The authors present the case of a boy with congenital pseudoarthrosis of the right clavicle who met all clinical and auxologic criteria of Prader-Willi's syndrome. Poor cooperation due to mental retardation was the reason for the primary conservative treatment. During this, deformity of the middle clavicle progressed, but without development of subjective complaints and functional deficit. At his 16 years, this cosmetic defect became unacceptable for his parents and, later than it is usually recommended, resection of pseudoarthrosis with plate osteosynthesis and autologous spongioplasty was indicated. The sufficient skeletal maturation and size of both fragments allowed us to perform stable osteosynthesis with the use of a contoured reconstruction plate, without the risk of insufficient osteosynthesis or clavicle fracture after the removal of osteosynthetic material.

• MeSH
• klíční kost patologie   chirurgie   MeSH
• lidé MeSH
• Praderův-Williho syndrom komplikace   MeSH
• předškolní dítě MeSH
• pseudoartróza komplikace   vrozené   patologie   chirurgie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH

Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.

• MeSH
• dítě MeSH
• dospělí MeSH
• intracelulární signální peptidy a proteiny mozkomíšní mok   nedostatek   MeSH
• lidé MeSH
• mladiství MeSH
• neuropeptidy mozkomíšní mok   nedostatek   MeSH
• orexiny MeSH
• Praderův-Williho syndrom mozkomíšní mok   patofyziologie   MeSH
• stadia spánku fyziologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• HCRT protein, human MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• neuropeptidy MeSH
• orexiny MeSH

• MeSH
• dítě MeSH
• karyotypizace MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• Praderův-Williho syndrom genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: In contrast to most human autosomal genes which are expressed biallelically, the expression of imprinted genes depends on the parental origin of the allele. Prader-Willi syndrome is a neurobehavioral disorder in which the expression of active paternal alleles of imprinted genes from chromosomal region 15q11-q13 is abolished by deletions, maternal uniparental disomy or imprinting defects. We report an unusual case of maternal uniparental disomy of chromosome 15 due to a balanced translocation t(8;15)(q24.1;q21.2) leading to Prader-Willi syndrome in a 3-year-old girl. METHODS AND RESULTS: Cytogenetic investigation revealed a balanced translocation t(8;15)(q24.1;q21.2) in the patient and subsequently also in her unaffected mother. Fluorescence in situ hybridization analysis did not reveal any deletion of the PWS critical region, but methylation analysis of the SNRPN gene showed an abnormal methylation pattern indicating the absence of paternal chromosome 15. Microsatellite analysis of multiple loci and methylation-specific MLPA analysis confirmed maternal uniparental heterodisomy of chromosome 15 as the cause of PWS in the patient. CONCLUSIONS: This example emphasizes the importance of uniparental disomy testing in pregnancies of carriers of chromosomal aberrations with participation of chromosomes carrying imprinted genes involved in human diseases.

• MeSH
• cytogenetické vyšetření MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• lidské chromozomy, pár 15 MeSH
• lidské chromozomy, pár 8 MeSH
• metylace DNA MeSH
• mikrosatelitní repetice MeSH
• Praderův-Williho syndrom genetika   MeSH
• předškolní dítě MeSH
• translokace genetická * MeSH
• uniparentální disomie genetika   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Prader-Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11-q13, but the specific contributions of individual genes remain unknown. Most paternal PWS deletions are bracketed by recurrent breakpoints BP1 or BP2 and BP3. Atypical deletions are very rare. In the present work, we describe the molecular analysis of two patients with atypical deletions using microsatellite analysis, methylation-specific MLPA, and microarray CGH. A deletion of about 2 Mb in Patient 1 started at BP2 and ended in the middle of the typically deleted region within the UBE3A gene. The deletion in Patient 2 started 1.3 Mb distal from BP2 within the C15ORF2 gene, extended over 9.5 Mb, and ended within the AVEN gene in proximal 15q14. In Patient 1 both deletion breakpoints involved repetitive regions, which precluded cloning of the junction and pointed to non-allelic homologous recombination as a possible mechanism of this rearrangement. The breakpoints in Patient 2 were sequenced, and their structure suggested non-homologous end joining as the most likely cause of this deletion. The phenotype of both patients did not depart significantly from the typical clinical picture of PWS, although some symptoms in Patient 2 were also reminiscent of the phenotype of individuals with the recently described 15q13.3 microdeletion syndrome. Our findings support previous observations of relatively mild phenotypic effects resulting from deletions that extend distally from the PWS region and observations of the modest effects of different types of genetic defects on the spectrum and severity of symptoms in PWS.

