Genetic, clinical and imaging implications of a noncompaction phenotype population with preserved ejection fraction.

Introduction: The genotype of symptomatic left ventricular noncompaction phenotype (LVNC) subjects with preserved left ventricular ejection fraction (LVEF) and its effect on clinical presentation are less well studied. We aimed to characterize the genetic, cardiac magnetic resonance (CMR) and clinical background, and genotype-phenotype relationship in LVNC with preserved LVEF. Methods: We included 54 symptomatic LVNC individuals (LVEF: 65 ± 5%) whose samples were analyzed with a 174-gene next-generation sequencing panel and 54 control (C) subjects. The results were evaluated using the criteria of the American College of Medical Genetics and Genomics. Medical data suggesting a higher risk of cardiovascular complications were considered "red flags". Results: Of the LVNC population, 24% carried pathogenic or likely pathogenic (P) mutations; 56% carried variants of uncertain significance (VUS); and 20% were free from cardiomyopathy-related mutations. Regarding the CMR parameters, the LVNC and C groups differed significantly, while the three genetic subgroups were comparable. We found a significant relationship between red flags and genotype; furthermore, the number of red flags in a single subject differed significantly among the genetic subgroups (p = 0.002) and correlated with the genotype (r = 0.457, p = 0.01). In 6 out of 7 LVNC subjects diagnosed in childhood, P or VUS mutations were found. Discussion: The large number of P mutations and the association between red flags and genotype underline the importance of genetic-assisted risk stratification in symptomatic LVNC with preserved LVEF.

[Current therapeutic and familial implications of the genetic background of prostate cancer]. / A prosztatarák genetikai hátterének aktuális terápiás és familiáris vonatkozásai.

Genetic testing for prostate cancer (PC) is becoming more widely used in the clinical routine, primarily due to the introduction of PARP inhibitors targeting genetically affected patients in their BRCA1/2 and other homologous recombination repair (HRR) genes. Simultaneously, the number of available therapies that are specifically targeting genetically defined PC subgroups is steadily increasing. As a result, the selection of treatment for PC patients is likely to require testing of multiple genes to enable more specific treatment sequences that consider the genetic characteristics of the tumor. Some of the mutations discovered by genetic testing may be hereditary, necessitating the use of germline testing from normal tissue, which is only permitted within the framework of clinical counseling. This change in PC care requires the collaboration by multiple specialists, including experts in molecular pathology, bioinformatics, biology, and genetic counseling. In this review, we aim to provide an overview on the currently relevant genetic alterations in PC for therapeutic purposes and their implications for familial testing.

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries.

OBJECTIVE: Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries. METHODS: We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers. RESULTS: We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations. CONCLUSIONS: Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.

Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement.

BACKGROUND: Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict "malignant" mutations. METHODS: 136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen the FBN1 gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA. RESULTS: 84 pathogenic mutations were detected, out of which 78 affected FBN1, 6 non-FBN1 mutations (2 TGFB2, 1 TGFBR2, 2 TGFBR1, 1 SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions of FBN1 gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p < 0.001). Patients with DN Cys required significantly more aortic surgeries than HI and DN non-Cys mutations (p = 0.042 and p = 0.015, respectively). CONCLUSIONS: Due to the relevant number of mutations affecting genes other than FBN1, preferred approach for testing individuals with Marfanoid habitus is using a gene panel rather than single-gene analysis, followed by MLPA for negative samples. DN Cys and HI mutations should be considered as risk factors for aortic involvement. Genetic testing for patients with Marfanoid features and a systemic score under 7 is recommended, as LDS patients may have lower scores, but they may have severe cardiovascular manifestations.

Broadening the phenotype of the TWNK gene associated Perrault syndrome.

BACKGROUND: Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves. CASE PRESENTATION: Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A). CONCLUSION: This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.

Implementation of personalized medicine in Central-Eastern Europe: pitfalls and potentials based on citizen's attitude.

OBJECTIVE: Next-generation sequencing is increasingly utilized worldwide as a research and diagnostic tool and is anticipated to be implemented into everyday clinical practice. Since Central-Eastern European attitude toward genetic testing, especially broad genetic testing, is not well known, we performed a survey on this issue among Hungarian participants. METHODS: A self-administered questionnaire was distributed among patients and patient relatives at our neurogenetic outpatient clinic. Members of the general population were also recruited via public media. We used chi-square testing and binary logistic regression to examine factors influencing attitude. RESULTS: We identified a mixed attitude toward genetic testing. Access to physician consultation positively influenced attitude. A higher self-determined genetic familiarity score associated with higher perceived genetic influence score, which in turn associated with greater willingness to participate in genetic testing. Medical professionals constituted a skeptical group. CONCLUSIONS: We think that given the controversies and complexities of the next-generation sequencing field, the optimal clinical translation of NGS data should be performed in institutions which have the unique capability to provide interprofessional health education, transformative biomedical research, and crucial patient care. With optimization of the clinical translational process, improvement of genetic literacy may increase patient engagement and empowerment. RELEVANCE OF THE ARTICLE FOR PREDICTIVE PREVENTIVE AND PERSONALIZED MEDICINE: The paper highlights that in countries with relatively low-genetic literacy, a special strategy is needed to enhance the implementation of personalized medicine.

[Vitamin D level in Hungarian patients with inflammatory bowel diseases]. / D-vitamin-szint mérése hazai gyulladásos bélbetegekben.

