V roce 2009 se metoda masivního paralelního sekvenování (NGS) prokázala jako velmi účinný nástroj při identifikaci variant, které souvisí s mnoha neurodegenerativními nemocemi. Množství genetických dat mělo významný dopad na klinickou diagnózu a zároveň významně přispělo k objevu molekulárních mechanismů, které jsou základem těchto onemocnění. Nicméně objasnění rolí nalezených variant identifikovaných NGS, a zejména variant nejasného významu (VUS), je náročné a je zcela klíčová spolupráce genetika, neurologa a neuropatologa. Vytvoření konsenzuálních postupů a vývoj veřejných genomických/fenotypových databází jsou proto zásadní pro usnadnění sdílení a ověřování údajů. Práce poskytuje systematický přehled nejčastějších mutací u neuropatologicky diagnostikovaných pacientů s neurodegenerativním onemocněním a shrnuje techniky genetické diagnostiky a význam bioinformatiky při interpretaci výsledků neurodegenerativních onemocnění na příkladu 5 zajímavých kazuistik.

In 2009, next-generation sequencing (NGS) proved to be a very powerful tool in identifying variants associated with many neurodegenerative diseases. Whole-exome sequencing and whole-genome sequencing are effective for identifying variants in new or unexpected genes responsible for inherited diseases, while targeted sequen­cing is useful in detecting variants in previously known disease-associated genes. The wealth of genetic data provided by NGS has had a significant impact on clinical diagnoses while contributing to these discoveries of the molecular mechanisms underlying disease. However, eluciding the roles of the found variants identified by NGS, and especially the variants of unclear significance (VUS), is challenging and the cooperation of a geneticist, a neurologist and a neuropathologist is absolutely key. The establishment of consensus guidelines and the development of public genomic/phenotypic databases are therefore essential to facilitate data sharing and validation. In this review article, we will provide a systematic overview of the most frequent mutations in neuropathologically diagnosed patients with neurodegenerative diseases and summarize genetic diagnostic techniques and the importance of bioinformatics in the interpretation of neurodegenerative disease results.

• MeSH
• Alzheimerova nemoc diagnóza   genetika   patologie   MeSH
• amyotrofická laterální skleróza diagnóza   genetika   patologie   MeSH
• Creutzfeldtova-Jakobova nemoc diagnóza   genetika   patologie   MeSH
• diagnostické techniky molekulární MeSH
• frontotemporální lobární degenerace diagnóza   genetika   patologie   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetické testování metody   MeSH
• Gerstmannova-Strausslerova-Scheinkerova nemoc diagnóza   genetika   patologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci * diagnóza   genetika   patologie   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

• MeSH
• erbB receptory genetika   MeSH
• laboratoře MeSH
• lidé MeSH
• mutace MeSH
• nádory plic * diagnóza   genetika   patologie   MeSH
• nemalobuněčný karcinom plic * diagnóza   genetika   patologie   MeSH
• pandemie MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Creutzfeldt-Jakob disease (CJD), the most common human prion disorder, may occur as "pure" neurodegeneration with isolated prion deposits in the brain tissue; however, comorbid cases with different concomitant neurodegenerative diseases have been reported. This retrospective study examined correlations of clinical, neuropathological, molecular-genetic, immunological, and neuroimaging biomarkers in pure and comorbid CJD. A total of 215 patients have been diagnosed with CJD during the last ten years by the Czech National Center for Prion Disorder Surveillance. Data were collected from all patients with respect to diagnostic criteria for probable CJD, including clinical description, EEG, MRI, and CSF findings. A detailed neuropathological analysis uncovered that only 11.16% were "pure" CJD, while 62.79% had comorbid tauopathy, 20.47% had Alzheimer's disease, 3.26% had frontotemporal lobar degeneration, and 2.33% had synucleinopathy. The comorbid subgroup analysis revealed that tauopathy was linked to putaminal hyperintensity on MRIs, and AD mainly impacted the age of onset, hippocampal atrophy on MRIs, and beta-amyloid levels in the CSF. The retrospective data analysis found a surprisingly high proportion of comorbid neuropathologies; only 11% of cases were verified as "pure" CJD, i.e., lacking hallmarks of other neurodegenerations. Comorbid neuropathologies can impact disease manifestation and can complicate the clinical diagnosis of CJD.

