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Genotype and fenotype characterization in patients with ALS and ALS-FTD in Czech and Slovak Republic
Navrátilová, Nela ; Šlachtová, Lenka (advisor) ; Šípek, Antonín (referee)
Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the degeneration of upper and lower motor neurons in the brain and spinal cord. It manifests itself with gradual muscle weakness and atrophy, and patients commonly succumb to respiratory failure within 2-4 years of disease onset. Frontotemporal dementia (FTD) is one of the three most prevalent early-onset dementias, characterized by the degeneration of frontal and temporal brain lobes leading to progressive deterioration of cognitive functions, behavior, and language abilities. These two clinical entities intersect within the ALS-FTD spectrum, histopathologically characterized by the presence of hyperphosphorylated TDP-43 and other proteinopathies. The aim of this thesis was to characterize the demographic and genetic background, phenotypic manifestations of ALS and ALS-FTD, and the potential occurrence of other neurodegenerative diseases in the family history of ALS patients. The demographic profile and analysis of phenotypic manifestations were conducted based on patient clinical records and questionnaire surveys. A total of 184 patients were examined, 146 were genetically analyzed, and 78 questionnaires were processed. Regarding the genetic background characterization, the study focused on...
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Molecular basic of disorders of sexual development in human
Kopanicová, Eliška ; Šípek, Antonín (advisor) ; Liška, František (referee)
The development of human internal and external reprodictive organs is regulated on chromosomal, gene and hormonal levels. Different types of mutations on chromosomal and gene level interrupt those pathways, which affect the further development of reproductive organs. Pathways are disrupted and couse variable developmental defects of both internal and external genital organs. The main goal of this work is to summarize these molecular processes that further affect the development of genitals in humans, possible developmental errors and their phenotypic subsequnet manifestations. Keywords: Reproductive organs, congenital anomalies, genetic disorders
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Variants of human chromosome 9 - from norm to pathology Epidemiology and significance for medical genetics.
Šípek, Antonín ; Panczak, Aleš (advisor) ; Šubrt, Ivan (referee) ; Vallová, Vladimíra (referee)
Heterochromatin variants of human chromosome 9 belong to the most common variabilities of human karyotype. The variability involves the large block of constitutive heterochromatin in the pericentric region of chromosome 9, which is composed of various types of repetitive DNA sequences. Those variants can be studied from population epidemiologic, molecular cytogenetic and clinical genetic point of view. We have performed a broad epidemiologic study of the incidence of pericentric inversion of chromosome 9 (inv(9)) and other variants of chromosome 9 in 6 different laboratory cohorts, which included the evaluation of more than 26.000 of cytogenetic reports, the study we published is currently the largest in the world. We expressed the overall incidence of inv(9) to be 1.6% and the total incidence of variants of chromosome 9 to be 3.3-3.9%. Inv(9) was more common in females, however the difference was not statistically significant. Molecular cytogenetic part of the project was based on our own diagnostic approach, which involved the combination of three different commercial FISH probes. Combination of those probes allowed us to differentiate particular subvariants of chromosome 9, which cannot be analyzed only by using G- or C-banding. Using our method, we tested 49 carriers of chromosome 9...
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Molecular basis of human congenital anomalies
Kovačičová, Denisa ; Šípek, Antonín (advisor) ; Rothová, Olga (referee)
This bachelor thesis deals with the topic of congenital anomalies. The sorting of the congenital anomalies is discussed in the first two chapters. The third chapter concerns the mutations of the short arm of chromosome 17. I have chosen to describe the Smith - Magenis syndrome, which is caused by the deletion of 17p11.2, and the Potocki - Lupski syndrome, which is its reciprocal duplication. The gene RAI1 is specified in this part. The other topic mentioned in this thesis are RASopathies. The research of this section deals with the Noonan syndrome and focuses on mutations in genes PTPN11, SOS1, RAF1, KRAS and NRAS. In the fifth chapter the issue of thalidomide, its history and the mechanisms of action discovered up to now are described. The critical period and the mechanisms of limb reduction defects related to the timing of exposure are also defined here. New methods and findings related to these topics are discussed in the end of this work. Key words: congenital anomalies, teratology, ontogenesis, Potocki - Lupski syndrome, Smith - Magenis syndrome, RASopathies, Noonan syndrome, thalidomide
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Heterochromatin variants of the human karyotype
Michalová, Michaela ; Šípek, Antonín (advisor) ; Forman, Martin (referee)
Chromosomes are cell structures consist of chromatin, out of which one kind is a constitutive heterochromatin, which contains non-coding sequences only and is transcriptionally inactive. Heterochromatin blocks consist of highly repetitive sequences of satellite DNAs, which allows the parts to be variable. The largest areas of heterochromatin can be found at long arms of chromosomes 1, 9, 16 and Y, but heterochromatin areas also affect the variability of the short arms of acrocentric chromosomes 13 - 15, 21 and 22. This bachelor thesis based on a number of scientific essays summarizes findings about heterochromatic variants, their occurrence, frequency, possibilities of examining as well as their clinical significance in today's world. It mainly highlights their possible connection with reproductive failures and contradictory results of individual observations. Contemporary results show the importance of new laboratory methods (molecularly cytogenetic), which can be used in specifying and more detailed sorting of findings, which were previously tagged as harmless variants according to less accurate banding methods. The summarization implies that emphasis should be put on the study of clinical meaning of heterochromatic variations. These can influence the progress of meiosis and thus trigger...
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Comparison of the occurrence of inversion at the 9th chromosome in infertile and sterile patients with literature dates
Šlégrová, Sandra ; Krkavcová, Miroslava (advisor) ; Šípek, Antonín (referee)
The pericentric inversion of the chromosome 9 [inv (9)] is the most common small-scale inversions in the human chromosomes. Some publications consider it as a variation of the human karyotype, which has no clinical manifestations. However there are mentioned the studies in this thesis that reports the inversion on the chromosome 9 in connection with the various pathological conditions, such as sterility, infertility, or some congenital anomalies. However, most attention is paid to the patients who were evaluated for the indication due to the failure of reproduction (sterility or infertility). The research was conducted in the accredited genetic laboratory GENvia s.r.o., where the data of the period 2004-2011 are collected. During this period a total of 5195 patients of variety indication reasons were examined. Totally 84 cases of them were found with inversion of the chromosome 9 with an incidence of 1.62 % laboratory. The indication diagnoses are divided into six created groups because of their quantity. One of them is called sterility/infertility. There were found 23 cases with inversion in the 9th chromosome in this group. It makes 27.38 % totally of the amount found in the chromosome inversions 9th. The occurrence of this inversion was also noticed in other indication groups: the congenital...
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