Lucie Schwarzová

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by a very early manifestation of a cardiovascular disease. Myocardial infarction is not an exception even in childhood. The therapy is based on high-dose statins, statins in combination with ezetimib and now also newly on PCSK9 inhibitors. Lomitapid and partly also mipomersen hold great promise for patients. LDL apheresis then represents an aggressive form of treatment. Lipoprotein lipase deficiency (type I HLP) is mainly characterized by severe hypertriglyceridemia, serum milky in colour, and xanthomatosis. A fatal complication is acute recurrent pancreatitis. A critical part of the treatment is diet, however it alone is not enough to control a genetic disorder. The only approved treatment is gene therapy. Experimentally, as an "off label" therapy, it is used in case studies with a lomitapid effect. We have our own experience with this experimental therapy. Dysbetalipoproteinemia is a congenital disorder of lipoprotein metabolism, characterized by high cholesterol (CH) and triglyceride (TG) levels. The underlying cause of this disease is the defect of the gene providing for apolipoprotein E. It is clinically manifested by xanthomatosis, however primarily by an early manifestation of atherosclerosis (rather peripheral than coronary).Key words: Lipoprotein lipase deficiency - dysbetalipoproteinemia - familial hypercholesterolemia - gene therapy - homozygous FH - LDL apheresis - lomitapid - mipomersen - PCSK9 inhibitors - rare diseases.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with almost 100 % risk of colorectal cancer. The typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by extracolonic manifestations, later onset and lower number of polyps in colon is characteristic of an attenuated form (AFAP). We analyzed the APC gene for germline mutations in 90 FAP/AFAP patients. Mutation screening was performed using Denaturing Gradient Gel Electrophoresis. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. APC-mutation-negative probands were screened for large deletions of the APC gene using multiplex ligation dependent probe amplification. Analysis of mRNA variants followed in probands with possible splicing mutation by PCR amplification of target site flanking exons and sequencing the normal and aberrant products. We identified 30 germline variants among 36 unrelated probands including large deletions. Eleven APC variants detected last two years have not been reported yet. At all, fifteen of them are expected to cause errors in mRNA splicing. Analysis of mRNA in ten of these patients revealed exon skipping in seven cases, exonisation of intron in one of these as well, change of the amount of alternatively spliced product in one case, and no effect was found in three cases. In two of the patients, the biopsy of colon mucosa and polyp enabled us to examine the effect of the mutation on splicing pattern in colon cells directly. The comparison of alternative and standard transcript amount showed similar transcription pattern of exon 14 in control colon mucosa tissue (9 samples) as in 51 blood control samples.

tI II Dichromatismus samců pěvců a da|šíaspekty pohlavního výběru Lucie Schwarzová l. Souhrn dizertační práce Ve svéprácijsem sesoustředilazejménanatestovániněkterýchpredikcíhypotéz vysvětlujícíchopožděnépřepeřovánímladýchsamců(DPM) namodelovémdruhu- rehkovi domócím(Phoenicurusochruros),SledovÁnabyladobapřílofuna hnízdiště'volikost kva|ita (mikrobiotopovésloŽení)a umístěníteritorii,agrosivitaprojovovanávůčiostafuimjedincům nahnízdištia korelacehormonr{lnihladiny(testosteronu)s barvounarůstajicihoopďení v doběpelichánipředodletemdo zimoviště. Rehkovédomáoípřilételinajihomoravskéhnízdištěbezrozdíluv dafupřllefumozi věkovýmiskupinami.Naopakv haze' kdoje počettoritoriivhodnýchprohnízděnirehhi omezsn'staršisamcipřilétrliprůměrněo ři dnydřívonežsubadulti'Vzhledernk podzimní toritorislitěstaršíohsamoůmohoumladísamcipřizpůsobitnaÓasovÁníjamlho nÁvrafu předpokládanékonkurenoiostatniohjedinců'ZjištěnItakovéhoflexibilníhorozhodování pďporuje hypoézuredukcoinvestic,v případě...

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these di...

The issue of plasma triglyceride levels relative to the risk of development of cardiovascular disease, as well as overall mortality, has been actively discussed for many years. Like other cardiovascular disease risk factors, final plasma TG values have environmental influences (primarily dietary habits, physical activity, and smoking), and a genetic predisposition. Rare mutations (mainly in the lipoprotein lipase and apolipoprotein C2) along with common polymorphisms (within apolipoprotein A5, glucokinase regulatory protein, apolipoprotein B, apolipo-protein E, cAMP responsive element binding protein 3-like 3, glycosylphosphatidylinositol-anchored HDL-binding protein 1) play an important role in determining plasma TG levels.

