X-linked inheritance
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The green anole, Anolis carolinensis (ACA), is the model reptile for a vast array of biological disciplines. It was the first nonavian reptile to have its genome fully sequenced. During the genome project, the XX/XY system of sex chromosomes homologous to chicken chromosome 15 (GGA15) was revealed, and 106 X-linked genes were identified. We selected 38 genes located on eight scaffolds in ACA and having orthologs located on GGA15, then tested their linkage to ACA X chromosome by using comparative quantitative fluorescent real-time polymerase chain reaction applied to male and female genomic DNA. All tested genes appeared to be X-specific and not present on the Y chromosome. Assuming that all genes located on these scaffolds should be localized to the ACA X chromosome, we more than doubled the number of known X-linked genes in ACA, from 106 to 250. While demonstrating that the gene content of chromosome X in ACA and GGA15 is largely conserved, we nevertheless showed that numerous interchromosomal rearrangements had occurred since the splitting of the chicken and anole evolutionary lineages. The presence of many ACA X-specific genes localized to distinct contigs indicates that the ACA Y chromosome should be highly degenerated, having lost a large amount of its original gene content during evolution. The identification of novel genes linked to the X chromosome and absent on the Y chromosome in the model lizard species contributes to ongoing research as to the evolution of sex determination in reptiles and provides important information for future comparative and functional genomics.
Kazuistika popisuje případ úspěšné prenatální diagnózy skeletální dysplazie v prvním trimestru gravidityu plodu ženy, postižené X-vázanou dominantní chondrodysplasia punctata (CDPX2). První těhotenství probandky bylo ukončeno vzhledem k postižení skeletu plodu ve druhém trimestru. V následujícím těhotenství byla diagnóza X-vázané dominantní chondrodysplasia punctata uzavřena v prvním trimestru gravidity –v 13. gestačním týdnu. Diagnostický závěr byl stanoven na podkladě ultrazvukového (UZ) vyšetření a DNA analýzy mutace v genu EBP v materiálu získaném biopsií choriových klků (CVS). KLÍČOVÁ SLOVA: prenatální diagnostika, ultrazvuk, X-vázaná dominantní chondrodysplasia punctata, DNA molekulární diagnostika
Case report describes successful prenatal diagnosis of skeletal dysplasia in the first trimester of pregnancy in a female patient affected with X-linked dominat chondrodysplasia punctata (CDPX2). Her first pregnancy was terminated in the second trimester due to skeletal dysplasia of the foetus. The diagnosis in the following pregnancy was finished in the first trimester – before the end of the 13th gestational week. The diagnosis was established on the basis of ultrasonographic (US) examination and mutation analysis of the EBP gene in the material of chorionic villus sampling (CVS). Keywords: prenatal diagnosis, ultrasonograpy, X-linked dominant chondrodysplasia punctata, DNA analysis
- Klíčová slova
- DNA molekulární diagnostika,
- MeSH
- chondrodysplasia punctata * diagnóza ultrasonografie MeSH
- diagnostické techniky molekulární MeSH
- dospělí MeSH
- genetické techniky MeSH
- geny vázané na chromozom X MeSH
- indukovaný potrat MeSH
- komplikace těhotenství MeSH
- lidé MeSH
- mutace genetika MeSH
- nemoci plodu ultrasonografie MeSH
- odběr choriových klků * MeSH
- prenatální diagnóza metody MeSH
- první trimestr těhotenství MeSH
- sekvenční analýza DNA MeSH
- ultrasonografie prenatální * metody MeSH
- vývojové onemocnění kostí ultrasonografie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Cíl. Předložit zkušenosti s hodnocením "Loes score" u pacientů s X-vázanou adrenoleukodystrofií (X-ADL). Toto hodnocení určuje rozsah postižení mozkové tkáně v obrazu magnetické rezonance (MR) a je významným kritériem pro indikaci transplantace kostní dřeně. Metoda. MR bylo provedeno u 9 pacientů, u 3 opakovaně. Protokol se skládal z transverzálních řezů v T1W, T2W a FLAIR. Výsledky. Průměrné "Loes score" bylo 2,5, nejnižší bylo 0,5, nejvyšší 7. Závěr. Zavedení "Loes score" do praxe je vzhledem k novým léčebným kritériím nutné. Chtěli jsme ukázat, jakým způsobem se škála používá a poukázat na některé problémy s interpretací nálezů.
