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Parameters of Drug Assessment in the Therapy of Rare Diseases
Ornstová, Eva ; Kostřiba, Jan (advisor) ; Klimeš, Jiří (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Social and Clinical Pharmacy Candidate Mgr. Eva Ornstová Consultant PharmDr. Jan Kostřiba, Ph.D Title of Thesis PARAMETERS OF DRUG ASSESSMENT IN THE THERAPY OF RARE DISEASES KEY WORDS: rare diseases, health technology assessment, health policy, drug policy OBJECTIVES The aim of this study was to find out how can the use of multiple criteria in Health technology assessment (HTA) influence outcome in different drug categories. Especially in relationship to orphan medicinal products. Next objective was to explore, which criteria are the most important in the value of the drug and to measure the difference in the preferences among three stakeholder groups in the Czech Republic. METHODS The set of 10 criteria was selected by the expert panel and 3 model treatments were described. Two-round questionnaire was developed and distributed among highly qualified representatives of three stakeholder groups (patients or carers, clinicians and policy makers). In the first round participants provided weights for each criterion by answering on the scale from 1 to 7. In second round participants scored model treatments according to their performance in each criterion. Normalized weights were combined with scores and treatments were...
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Genome analysis techniques and their applications in elucidation of molecular underpinnings of rare genetic diseases.
Přistoupilová, Anna ; Kmoch, Stanislav (advisor) ; Sedláček, Zdeněk (referee) ; Pačes, Jan (referee)
Rare diseases represent a heterogeneous group of more than ~7000 different diseases, affecting 3,5-5,9% of the global population. Most rare diseases are genetic, but causal genes are known only in some of them. Many patients with rare diseases remain without a diagnosis, which is crucial for genetic counseling, prevention, and treatment. With the development of new methods of genome analysis, decreasing cost of sequencing, and increasing knowledge of the human genome, a new concept for identifying disease-causing genes was established. It is based on comparing the patient's genetic variability with the genetic variability of the general population. This dissertation describes next-generation sequencing technologies (NGS), bioinformatic analysis of acquired data and their applications in the elucidation of molecular underpinnings of rare genetic diseases. These procedures have led to the identification and characterization of causal genes and gene mutations in autosomal dominant tubulointerstitial kidney disease (SEC61A1, MUC1), autosomal dominant neuronal ceroid lipofuscinosis (CLN6, DNAJC5), neurodegenerative disease of unknown etiology (VPS15), Acadian variant of Fanconi syndrome (NDUFAF6) and spinal muscular atrophy (SMN1). The application of novel genome analysis techniques increased the...
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Use of Canistherapy for Stimulation of Persons with Rare Diseases
Prokopová, Zuzana ; Hájková, Vanda (advisor) ; Šumníková, Pavlína (referee)
The aim of this thesis was to assess the influence of canistherapeutic intervention on the level of fine motor skills in patients with rare diseases, namely mitochondrial encephalocardiomyopathy caused by TMEM70 gene mutation and Leigh syndrome. Canistherapeutic intervention in these patients is based on activation of motoric functions during programme reasonably designed according to the needs of specific patients. The assistance of the dog is used to achieve this activation. The dog acts as an important motivational factor and the direct contact with it contributes to development of sensomotoric skills of these patients. The thesis summarizes general information about rare diseases and focuses on one of the subgroups of mitochondrial disorders. It presents knowledge about the Leigh syndrome and mitochondrial encephalocardiomyopathy caused by TMEM70 gene mutation. Subsequently the thesis presents information about canistherapy and fine motor skills. The thesis further contains case reports of patients, data from research units and their evaluation. The aim of the thesis was to find out whether patients with mitochondrial disease show improvement of quality and effectivity of selected grasp forms and thus faster and more precise execution assigned tasks focusing on object manipulations. Partial...
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Characterisation of rare genetic diseases using genomic techniques.
Kmochová, Tereza ; Hodaňová, Kateřina (advisor) ; Schierová, Michaela (referee)
In this thesis the importance of studying genetically determined rare diseases is described and current methods and options to determine their genetic causes are evaluated. The introduction describes the definition of rare diseases and the reasons why we study them. Currently it is known about 8,000 diseases which are caused by functionally serious mutations in one or more genes. The clinical symptoms of genetically caused rare diseases and the results of common functional and biochemical tests do not allow the exact diagnosis in most cases. The absence of the diagnosis and the causes of diseases reduces the quality of life of patients and their families. The determination of genetic causes allows accurate classification of studied cases and it is a base for qualified genetic counseling and prevention of rare diseases in the families. The next chapters describe the methods of DNA analysis (DNA sequencing using different methods), the possibilities of finding the genetic cause of a disease and show the basic approaches to the study of functional impact of the mutations. The practical use of these methods is shown in the case of two siblings with delayed psychomotoric development, special hair quality (pili torti), hearing impairment and hyperuricemic nephropathy in which the genetic analysis...
