GERVÁN Patrícia, KOVÁCS Ilona

[Background and purpose - Reports on twin pairs concordant and discordant for Williams syndrome were published before, but no study unravelled sleep physiology in these cases yet. We aim to fill this gap by analyzing sleep records of a twin pair discordant for Williams syndrome extending our focus on presleep wakefulness and sleep spindling. Methods - We performed multiplex ligation-dependent probe amplification of the 7q11.23 region of a 17 years old dizygotic opposite-sex twin pair discordant for Williams syndrome. Polysomnography of laboratory sleep at this age was analyzed and followed-up after 1.5 years by ambulatory polysomnography. Sleep stages scoring, EEG power spectra and sleep spindle analyses were carried out. Results - The twin brother showed reduced levels of amplification for all of the probes in the 7q11.23 region indicating a typical deletion spanning at least 1.038 Mb between FKBP6 and CLIP2. The results of the twin sister showed normal copy numbers in the investigated region. Lower sleep times and efficiencies, as well as higher slow wave sleep percents of the twin brother were evident during both recordings. Roughly equal NREM, Stage 2 and REM sleep percents were found. EEG analyses revealed state and derivation- independent decreases in α power, lack of an α spectral peak in presleep wakefulness, as well as higher NREM sleep σ peak frequency in the twin brother. Faster sleep spindles with lower amplitude and shorter duration characterized the records of the twin brother. Spectra show a striking reliability and correspondence between the two situations (laboratory vs. home records). Conclusion - Alterations in sleep and specific neural oscillations including the α/σ waves are inherent aspects of Williams syndrome.]

Clinical Neuroscience

JULY 30, 2007

[DYT1 POSITIVE GENERALISED DYSTONIA: A CASE STUDY OF TWO SIBLINGS]

BEREZNAI Benjámin, BARACZKA Krisztina, NAGY Zoltán, MOLNÁR Mária Judit

[The early-onset generalised dystonia is a dyskinetic movement disorder with a wide variety in phenotype and poor response to pharmacological treatment. A mutation on the DYT1 gene is responsible for the disease in more than 50% of cases with typical early-onset dystonia beginning in a limb. We describe the medical history of two brothers with first signs of focal dystonia at age 12 starting with right side lower limb dystonia of the older brother and writers cramp of the younger one. In both over a period of 6 and 10 years dystonia generalised. The negativ results of MRI, electrophisiological testing and muscle biopsy corroborate the diagnosis of primary dystonia. The DNA from the older patient was tested for the 3 bp deletion in exon 5 of the DYT1 gene by restriction enzyme. The positive result confirmed the diagnosis of early-onset primary dystonia. A short synopsis of routine molecular genetic tests indications and treatment options is outlined.]

Clinical Neuroscience

DECEMBER 20, 2008

[Clinical and genetic diagnosis of dravet syndrome: report of 20 cases]

SIEGLER Zsuzsa, NEUWIRTH Magdolna, HEGYI Márta, PARAICZ Éva, PÁLMAFY Beatrix, TEGZES Andrea, BARSI Péter, KARCAGI Veronika, CLAES Lieve, DE Jonghe Peter, HERCZEGFALVI Ágnes, FOGARASI András

[Objective and background - Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by prolonged febrile hemiconvulsions or generalized seizures starting in the first year of life. Later on myoclonic, atypical absence, and complex partial seizures appear. When one of these seizure forms is lacking the syndrome of borderline SMEI (SMEB) is defined. Psychomotor delay resulting in mental retardation is observed during the second year of life. In most patients a de novo sodium channel alfa-1 subunit (SCN1A) mutation can be identified. By reviewing the clinical, laboratory, and neuroimaging data of our SMEI patients diagnosed between 2000 and 2008, we would like to share our experiences in this rare but challenging syndrome. Our results will facilitate the earlier and better diagnosis of Hungarian children with SMEI. Patients and methods - Clinical, EEG, MRI and DNA mutation data of 20 SMEI patients treated in the Bethesda Children’s Hospital (Budapest) were reviewed. Results - The first seizure appeared at age 6.3±3.0 months. At least one of the first two seizures were complex febrile seizures in 19/20 and unilateral seizures in 12/20 children. All children except for one showed hemiconvulsions at least once; all children had seizures lasting longer than 15 minutes. Eight of twenty patients had SMEB. DNA diagnostics identified an SCN1A mutation in 17 patients (6 missense, 4 nonsense, 4 frameshift, 2 splice site, 1 deletion) while 3 children had no mutation. Conclusion - Early diagnosis of SMEI is important for the avoiding unnecessary examinations and false therapies as well as for genetic counselling. Typical symptoms of SMEI are early and prolonged febrile hemiconvulsions with neurological symptoms, mental retardation and secondary seizure types later on. The presence of an SCN1A mutation supports the diagnosis. We propose the availability of molecular diagnostics and stiripentol therapy for SMEI children in Hungary.]

