Мультипарадигмальний підхід до аналізу феномену нігілізму

У статті розглянуто нігілізм як неоднозначне й поліморфне поняття. Досліджено різні підходи до тлумачення та розв’язання питань, пов’язаних із нігілізмом. Розкрито людиномірність нігілізму в контексті відстеження варіативного смислового навантаження феномену. Встановлено, що нігілізм потрібно позиціонувати як спосіб пробудження людського духу, заперечення деструктивного конформізму й відсутності опору (пасивний песимізм).В статье рассмотрен нигилизм как неоднозначное и полиморфное понятие. Исследованы различные подходы к толкованию и решению вопросов, связанных с нигилизмом. Раскрыта человекомерность нигилизма в контексте отслеживания вариативной смысловой нагрузки феномена. Установлено, что нигилизм нужно позиционировать как способ пробуждения человеческого духа, отрицание деструктивного конформизма и отсутствия сопротивления (пассивный пессимизм).Nihilism is considered as ambiguous and polymorphic concept. Different approaches to the interpretation and solution of issues associated with nihilism are investigated. Human measurement of nihilism in the context of tracking meaning of varied semantic capacity of the phenomenon is revealed. It is determined that nihilism must be positioned as a way of awakening of the human spirit, denial of destructive conformism and absence of resistance (passive pessimism)

Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective

Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c.2991+1655A>G mutation in CEP290

PURPOSE. To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. METHODS. Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. RESULTS. A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12–1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22–1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. CONCLUSIONS. Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT

Joubert syndrome in the Netherlands. Clinical and genetic aspects

The ciliopathies, a collective of diseases caused by dysfunction of the primary cilia, have proven to be one of the most exciting groups of new diseases of the last ten years. Joubert syndrome (JBS), a rare neurodevelopmental disorder described for the first time in 1969, has turned out to be one of the quintessential ciliopathies. JBS shows the wide range of clinical features and genetic heterogeneity typical of the ciliary diseases. Our knowledge on the syndrome has expanded considerably over the last twenty years (for a general overview, I also refer to some of the excellent reviews 1-6). However, many questions on the phenotypical variability and the complex genetic background of JBS have not been answered yet. The literature on JBS started with the report of Marie Joubert et al. in 1969 7. She described four siblings with hyperventilation, abnormal eye movements and psychomotor retardation. Boltshauser described the first European cases 8; this is why JBS is also known as Joubert-Boltshauser syndrome. In the initial reports hallmarks of the syndrome were considered to be mental (and motor) retardation, hypotonia, and, specifically, periodic hyperpnea, abnormal eye movements, and vermis aplasia. Several authors recognized the overlap of clinical features with other syndromes (e.g. with orofacialdigital syndrome type 1 9, or CHARGE syndrome 10). In the years following the initial descriptions, many reports have been published adding additional symptoms to the phenotype. For instance, retinal colobomas as part of the Joubert phenotype were reported by Lindhout et al. (1980) 11, and Aicardi et al. (1983) 12, and polydactyly by Egger et al. (1982) 13. The first reports on retinal dysplasia/Lebers congenital amaurosis were in the early eighties of the last century 12,14,15, and in the nineties cystic kidney disease and hepatic fibrosis were recognized as features of JBS 16. Over the years, lumpers and splitters have defined the shifting boundaries between JBS and syndromes with overlapping symptoms, e.g. COACH syndrome (cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis 17), and ARIMA syndrome (cerebellar hypoplasia, retinal disease and cystic kidney disease) 18. The term “Joubert syndrome and related disorders (JSRD)” was coined to cope with this ongoing debate. Little has been published on JBS in the Netherlands, since the description of the first case in 1980 1 At the start of this study, we aimed to obtain an overview of the Dutch population of JBS patients, to estimate the Dutch birth prevalence, and to gain insight into the clinical course and genetic background of Dutch JBS cases. This thesis describes the results of our efforts to solve these questions, and related topics that we encountered on the way. Chapters 2 and 3 are focused on clinical aspects of JBS. In Chapter 2 we investigated hearing loss in the Dutch JBS patient cohort. Many studies have addressed the visual features of JBS, but none have investigated hearing. Hearing loss has been reported in some ciliopathies, e.g. Alstrom disease and BBS. Given the fact that many JBS patients have reduced vision and impaired speech development, adequate hearing is extremely important. In Chapter 3 we discuss the diagnostic pitfalls in JBS, especially the correct interpretation of MRI results when evaluating the molar tooth sign. Two patients are described with an initial diagnosis of JBS, who turned out to have chromosomal rearrangements not related to JBS. In Chapter 4 we report a family with a JBS-like phenotype with a pedigree in line with X-linked inheritance. We were especially interested in this family because of the excess of male patients in the Dutch JBS population and our expectation to find involvement of X-linked genes. Chapters 5 to 7 describe the results of molecular studies in the Dutch JBS cohort. In Chapter 5, we investigated the AHI1 gene, the NPHP1 gene, and the CYCLIN D1 gene. At the start of this study, Sanger sequencing was the only tool available. At the time AHI1 and NPHP1 had just been identified as JBS causing genes. Since large families suitable for linkage analysis or consanguineous families suitable for homozygosity mapping are relatively rare in the Dutch population, we chose a candidate gene approach based on a combination of JBS loci and animal models, and also investigated CYCLIN D1 as a possible new JBS gene (OMIM # 168461). In Chapter 6 and 7 we utilized the new possibilities of next generation sequencing. We developed a targeted NGS array containing 22 JBS genes and named it the Joubertome. The molecular cause of JBS remains elusive in about half of the cases, and therefor we added around 600 candidate genes selected from the literature and the ciliary proteome database [http://v3.ciliaproteome.org]. The results of the Joubertome analysis and the finding of MKS1 as a novel gene for JBS are reported in Chapter 6 and 7