Aim. The introduction of the "Loes score" into clinical practice is needed to ensure compliance with new medical treatment criteria. Experience of "Loes Score" evaluation in patients with X-linked adrenoleukodystrophy (X-ADL) is presented. This evaluation determines the extent of brain damage in MRI and is a significant criterion for the indication of bone transplantation. Method. MR was performed on 9 patients using the following protocol: T1W, T2W and FLAIR in the transversal plane. Results. The median of the Loes score was 2.5 (between 0.5 and 7). Conclusion. The introduction of the Loes score into clinical practice is needed to ensure compliance with new medical treatment criteria. We have demonstrated how to use this score and pinpointed some of the problems associated with the interpretation of MRI findings.
- MeSH
- adrenoleukodystrofie diagnóza etiologie patofyziologie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- financování organizované MeSH
- lidé MeSH
- magnetická rezonanční tomografie využití MeSH
- metabolické nemoci mozku vrozené diagnóza etiologie genetika MeSH
- muži MeSH
- stupeň závažnosti nemoci MeSH
- transplantace kostní dřeně využití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
Patogenní varianty v genu ABCD1 jsou genetickou příčinou X‐vázané adrenoleukodystrofie (X‐ALD). X‐ALD se může manifestovat jako závažná letální adrenoleukodystrofie (ALD), mírnější adrenomyeloneuropatie (AMN) nebo adrenální insuficience (Addisonova nemoc), ale může se klinicky projevit jen jako mírná spastická paraparéza, zejména u žen přenašeček. Během několika let genetické diagnostiky dědičných spastických paraparéz (HSP) byly diagnostikovány čtyři české rodiny s patogenní variantou v genu ABCD1, kdy byl některý ze členů rodiny odeslán k vyšetření genů spojovaných s hereditární spastickou paraparézou, která byla jediným klinickým projevem nemoci, někdy dokonce u více členů rodiny. Až na základě genetické diagnostiky a po nalezení kauzální patogenní varianty v genu ABCD1 bylo možné zpětně správně stanovit diagnózu některých příslušníků rodin, neboť byli vedeni (případně i zemřeli) s diagnózou roztroušená skleróza, nemoci motoneuronu aj. Znalost kauzální patogenní varianty je velmi důležitá a na jejím základě lze pak v rodině stanovit riziko zejména pro mužské jedince, protože u nich vzhledem k X-vázané dědičnosti hrozí závažný až fatální průběh onemocnění. X‐vázaná dědičnost v rodině, mírnější klinické projevy v podobě spastické paraparézy u žen a projevy ALD, AMN nebo adrenální insuficience (Addisonova nemoc) u mužů v rodině mohou být dobrým vodítkem při podezření na tuto diagnózu. Počet takových rodin může být v ČR mnohem vyšší. Jedním z klinických projevů a biochemickým ukazatelem onemocnění jsou vysoké hladiny mastných kyselin s velmi dlouhým řetězcem (VLCFA) v krevním séru, které jsou jednoduše diagnostikovatelné. Pro genetické potvrzení diagnózy jsou k dispozici klasické i nové metody genomiky.
Pathogenic variants in the ABCD1 gene are the genetic cause of X-linked adrenoleukodystrophy (X-ALD). X-ALD can manifest as severe fatal adrenoleukodystrophy (ALD), milder adrenomyeloneuropathy (AMN), or adrenal insufficiency (Addison's disease), but it can present clinically only as mild spastic paraparesis, particularly in female carriers. During several years of genetically diagnosing hereditary spastic paraparesis (HSP), four Czech families were diagnosed with a pathogenic variant in the ABCD1 gene when one of the family members was referred for testing of genes associated with hereditary spastic paraparesis that was the only clinical manifestation of the disease, sometimes even in several family members. Only on the basis of genetic diagnosis and after identification of the causative pathogenic variant in the ABCD1 gene, it was possible to retrospectively determine the correct diagnosis of some family members, as they had been diagnosed (or died) with multiple sclerosis, motor neurone disease, and others. The knowledge of the causative pathogenic variant is very important and it is on its basis that the risk can be determined in the family, particularly for male individuals because they are at risk of severe to fatal course of the disease due to X-linked inheritance. X-linked inheritance in the family, milder clinical manifestations in the form of spastic paraparesis in women, and manifestations of ALD, AMN, or adrenal insufficiency (Addison's disease) in male family members can all be good clues to lead one to suspect this diagnosis. The number of such families may be much higher in the Czech Republic. One of the clinical manifestations and biochemical markers of the disease are high levels of very long-chain fatty acids (VLCFA) in the blood serum which are easy to diagnose. Classic as well as novel methods of genomics are available for genetic confirmation of the diagnosis.