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Molecular basis of selected inherited rare diseases
Hartmannová, Hana
Rare diseases represent a clinically and genetically heterogeneous group of diseases affecting various organs and presenting at different ages. Identification and functional characterization of genetic defects causing individual rare diseases represent unique opportunity to understand biological functions of human genes and gene products as well as to basic pathogenetic mechanisms of individual diseases. This knowledge is prerequisite for their effective diagnosis, specific treatment and prevention and it also opens up an avenue for better understanding of complex diseases. My thesis documents basic conceptual and methodological developments of biochemical genetics, functional cloning, genetic mapping, positional cloning, DNA microarrays and genomic sequencing, which have provided a universal framework for effective characterization of the genetic architecture of almost all human diseases. This conceptual and technological developments are demonstrated on several cases of rare genetic diseases - adenylosuccinate lyase deficiency, mucopolysacharidosis type IIIC, Rotor syndrome, deficiency of ATP synthase, neuronal ceroid lipofuscinosis, GAPO syndrome and X -linked restrictive cardiomyopathy, which genetic and molecular basis I have helped to elucidate.
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Needs and Experience of Families with Child Suffering from Spinal Muscular Atrophy - Current Situation and Challenges for Social and Health Care System in Czech Republic
Schagererová, Iveta ; Štegmannová, Ingrid (advisor) ; Tichá, Růžena (referee)
Situation of families in which a child with spinal muscular atrophy was born, is the topic of this thesis. This rare genetic disease affects neuromuscular system of children and shortens their lives. In most severe cases the failure of respiratory functions comes in the first year of child's life. This thesis is focused on support that Czech system of social and medical services provides to families with this disease. Next, it looks into needs of these families and examine the extent to which the system is able to saturate them. Very important point in this research is also families' perception of quality of care. The research was implemented with use of qualitative methods, mostly by semi-structured interviews which followed families' journey through the system of social and medical services. Then there is a comparison of experience of families with theories, policy and other normative framework and suggestion of steps that should be taken to improve families' satisfaction with services they receive concerning the child's disease. Key words: spinal muscular atrophy, rare diseases, patient's autonomy, patient- centered care, patient journey, quality of care.
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Current methods of genome analysis and their use in identification of genetic determinants of human diseases
Stránecký, Viktor ; Kmoch, Stanislav (advisor) ; Kleibl, Zdeněk (referee) ; Pačes, Jan (referee)
The study of rare genetic diseases presents unique opportunity to uncover the genetic and molecular basis of human traits and greatly helped to the identification of genes, to the elucidation of their function and to the characterization of metabolic pathways and cellular processes. Over the past decades, linkage analysis has been appropriate approach to search for the genes causing Mendelian diseases and contributed to the identification of many genes, but the genetic cause of many diseases remains unknown. New methods of studying the human genome, microarray technology and massively parallel sequencing (next generation sequencing), represent a way to efficiently identify the cause of genetically determined diseases, based on direct observation of mutations in the genome of affected individuals. These techniques replaced the traditional method of disease gene identification represented by linkage analysis and sequencing of candidate genes and have become the standard approach to elucidate the molecular basis of diseases. In this work, i describe the the results achieved by using these methods - identification of the genes underlying mucopolysacharidosis type IIIC, isolated defect of ATP synthase, Rotor syndrome, autosomal dominat ANCL and GAPO syndrome.
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Application of novel genomic techniques in studies of pathogenesis of selected rare inherited disorders
Nosková, Lenka ; Kmoch, Stanislav (advisor) ; Sedláček, Zdeněk (referee) ; Živný, Jan (referee)
Rare diseases are a heterogeneous group of disorders. Knowledge of their molecular basis is poor and till recently there were no appropriate methodical approaches due to a limited number of patients. Novel genomic techniques, especially the DNA array technology and the next generation sequencing emerging in last few years, enabled studies of these diseases even in small families and sporadic cases. This PhD thesis focuses on application of novel genomic techniques in studies of rare inherited diseases. It describes a use of DNA array technology in linkage analysis, analysis of differential gene expression, analysis of copy number variations and homozygous mapping, and a use of next generation sequencing technology. Combination of these methods was used for identification of molecular basis of adult neuronal ceroid lipofuscinosis, Rotor syndrome, isolated defect of ATP synthase and mucopolysaccharidosis type IIIC.
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Molecular basis of selected inherited rare diseases
Hartmannová, Hana ; Kmoch, Stanislav (advisor) ; Krebsová, Alice (referee) ; Živný, Jan (referee)
Rare diseases represent a clinically and genetically heterogeneous group of diseases affecting various organs and presenting at different ages. Identification and functional characterization of genetic defects causing individual rare diseases represent unique opportunity to understand biological functions of human genes and gene products as well as to basic pathogenetic mechanisms of individual diseases. This knowledge is prerequisite for their effective diagnosis, specific treatment and prevention and it also opens up an avenue for better understanding of complex diseases. My thesis documents basic conceptual and methodological developments of biochemical genetics, functional cloning, genetic mapping, positional cloning, DNA microarrays and genomic sequencing, which have provided a universal framework for effective characterization of the genetic architecture of almost all human diseases. This conceptual and technological developments are demonstrated on several cases of rare genetic diseases - adenylosuccinate lyase deficiency, mucopolysacharidosis type IIIC, Rotor syndrome, deficiency of ATP synthase, neuronal ceroid lipofuscinosis, GAPO syndrome and X -linked restrictive cardiomyopathy, which genetic and molecular basis I have helped to elucidate.
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