Disclosure of individual genetic data to research participants: the debate reconsidered

Despite extensive debate, there is no consensus on whether individual genetic data should be disclosed to research participants. The emergence of whole-genome sequencing methods is increasingly generating unequalled amounts of genetic data, making the need for a clear feedback policy even more urgent. In this debate two positions can be broadly discerned: a restrictive disclosure policy ('no feedback except life-saving data') and an intermediate policy of qualified disclosure ('feedback if the results meet certain conditions'). We explain both positions and present the principal underlying arguments. We suggest that the debate should no longer address whether genetic research results should be returned, but instead how best to make an appropriate selection and how to strike a balance between the possible benefits of disclosure and the harms of unduly hindering biomedical research.

Mitochondrial dysfunction in a patient with Joubert syndrome.

Contains fulltext : 48821.pdf (publisher's version ) (Closed access)Joubert syndrome is a genetically heterogeneous disorder. The diagnostic criteria include episodic hyperventilation, abnormal eye movements, psychomotor retardation, hypotonia, ataxia, and the characteristic neuro-imaging findings (molar-tooth sign). Many of these clinical features have been observed in new-borns with mitochondrial disorders as well. Congenital brain malformations, including cerebellar hypoplasia, have been described in pyruvate dehydrogenase deficiency. Malformations of the vermis and the cerebellar peduncles, with the lack of axonal decussations, however, are characteristic for Joubert syndrome but unique in patients with mitochondrial disorders. Here, we describe a child with Joubert syndrome presenting with primary lactic acidemia, decreased pyruvate oxidation rates, decreased ATP production, and a mildly decreased pyruvate dehydrogenase complex activity measured in a fresh muscle biopsy. Sequence analysis of the PDHc E1 alpha gene and the PDHX genes revealed no mutations. The patient received continuous feeding through a feeding tube for two years and showed a significant clinical improvement with a complete resolution of the chronic lactic acidemia. A second muscle biopsy revealed significantly decreased pyruvate oxidation rates and ATP production, but a normal pyruvate dehydrogenase complex activity. We suggest that the described mitochondrial dysfunction in our patient is secondary to an underlying mutation leading to Joubert syndrome