• MeSH
• chromozomální delece * MeSH
• fenotyp MeSH
• klonování DNA MeSH
• lidé MeSH
• lidské chromozomy, pár 15 * MeSH
• metylace DNA MeSH
• mikrosatelitní repetice MeSH
• mladiství MeSH
• molekulární sekvence - údaje MeSH
• Praderův-Williho syndrom genetika   MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• zlomy chromozomů MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctive diseases with severe impairment of psychomotoric development and behaviour. Both syndromes are caused by the loss of paternal (PWS) or maternal (AS) gene expression of chromosomal region 15q11-13. The work reveals the various causes of this loss. The choice of the most suitable method for screening of the genome mutations in the patients suspected of PWS and AS is another purpose of the work. METHODS AND RESULTS: The methyl specific analysis (MS PCR) in locus SNRPN, short tandem repeat (STR) analysis and fluorescent in situ hybridization (FISH) were used. In the group of 55 patients tested for PWS and AS only maternal allele was present in 11 patients and only paternal allele was present in 1 patient in the locus SNRPN: 10 microdeletions 15q11-13, 1 UPD(15)mat and 1 UPD(15)pat. CONCLUSIONS: MS PCR seems to be the most profitable method for the first step of selection of PWS patients. In positive cases is inevitable to use also additional tests of molecular diagnosis to distinguish the particular mechanism leading to the disorders. In AS patients is also MSPCR recommended as the first step although it is necessary to exclude mutation in UBE3A gene in case of MS PCR negativity.

• MeSH
• Angelmanův syndrom genetika   MeSH
• autoantigeny MeSH
• chromozomální delece MeSH
• dítě MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• jádro snRNP - proteiny MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy, pár 15 MeSH
• metylace DNA MeSH
• mladiství MeSH
• novorozenec MeSH
• polymerázová řetězová reakce MeSH
• Praderův-Williho syndrom genetika   MeSH
• předškolní dítě MeSH
• ribonukleoproteiny malé jaderné genetika   MeSH
• tandemové repetitivní sekvence MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoantigeny MeSH
• jádro snRNP - proteiny MeSH
• ribonukleoproteiny malé jaderné MeSH
• SNRPN protein, human MeSH Prohlížeč

• MeSH
• glykogenóza komplikace   MeSH
• kojenec MeSH
• lidé MeSH
• Praderův-Williho syndrom komplikace   MeSH
• předškolní dítě MeSH
• svalová hypotonie etiologie   MeSH
• syndrom MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