Clinical Neuroscience

JANUARY 20, 2009

[Genetically determined neuromuscular disorders of some roma families living in Hungary (in English language)]

LÁSZLÓ Aranka, MAYER Péter, KÓBOR Jenõ, RÁCZ Katalin, TÁLOSI Gyula, ENDREFFY Emőke, HERCZEGFALVI Ágnes, HORTOBÁGYI Tibor, TISZLAVICZ László, BEREG Edit, KATONA Márta, SZABÓ János, KARCAGI Veronika

[The authors discuss the clinical and molecular genetic aspects of genetically determined neuromuscular disorders of some Roma families living in Hungary. Among the autosomal recessively inherited spinal muscular atrophic (SMA) group, 8 Caucasian children had the typical 7-8 exonal deletions of the SMA gene, but only 2 patients belonged to the Roma population. There was no difference in the molecular genetic findings among the Caucasian and the Roma SMA patients. All of them had 7- 8 exonal deletions of the SMA gene. We wanted to call attention to the founder mutation of the Roma population in 7 patients suffering from congenital myasthenia (CMS) from 3 Roma families. The 1267G deletion for CMS was detected by molecular genetic method. Clinical onset was pubertal and relatively slow progression of specific and phenotypic features for this founder mutation of acetyl-cholin receptor epsylon gene. In 2 patients (sister and brother) the sarcoglycanopathy 2C type C283Q mutation was proven in one Roma family suffering from limb-girdle muscular dystrophy (LGMD). Two out of the three facioscapular-humeral dystrophy (FSHD) Roma families carried 21.8 kb and 18.5 kb alleles in FSHD A1 gene (D4S139). In one family together with prenatal diagnosis founder mutation in FSHD A1 gene was detected, according to the autosomal dominant (AD) inheritence. In (F2) prenatal diagnosis was carried out, 18.5 kb/18.5 kb homozygosity was proven in the fetus, so the pregnancy was interrupted. In the CMS, LGMD and FSHD Roma patients ancient typical Roma founder mutations were found.]

Clinical Neuroscience

JUNE 20, 2002

[Investigation of insertion/deletion polymorphism of the ACE gene on stroke patients]

PONGRÁCZ Endre, TORDAI Attila, CSORNAI Márta, NAGY Zoltán

[Introduction - This is the first Hungarian paper on the insertion/deletion polymorphism of ACE gene in stroke patients. According to literature data, the role of this polymorphism is controversial in the pathogenesis of stroke. The aim was to study the prevalence of the polymorphism in healthy persons and in stroke patients. Patients and methods - Blood samples from 173 unrelated healthy donors and 253 stroke patients were investigated by polymerase chain reaction (PCR). Preivous stroke was documented by CT or MRI and CDS. A routine questionnaire was used to study previous vascular events and the risk profile of patients. Results - I/I allele was found in 20%, I/D 52% and D/D 28% in the healthy group. Prevalence of the pathologic D/D allele did not differ between healthy and patients group (28% and 27%, OR: 0.88, and in subgroup age under 50 years OR: 1.00). No correlation was found between D/D and conventional risk profile but a positiv correlation was found in young patients having D/D and hyperlipidemia (p<0.05) and hyperfibrinogenemia (p<0.05). D/D prevalence was found higher in patients with family anamnesis of myocardial infarction (p<0.05). Very low prevalence of D/D allele was found in cardiogen embolic group (p>0.05). Conclusions - The ACE polymorphism does not seem to be an independent risk factor for stroke. However, in young stroke patients with D/D allele, hyperlipidemia and/or hyperfibrinogenemia present very high risk for stroke.]

Clinical Neuroscience

NOVEMBER 30, 2009

[Quantitative analysis of the genes determining spinal muscular atrophy]

NAGYMIHÁLY Mariann, HERCZEGFALVI Ágnes, TÍMÁR László, KARCAGI Veronika

[Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately one in 10.000 live births and with a carrier frequency of approximately one in 35. The disease is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. Due to a single nucleotide polymorphism in exon 7, SMN2 produces less full-length transcript than SMN1 and cannot prevent neuronal cell death at physiologic gene dosages. On the other hand, the copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1 exon 7. This study provides copy number estimation of SMN1 gene by real-time PCR technique in 56 SMA type I., II., III. patients, 159 parents and healthy relatives and in 152 undefined SMA patients. Among the family members, 91 carriers have been detected and in 56 patients homozygous deletion of SMN1 exon 7 has been confirmed. Moreover, in 12 patients compound heterozygosity of SMN1 exon 7 mutation has been detected, thus providing the possible diagnosis of SMA. In 94 patients, copy number of SMN2 has also been evaluated and a good correlation has been found with the phenotype of the disease. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counselling are particularly important for the families. These new results provide improvement of the diagnostic service in SMA in Hungary with focus on proper genetic counselling and possible enrolment of the patients in future therapeutic interventions.]