INTRODUCTION: Vitamin D has an important role in the immune regulation. Vitamin D is essential for innate and adaptive immune systems and it plays a significant role in the formation of immune tolerance, as well. AIM: Vitamin D deficiency has been observed in patients with inflammatory bowel diseases in Western Europe, but there is no data available from Eastern Europe. METHOD: The study included 169 patients with inflammatory bowel disease. RESULTS: The median vitamin D level was 22.7±10.6 ng/ml. Only 20% of the patients had adequate vitamin D level (>30 ng/ml), 52% had vitamin D insufficiency (15-30 ng/ml), and 28% of them had severe vitamin D deficiency (<15 ng/ml). Vitamin D concentration failed to correlate with clinical activity indexes (partial Mayo score: r = -0.143; Crohn's disease activity index: r = -0.253) and with inflammatory parameters (C-reactive protein: r = 0.008; erythrocyte sedimentation rate: r = 0.012). CONCLUSIONS: Since vitamin D deficiency can be frequently observed in Hungarian patients with inflammatory bowel disease, its level should be tested in these patients.

Does dermatitis herpetiformis result in bone loss as coeliac disease does? A cross sectional study.

INTRODUCTION AND OBJECTIVES: coeliac disease (CD) and its cutaneous manifestation, dermatitis herpetiformis are both (DH) gluten-sensitive diseases. Metabolic bone disease is common among patients with CD, even in asymptomatic forms. Data are scarce about bone density in patients with dermatitis herpetiformis. The aim of our study was to compare bone mineral density (BMD) of celiac and dermatitis herpetiformis patients. METHODS: 34 coeliac patients, 53 with dermatitis herpetiformis and 42 healthy controls were studied. The mean age was 38.0 +/- 12.1, 32.18 +/- 14.95, 35.33 +/- 10.41 years in CD, dermatitis herpetiformis, and healthy controls, respectively. Bone mineral density of the lumbar spine, the left femoral neck and radius were measured by dual-energy X-ray absorptiometry. Low bone density, osteopenia and osteoporosis were defined as a body mass density (BMD) T-score between 0 and -1, between -1 and -2.5, and under -2.5, respectively. RESULTS: at lumbar region, consisting of dominantly trabecular compartment, a decreased BMD was detected in 49 % (n = 26) patients with dermatitis herpetiformis, 62 % (n = 21) of CD patients, and 29 % (n = 12) of healthy controls, respectively. Lower BMD were measured at the lumbar region in dermatitis herpetiformis and CD compared to healthy subjects (0.993 +/- 0.136 g/cm2 and 0.880 +/- 0.155 g/cm2 vs. 1.056 +/- 0.126 g/cm2; p < 0.01). Density of bones consisting of dominantly cortical compartment (femoral neck) did not differ in dermatitis herpetiformis and healthy subjects. CONCLUSIONS: our results show that a low bone mass is also frequent among patients with dermatitis herpetiformis. Bone mineral content in these patients is significantly lower in those parts of the skeleton which contain more trabecular than cortical bone.

[Prevalence of gastric polypoid lesions at an endoscopic facility]. / A gyomor polypoid képleteinek gyakorisága egy endoszkópos centrumban.

BACKGROUND: The prevalence of gastric polyps is unknown in Hungary. AIM: The aim of the authors was to assess the prevalence of polypoid lesions of the stomach in the endoscopic centre of the 2nd Department of Medicine, Semmelweis University. METHODS: Results of upper gastrointestinal endoscopies carried out between March 2010 and June 2011 were analysed. RESULTS: 193 cases with polyps were diagnosed in 4174 endoscopies (4.62%). Hyperplastic polyps, fundic gland polyps and malignant lesion were detected in 33.67%, 31.09% and 2.07% of the cases, respectively. Proton pump inhibitor use was more frequent among patients diagnosed with fundus gland polyps (p = 0.007), while hyperplastic polyps were diagnosed more frequently in patients with chronic gastritis (p = 0.032). CONCLUSIONS: The frequency of gastric polyps was higher than expected from data published in the literature. Long-term proton pump-inhibitor use and chronic gastritis were associated with fundus gland and hyperplastic polyps, respectively.

Does dermatitis herpetiformis result in bone loss as coeliac disease does? A cross sectional study / ¿Provoca la dermatitis herpetiforme pérdida ósea al igual que la enfermedad celiaca? Un estudio transversal

Introduction and objectives: coeliac disease (CD) and its cutaneous manifestation, dermatitis herpetiformis are both (DH) glutensensitive diseases. Metabolic bone disease is common among patients with CD, even in asymptomatic forms. Data are scarce about bone density in patients with dermatitis herpetiformis. The aim of our study was to compare bone mineral density (BMD) of celiac and dermatitis herpetiformis patients. Methods: 34 coeliac patients, 53 with dermatitis herpetiformis and 42 healthy controls were studied. The mean age was 38.0 ± 12.1, 32.18 ± 14.95, 35.33 ± 10.41 years in CD, dermatitis herpetiformis, and healthy controls, respectively. Bone mineral density of the lumbar spine, the left femoral neck and radius were measured by dual-energy X-ray absorptiometry. Low bone density, osteopenia and osteoporosis were defined as a body mass density (BMD) T-score between 0 and -1, between -1 and -2.5, and under -2.5, respectively. Results: at lumbar region, consisting of dominantly trabecular compartment, a decreased BMD was detected in 49 % (n = 26) patients with dermatitis herpetiformis, 62 % (n = 21) of CD patients, and 29 % (n = 12) of healthy controls, respectively. Lower BMD were measured at the lumbar region in dermatitis herpetiformis and CD compared to healthy subjects (0.993 ± 0.136 g/cm2 and 0.880 ± 0.155 g/cm2 vs. 1.056 ± 0.126 g/cm2; p < 0.01). Density of bones consisting of dominantly cortical compartment (femoral neck) did not differ in dermatitis herpetiformis and healthy subjects. Conclusions: our results show that a low bone mass is also frequent among patients with dermatitis herpetiformis. Bone mineral content in these patients is significantly lower in those parts of the skeleton which contain more trabecular than cortical bone (AU)