• Publikační typ
• časopisecké články MeSH

Human prion disorders (transmissible spongiform encephalopathies, TSEs) are unique, progressive, and fatal neurodegenerative diseases caused by aggregation of misfolded prion protein in neuronal tissue. Due to the potential transmission, human TSEs are under active surveillance in a majority of countries; in the Czech Republic data are centralized at the National surveillance center (NRL) which has a clinical and a neuropathological subdivision. The aim of our article is to review current knowledge about human TSEs and summarize the experience of active surveillance of human prion diseases in the Czech Republic during the last 20 years. Possible or probable TSEs undergo a mandatory autopsy using a standardized protocol. From 2001 to 2020, 305 cases of sporadic and genetic TSEs including 8 rare cases of Gerstmann-Sträussler-Scheinker syndrome (GSS) were confirmed. Additionally, in the Czech Republic, brain samples from all corneal donors have been tested by the NRL immunology laboratory to increase the safety of corneal transplants since January 2007. All tested 6590 corneal donor brain tissue samples were negative for prion protein deposits. Moreover, the routine use of diagnostic criteria including biomarkers are robust enough, and not even the COVID-19 pandemic has negatively impacted TSEs surveillance in the Czech Republic.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal progressive degenerative disorder of motor neurons that overlaps with frontotemporal lobar degeneration (FTLD) clinically, morphologically, and genetically. Although many distinct mutations in various genes are known to cause amyotrophic lateral sclerosis, it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Many of the gene mutations are in proteins that share similar functions. They can be grouped into those associated with cell axon dynamics and those associated with cellular phagocytic machinery, namely protein aggregation and metabolism, apoptosis, and intracellular nucleic acid transport. Analysis of pathways implicated by mutant ALS genes has provided new insights into the pathogenesis of both familial forms of ALS (fALS) and sporadic forms (sALS), although, regrettably, this has not yet yielded definitive treatments. Many genes play an important role, with TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly, C9orf72 being critical genetic players in these neurological disorders. In this mini-review, we will focus on the molecular mechanisms of these two diseases.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Interactions between prion protein (PrP) and tau protein have long been discussed, especially in relation to the pathogenesis of neurodegenerative diseases. The presence of tauopathy in the genetic forms of Creutzfeldt-Jakob disease (CJD) brains is not uncommon. Molecular interactions between PrP and tau protein have been demonstrated in animal models; the role is attributed to the structural properties of misfolded isoform of the host-encoded prion protein (PrPSc) aggregates, especially amyloid, which contributes to the phosphorylation of tau protein, which is reflected in the frequent occurrence of tau pathology in inherited prion amyloidoses. The question is the relationship between PrPSc and hippocampal tau pathology without amyloid deposits (i.e. PART and ARTAG) in sporadic CJD (sCJD). The co-occurrence of these two proteinopathies in sCJD brains is quite rare. These pathological entities have been described in only a few cases of sCJD, all of them were older than 70 years. There have been speculations about the possibility of accelerating the course of pre-existing tauopathy or the possibility of accelerating the ageing process in the CJD brains. Here we present the clinical course and neuropathological findings of a patient with sCJD in whom the above mentioned tauopathies PART and ARTAG, considered to be typical for older age, were found as early as 58 years of age. According to the available information, this case represents an unusually early occurrence of age-related tauopathies not only in relation to sCJD, but also in general.

• MeSH
• Creutzfeldtova-Jakobova nemoc * genetika   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• prionová bílkovina genetika   MeSH
• priony * genetika   metabolismus   MeSH
• senioři MeSH
• tauopatie * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Příručka, která se zaměřuje na základy genetiky. Určeno praktickým lékařům.; Soubor kapitol odráží stav poznatků o dědičnosti, ke kterým genetická věda dospěla během posledního desetiletí, kdy postupně pronikla prakticky do všech klinických oborů, v nichž pevně zakotvila jako jejich nedílná součást. Převážně pochopitelně v diagnostice, neboť náš genom je, jak na úrovni člověka-jedince nebo lidské populace, tak na úrovni jeho základních součástí, tj. buněk, rozhodující pro stav zdraví a nemoci. A vedle porodníků a dětských lékařů jsou to právě všeobecní praktičtí lékaři, kteří stojí v první linii zdravotního systému, aby mohli zásadním způsobem rozhodovat o procesech, do nichž pacient vstoupí. V posledních letech se dokonce začínáme pokoušet o jeho úpravu tzv. genovou editací. A i když se zatím nestala běžnou klinickou aplikací, je pravděpodobné, že se i tento dávný sen genetického inženýrství nakonec splní a budeme moci k diagnostice připojit i terapii.

• MeSH
• genetika MeSH
• praktické lékařství MeSH
• Publikační typ
• příručky MeSH

• Konspekt
• Obecná genetika. Obecná cytogenetika. Evoluce
• NLK Obory
• genetika, lékařská genetika
• všeobecné lékařství
• NLK Publikační typ
• kolektivní monografie

Background: Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of a group of transmissible spongiform encephalopathies (prion diseases). The etiology of the sporadic form of CJD is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), e.g., is often seen in conjunction with sCJD. Method: In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis, prion disease, and Parkinson's disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau (MAPT) haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between the Apolipoprotein E gene (APOE) and PRNP in sCJD patients. Results: We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G missense variant of uncertain significance (VUS) in PSEN1 in three patients. In PRNP, we also found a previously described non-pathogenic insertion (p.P84_Q91Q). Conclusion: Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.

• Publikační typ
• časopisecké články MeSH

• MeSH
• Alzheimerova nemoc * genetika   MeSH
• genetické testování MeSH
• lidé MeSH
• neurodegenerativní nemoci * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Cíl: Cílem naší práce je posoudit prognostickou hodnotu radiologického Basilar Artery on Computed Tomography Angiography (BATMAN) skóre u akutního uzávěru arteria basilaris (AB). Soubor a metodika: Retrospektivně byl analyzován soubor pacientů s akutním uzávěrem AB léčených na iktové jednotce ÚVN v Praze v letech 2006– 2018. Uzávěr AB byl vždy verifikovan podle CTA. BATMAN skóre je 10stupňové hodnocení zahrnující lokalizaci uzávěru AB a přítomnost kolaterál. Výsledný klinický stav byl posuzován s odstupem 90 dnů podle modifikované Rankinovy škály (mRS) a hodnocen jako dobrý při mRS 0– 3. Výsledky: Soubor zahrnoval 67 pacientů (37 mužů) průměrného věku 63 (31– 82) let. Průměrné National Institutes of Health Stroke Scale (NIHSS) bylo 16; v rozmezí 2– 36. Úspěšné rekanalizace Thrombolysis in Cerebral Infarction (TICI) 2b-3 bylo dosaženo u 91 % (61/ 67) pacientů. Multivarietní regresní analýza prokázala BATMAN skóre ≤ 7 (OR 27,59; 95% CI 5,78– 131,81; p = 0,001) a vstupní NIHSS ≥ 10 (OR 9,62; 95% CI 1,47– 63,10; p = 0,0183) jako nezávislé prediktory špatného výsledného klinického stavu. Závěr: Hodnocení BATMAN skóre umožňuje predikovat špatný výsledný klinický stav u pacientů s akutním uzávěrem AB léčených mechanickou trombektomií.

Aim: We evaluated the prognostic value of a radiological Basilar Artery on Computed Tomography Angiography (BATMAN) score in patients with acute arterial basilaris occlusion (BAO). Methods: We retrospectively analyzed clinical and imaging data of consecutive endovascular therapy-treated patients with BAO in our stroke unit between 2006– 2018. The diagnosis of BAO was made on CTA. BATMAN score is a 10-point CTA-based grading system. Good outcome was defi ned as a modified Rankin Scale score of 0– 3 within 3 months. Results: We included 67 patients (37 men) with BAO treated with endovascular therapy (mechanical thrombectomy): mean age 63 years (range 31– 82 years), median National Institutes of Health Stroke Scale (NIHSS) 16; and interquartile range 2– 36. Succesful recanalization modified as Thrombolysis in Cerebral Infarction (TICI) 2b-3 was achieved in 91% (61/ 67) of patients. Multivariate logistic regres sion analysis identified BATMAN score ≤ 7 (OR 27.59; 95% CI 5.78– 131.81; P = 0.001) and initial NIHSS ≥ 10 (OR 9.62; 95% CI 1.47– 63.10; P = 0.0183) as independent predictors of poor outcome. Conclusion: The BATMAN score Demonstrated its ability to predict severe disability and death after BAO despite endovascular reperfusion therapies.

• Klíčová slova
• okluze arteria basilaris, BATMAN skóre,
• MeSH
• arteria basilaris diagnostické zobrazování   patologie   MeSH
• CT angiografie metody   MeSH
• endovaskulární výkony metody   MeSH
• kolaterální oběh * MeSH
• lidé MeSH
• retrospektivní studie MeSH
• vertebrobazilární insuficience * diagnostické zobrazování   patologie   terapie   MeSH
• Check Tag
• lidé MeSH