Chromosomal abnormalities resembling Joubert syndrome: two cases illustrating the diagnostic pitfalls

We describe two patients with severe developmental delay, hypotonia and breathing abnormalities initially diagnosed with the autosomal recessive Joubert syndrome (JBS) who at a later stage appeared to carry chromosomal abnormalities. One case was due to a 4.8 Mb terminal 1q44 deletion, and the other due to a 15.5 Mb duplication of Xq27.2-qter containing the MECP2 gene. Critical evaluation of the clinical data showed that, retrospectively, the cases did not fulfil the diagnostic criteria for JBS, and that the diagnosis of JBS was incorrectly made. We discuss the diagnostic pitfalls and recommend adhering strictly to the JBS diagnostic criteria in the case of a negative molecular diagnosis. Critical assessment of the MRI findings by a specialized neuroradiologist is imperative. As chromosomal abnormalities may give rise to symptoms resembling JBS, we recommend array-based screening for segmental aneuploidies as an initial genetic test in all cases with a JBS-like phenotype

Non-invasive sources of cells with primary cilia from pediatric and adult patients

Contains fulltext : 153513.pdf (publisher's version ) (Open Access)BACKGROUND: Ciliopathies give rise to a multitude of organ-specific pathologies; obtaining relevant primary patient material is useful for both diagnostics and research. However, acquisition of primary ciliated cells from patients, particularly pediatric patients, presents multiple difficulties. Biopsies and blood samples are invasive, and patients (and their parents) may be reluctant to travel to medical centers, especially for research purposes. We sought to develop non-invasive methods of obtaining viable and ciliated primary cells from ciliopathy patients which could be obtained in the home environment. FINDINGS: We introduce two methods for the non-invasive acquisition of primary ciliated cells. In one approach, we collected spontaneously shed deciduous (milk) teeth from children. Fibroblast-like cells were observed after approximately 2 weeks of culture of fragmented teeth. Secondly, urine samples were collected from children or adults. Cellular content was isolated and after approximately 1 week, renal epithelial cells were observed. Both urine and tooth-derived cells ciliate and express ciliary proteins visible with immunofluorescence. Urine-derived renal epithelial cells (URECs) are amenable to 3D culturing, siRNA knockdown, and ex vivo drug testing. CONCLUSIONS: As evidence continues to accumulate showing that the primary cilium has a central role in development and disease, the need for readily available and ciliated patient cells will increase. Here, we introduce two methods for the non-invasive acquisition of cells with primary cilia. We believe that these cells can be used for further ex vivo study of ciliopathies and in the future, for personalized medicine

Is hearing loss a feature of Joubert syndrome, a ciliopathy?

Objective: To assess if hearing loss is a feature of Joubert syndrome (JBS), one of the ciliopathies and therefore possibly associated with hearing loss. Design: Retrospective case series. Setting: University Children's Hospital. Patients: Dutch patients with JBS. Main outcome measures: Audiological data. Results: Data from 22 Dutch Joubert syndrome (JBS) cases (17 males, 5 females) aged 3-40 years were available. Audiological tests were successfully performed in 14 cases. Three cases (aged 17-26 years) showed very mild sensorineural hearing loss (SNHL) at different frequencies. Conductive hearing loss due to middle ear infections occurred frequently in young JBS children (6 out of 22 cases). In three cases (aged 3-13 years) the parents reported the child was hypersensitive to sound. Conclusion: We found no evidence for significant hearing loss in Joubert syndrome patients. However, given the compromised speech development in JBS, conductive hearing loss due to middle ear infections should be treated vigorously. SNHL at a later age cannot be excluded on the basis of our data, given the sample size. Three of the older cases showed discretely increased hearing thresholds. Analogous to the ciliopathy Bardet-Biedl syndrome, where hearing thresholds were reported to be subclinically increased in a group of adolescents patients, we recommend follow-up of JBS patients in view of the possibility of progressive, late-onset SNHL. © 2010 Elsevier Ireland Ltd