ABSTRACT The different arrival times of 1-year-old and older males is a widely recognised phenomenon in most migrating passerines. The converse pattern, i.e. the yearlings arriving at the breeding grounds at the same time as adults, has been reported only exceptionally. Two hypotheses have been formulated to explain the delayed arrival of yearling males: investment reduction, and energetic constraint hypotheses, respectively. However, which of these is the more appropriate to explain the phenomenon remains unclear. We studied arrival timing in two distinct urban populations of Black Redstart (Phoenicurus ochruros), a small passerine exhibiting delayed plumage maturation, whereby dull-coloured yearlings are easily distinguishable from black adults. The birds inhabiting South Moravian villages did not show differential timing of arrivals between yearlings and older birds in the resource-rich environment. On the other hand, under suboptimal conditions in Prague the yearlings were delayed by three days on average compared to the adult males. We discuss the possibility that the young birds of this species sample the situation on a potential breeding site during the autumnal singing period and flexibly adapt their migrating behaviour according to the circumstances. In such a case the investment reduction hypothesis is the best explanation for different arrival timing of yearling and adult males in Black Redstart.

Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of indiv...

Muir-Torre syndrome (MTS), a rare variant of the hereditary non polyposis colorectal cancer syndrome, is an autosomal dominant genodermatosis characterised by coincidence of sebaceous gland neoplasms (sebaceous adenoma, epithelioma, or carcinoma) and at least one internal malignancy. The underlying cause of MTS is a germline mutation in DNA mismatch repair genes MSH2, MLH1 and MSH6. We report the case of a 52-year-old caucasian woman with the development of metachronous colon cancer at the age of 38 years, uterine cancer at the age of 43 years, and unique occurrence of synchronous gastric and sebaceous carcinomas related to germline point mutation c. 2194A>T in the last exon of MLH1 gene, resulting in truncated protein in C-terminal region p. Lys732X due to premature stop codon. This mutation, not previously reported in MTS, disrupts the function of MutL complexes presumably by preventing the interaction with PMS1/PMS2 and impairing the endonuclease active site. This case points ...

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome with almost 100 % risk of colorectal cancer. The typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by extracolonic manifestations, later onset and lower number of polyps in colon is characteristic of an attenuated form (AFAP). We analyzed the APC gene for germline mutations in 90 FAP/AFAP patients. Mutation screening was performed using Denaturing Gradient Gel Electrophoresis. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. APC-mutation-negative probands were screened for large deletions of the APC gene using multiplex ligation dependent probe amplification. Analysis of mRNA variants followed in probands with possible splicing mutation by PCR amplification of target site flanking exons and sequencing the normal and aberrant products. We identified 30 germline variants among 36 unrelated probands including large deletions. Eleven APC variants detected last two years have not been reported yet. At all, fifteen of them are expected to cause errors in mRNA splicing. Analysis of mRNA in ten of these patients revealed exon skipping in seven cases, exonisation of intron in one of these as well, change of the amount of alternatively spliced product in one case, and no effect was found in three cases. In two of the patients, the biopsy of colon mucosa and polyp enabled us to examine the effect of the mutation on splicing pattern in colon cells directly. The comparison of alternative and standard transcript amount showed similar transcription pattern of exon 14 in control colon mucosa tissue (9 samples) as in 51 blood control samples.

ABSTRACT Females of many socially monogamous bird species engage in — or even actively seek — copulations outside their social pair bond. However, in socially monogamous birds with low breeding abundance, such as the Red-backed Shrike, extra-pair paternity (EPP) was thought to be an exceptional and random incident. Drawing on samples collected in an unusually dense Red-backed Shrike population in the Czech Republic, we show through DNA microsatellite typing that among 65 chicks from 15 nests, 10 individuals (26.5%) had been sired by males other than the nest-attending social mate. All 10 extra pair young were of male sex. In all cases, genetic fathers of extra pair young stemmed from neighbouring territories. Extra pair fathers had significantly longer tarsi than social mates, indicating that female choice was a function of age-class dependent male body size. Our findings support sex allocation theory, which suggests that promiscuous females mating with higher quality males should produce mostly sons.

ABSTRACT The different arrival times of 1-year-old and older males is a widely recognised phenomenon in most migrating passerines. The converse pattern, i.e. the yearlings arriving at the breeding grounds at the same time as adults, has been reported only exceptionally. Two hypotheses have been formulated to explain the delayed arrival of yearling males: investment reduction, and energetic constraint hypotheses, respectively. However, which of these is the more appropriate to explain the phenomenon remains unclear. We studied arrival timing in two distinct urban populations of Black Redstart (Phoenicurus ochruros), a small passerine exhibiting delayed plumage maturation, whereby dull-coloured yearlings are easily distinguishable from black adults. The birds inhabiting South Moravian villages did not show differential timing of arrivals between yearlings and older birds in the resource-rich environment. On the other hand, under suboptimal conditions in Prague the yearlings were delayed by three days on average compared to the adult males. We discuss the possibility that the young birds of this species sample the situation on a potential breeding site during the autumnal singing period and flexibly adapt their migrating behaviour according to the circumstances. In such a case the investment reduction hypothesis is the best explanation for different arrival timing of yearling and adult males in Black Redstart.