OBJECTIVES: Subsequent to early life feeding issues, children with Prader-Willi syndrome (PWS) develop hyperphagia and severe obesity. Growth hormone (GH) therapy has been approved in PWS to improve growth, body composition, and BMI. We aimed to clarify the role of age at GH therapy onset on growth and BMI trajectories in children with PWS. METHODS: We analyzed height and BMI in 114 patients (58 boys) from REPAR - Czech national GH registry. From them, 69 started GH therapy prior to 2 y/o (age 0.8 ± 0.4 years; mean ± SD; early-onset group [EO]), and 45 later (age 7.1 ± 4.1 years; late-onset group [LO]). RESULTS: Height-SDS before therapy was similar in all (EO: -1.9 ± 1.2 [mean ± SD]; LO: -1.7 ± 1.1). After the first year of GH therapy, height-SDS in the EO group increased to -1.0 ± 1.2, in the LO group to -0.9 ± 1.1. After 5 years, height fully normalized in all (-0.1 ± 1.1 SDS). The LO children were already obese at treatment initiation (BMI-SDS: 2.9 ± 2.2), and their BMI-SDS decreased after 1 year of GH therapy by 0.9 (p=0.003). The weight in EO children was below average before GH treatment (BMI-SDS: -0.9 ± 1.2) and their BMI-SDS increased to the overweight range of 1.3 ± 2.2 (p<0.001) within the oncoming 3 years. Albeit BMI-SDS was around the obesity limit in most children after 5 years on GH therapy, the highest lifetime BMI-SDS was lower in EO (2.2 ± 2.6) than in LO (3.7 ± 2.2; p<0.001). CONCLUSIONS: GH treatment in PWS normalizes body height. After 5 years of GH therapy, BMI-SDS in EO and LO groups are similar; however, the EO group is exposed to lower maximal BMI-SDS values.

• Klíčová slova
• BMI, Prader–Willi syndrome, growth, growth hormone treatment, obesity,
• Publikační typ
• časopisecké články MeSH

Animal models and family studies led to the identification ofcases of rare monogenic forms of human obesity. Rare Mendelian syndromes as Prader-Willi syndrome and Bardet-Biedl syndrome represent cases of genetically determined obesity. Genome wide linkage and classical candidate gene studies were in general unsuccessful concerning the identification of genes of common obesity. On the other hand, genome-wide association studies (GWAS) were found to be effective, as also variants with only a minor effect have been detected. Seventeen polygenic variants influencing body weight regulation were clearly confirmed. It is assumed that more of these variants exist and therefore they might be identified in near future by GWAS. It is possible that the size effect of some variants can be within few grams of body weight. In order to detect variants with small effect there is a need of meta-analyses based on hundreds of thousands of individuals. Newly identified variants result in an increase of 0.06-0.33 kg/m2 of BMI per allele. In an adult of an average height of 170cm, it corresponds to 173-954 g per risk allele. It was estimated that subjects carrying 13 or more risk alleles were on average 1.46 body mass index units heavier (representing 3.7-4.7 kg) than carriers of less than three risk alleles. Further research should be focused on a gene-gene interaction. An interaction ofgene and environment should be statistically analyzed in adequate proband cohorts. If we are able to identify a large number of risk variants, the predisposition to a certain disease could be predicted. Currently a detailed family history has more predictive power.

• MeSH
• Alströmův syndrom genetika   MeSH
• Bardetův-Biedlův syndrom genetika   MeSH
• celogenomová asociační studie MeSH
• epigeneze genetická MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• obezita epidemiologie   genetika   MeSH
• Praderův-Williho syndrom genetika   MeSH
• tělesná hmotnost genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH

Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.

• Klíčová slova
• Angelman syndrome, CRISPR/Cas9, Prader-Willi syndrome, Silver-Russell syndrome, epigenome editing, genomic imprinting, rare disease, transcriptome editing, transient neonatal diabetes mellitus,
• MeSH
• Angelmanův syndrom genetika   metabolismus   MeSH
• CRISPR-Cas systémy * MeSH
• diabetes mellitus genetika   metabolismus   MeSH
• editace genu metody   MeSH
• epigeneze genetická MeSH
• epigenom účinky léků   genetika   MeSH
• genomový imprinting genetika   MeSH
• lidé MeSH
• metylace DNA MeSH
• nemoci novorozenců genetika   metabolismus   MeSH
• Praderův-Williho syndrom genetika   metabolismus   MeSH
• Silverův-Russellův syndrom genetika   metabolismus   MeSH
• vzácné nemoci genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH