About 5-10 % of cancer diseases may be caused by genetic predisposition, in ovarian cancer it could be almost 20 % of cases. The cause is mostly a pathogenic germline mutation in tumor suppressor genes, DNA repair genes, less frequently in oncogenes. So far, we know more than 200 hereditary cancer syndromes. The most frequently tested are hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), quite frequent are also hereditary gastrointestinal polyposes. Genetic counseling and testing are routinely available for patients or their relatives. Testing methods are changing; nowadays we use next generation sequencing methods (massive parallel sequencing) with testing of panels of high-risk genes. If the mutation is discovered, we may offer the testing to relatives. Genetic testing is indicated by medical geneticist after the genetic counseling session. High-risk individuals should be followed oncology clinics or by other specialists.

• Klíčová slova
• genetic counseling, genetic testing, hereditary cancer syndromes,
• MeSH
• dědičné nádorové syndromy * diagnóza   genetika   prevence a kontrola   MeSH
• dědičné nepolypózní kolorektální nádory * diagnóza   genetika   prevence a kontrola   MeSH
• genetická predispozice k nemoci MeSH
• genetické poradenství MeSH
• genetické testování MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.

• Klíčová slova
• Lynch syndrome, Peutz-Jeghers syndrome, endometrial stromal tumors, female genital tract, hereditary breast and ovarian cancer syndrome, hereditary cancer predisposition syndromes, hereditary neoplastic syndromes, immunohistochemistry, mesenchymal uterine tumors, molecular classification, smooth muscle tumors, undifferentiated uterine sarcoma,
• MeSH
• DEAD-box RNA-helikasy MeSH
• dědičné nádorové syndromy * genetika   MeSH
• dědičné nepolypózní kolorektální nádory * genetika   MeSH
• genetická predispozice k nemoci MeSH
• leiomyomatóza * MeSH
• lidé MeSH
• nádory ledvin * MeSH
• ribonukleasa III MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• DEAD-box RNA-helikasy MeSH
• DICER1 protein, human MeSH Prohlížeč
• ribonukleasa III MeSH

Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results. ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations.

• Klíčová slova
• ATL1, HSP, SPG3A, hereditary spastic paraplegia,
• MeSH
• dítě MeSH
• exony MeSH
• introny MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• missense mutace MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA MeSH
• proteiny vázající GTP genetika   MeSH
• rodokmen MeSH
• spastická paraplegie dědičná genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ATL1 protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• proteiny vázající GTP MeSH

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

• Klíčová slova
• HPDL, HSP, autosomal recessive, hereditary spastic paraplegia, mitochondrial disorder,
• MeSH
• dánio pruhované MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• oxygenasy genetika   MeSH
• rodokmen MeSH
• spastická paraplegie dědičná genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• oxygenasy MeSH

The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case.

• Klíčová slova
• DNAJC30, LHON, Leigh syndrome, mitochondrial disease,
• MeSH
• dědičné atrofie optického nervu MeSH
• dítě MeSH
• dospělí MeSH
• Leberova atrofie zrakového nervu * genetika   MeSH
• Leighova nemoc * genetika   MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• mutace genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální DNA MeSH

In this paper the problem of Crohn's disease incidence among the nearest relatives is discussed. Within a short period of time a daughter, a son and their mother had to undergo an operation successively.

• MeSH
• Crohnova nemoc genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• chronická nemoc MeSH
• dědičná nefritida genetika   MeSH
• dítě MeSH
• dospělí MeSH
• glomerulonefritida patologie   MeSH
• hluchota genetika   MeSH
• ledviny abnormality   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• myopie genetika   MeSH
• nefritida genetika   patologie   MeSH
• pitva MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous, neurodegenerative movement disorder. A total of eight KIAA0196/strumpellin variants have thus far been associated with SPG8, a rare dominant HSP. We present a novel strumpellin alteration in a small family with clinically pure HSP. We corroborated its causality by comparing it to rare benign variants at several levels, and, along this line, also re-considered previous genetic reports on SPG8. These analyses identified significant challenges in the interpretation of strumpellin alterations, and suggested that at least two of the few families claimed to suffer from SPG8 may have been genetically misdiagnosed.

• Klíčová slova
• Hereditary spastic paraplegic, KIAA0196, Pathogenicity prediction, SPG8, Strumpellin,
• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• proteiny genetika   MeSH
• rodokmen MeSH
• spastická paraplegie dědičná diagnóza   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny MeSH
• WASHC5 protein, human MeSH Prohlížeč

PURPOSE: In this prospective observational comparative case series, we aimed to study the peripapillary capillary network with spectral-domain optical coherence tomography angiography (OCT-A) in Leber hereditary optic neuropathy (LHON). METHODS: Twelve eyes of six individuals, of these three males (five eyes) after clinical onset of visual impairment were imaged by OCT-A with scans centred on optic discs. Control group consisted of 6 eyes with no visual impairment. RESULTS: The three affected individuals lost vision 6 years (at age 22 years), 2 years and 3 months (at age 26 years) and 1 year and 2 months (at age 30 years) prior to OCT-A examination. All five affected eyes had alterations in density of the radial peripapillary microvascular network at the level of retinal nerve fibre layer, including an eye of a patient treated with idebenone that underwent almost full recovery (best corrected visual acuity 0.87). Interestingly, the other eye showed normal ocular findings 14 months after onset. Results of OCT-A examination in this eye were unfortunately inconclusive due to a delineation error. At the level of the ganglion cell layer differences could be also noted, but only in two severely affected individuals. There were no differences between unaffected mutation carriers and control eyes. CONCLUSION: Optical coherence tomography angiography scans confirmed that the peripapillary microvascular network is highly abnormal in eyes manifesting visual impairment due to LHON. These findings support the hypothesis that microangiopathy contributes to the development of vision loss in this mitochondrial disorder.

• Klíčová slova
• Leber hereditary optic neuropathy, microangiopathy, mitochondrial, optical coherence tomography angiography, peripapillary microcirculation,
• MeSH
• discus nervi optici krevní zásobení   diagnostické zobrazování   MeSH
• dítě MeSH
• dospělí MeSH
• fluoresceinová angiografie metody   MeSH
• fundus oculi MeSH
• Leberova atrofie zrakového nervu diagnóza   patofyziologie   MeSH
• lidé MeSH
• mikrocévy diagnostické zobrazování   MeSH
• mikrocirkulace fyziologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nervová vlákna patologie   MeSH
• optická koherentní tomografie metody   MeSH
• prospektivní studie MeSH
• retinální cévy diagnostické zobrazování   patofyziologie   MeSH
• retinální gangliové buňky patologie   MeSH
• zraková ostrost * MeSH
• zraková pole MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• srovnávací studie MeSH

BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center. METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine. RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05). CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.

• Klíčová slova
• Cobalamin, Hereditary optic atrophy, LHON, Leber optic atrophy, Mitochondrial disease, Vitamin B12,
• MeSH
• dítě MeSH
• dospělí MeSH
• Leberova atrofie zrakového nervu * epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• nedostatek vitaminu B12 * epidemiologie   genetika   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vitamin B 12 MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální DNA MeSH
• vitamin B 12 MeSH