- MeSH
- adrenoleukodystrofie * diagnostické zobrazování klasifikace patologie terapie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mastné kyseliny analýza MeSH
- spastická paraparéza * diagnóza etiologie genetika MeSH
- věkové faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
X-linked agammaglobulinemia (XLA) was one of the first inborn errors of immunity to be described. It is caused by pathogenic variants in the gene for Bruton tyrosine kinase (BTK), which has important functions in B cell development and maturation. Recurrent bacterial infections in the first two years of life and hypogammaglobulinemia with absent B cells in male patients are the most common symptoms. A four-month-old male patient underwent surgical removal of urachus persistens complicated with recurrent scar abscesses. Hypogammaglobulinemia (IgG, IgA, and IgM), low phagocytic activity, mild neutropenia, and a normal percentage of B cells were observed in the patient's immune laboratory profile. Over time, he suffered recurrent respiratory infections (otitis media and rhinosinusitis) and developed B cell depletion, but interestingly, this was with a normalisation of IgG and IgA levels along with undetectable IgM. Molecular-genetic testing confirmed the presence of the pathogenic variant c.1843C>T in the BTK gene, which is associated with a milder phenotype of XLA. Molecular-genetic testing uncovers the variability of clinical and laboratory features of apparently well-known inherited disorders. Patients with mild "leaky" XLA may have normal levels of non-functional or oligoclonal immunoglobulins.
- MeSH
- agamaglobulinemie * genetika diagnóza MeSH
- genetické nemoci vázané na chromozom X * genetika diagnóza MeSH
- genetické testování * MeSH
- kojenec MeSH
- lidé MeSH
- proteinkinasa BTK * genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
BACKGROUND: Hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction has been associated with marked exercise intolerance and poor prognosis. However, molecular pathogenesis of this phenotype remains unexplained in a large proportion of cases. METHODS AND RESULTS: We performed whole exome sequencing as an initial genetic test in a large Czech family with 3 males affected by nonobstructive hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction in end-stage disease. A novel frameshift mutation of four-and-a-half LIM domain 1 gene (FHL1) (c.599_600insT; p.F200fs32X) was detected in these individuals. The mutation does not affect transcription, splicing, and stability of FHL1 mRNA and results in production of truncated FHL1 protein, which is contrary to heart tissue homogenate not detectable in frozen tissue sections of myocardial biopsy of affected males. The identified mutation cosegregated also with abnormal ECG and with 1 case of apical hypertrophic cardiomyopathy in heterozygous females. Although skeletal muscle involvement is a common finding in FHL1-related diseases, we could exclude myopathy in all mutation carriers. CONCLUSIONS: We identified a novel FHL1 mutation causing isolated hypertrophic cardiomyopathy with X-chromosomal inheritance.
- MeSH
- dospělí MeSH
- elektrokardiografie MeSH
- elektronová mikroskopie MeSH
- genetická predispozice k nemoci genetika MeSH
- geny vázané na chromozom X genetika MeSH
- hypertrofická kardiomyopatie genetika metabolismus patofyziologie MeSH
- imunohistochemie MeSH
- intracelulární signální peptidy a proteiny genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mutace * MeSH
- myokard metabolismus patologie ultrastruktura MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proteiny s doménou LIM genetika metabolismus MeSH
- rodokmen MeSH
- senioři nad 80 let MeSH
- svalové proteiny genetika metabolismus MeSH
- zdraví rodiny MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chondrodysplasia punctata represents clinically and genetically a heterogeneous group of disorders characterized by the presence of multiple congenital anomalies and stippled epiphyses. We present clinical course of the disease and the results of metabolic, X-ray and molecular analyses in 19-months old girl with X-linked dominant chondrodysplasia punctata with intrauterine growth retardation, craniofacial dysmorphy, cataracts, cutaneous anomalies including ichthyosis, asymmetric rhizomesomelic shortness of the limbs, deformity of the spine, club foot, polydactyly, syndactyly, epiphyseal stippling and low cholesterol (2.29 mmol/l). Spectrophotometric analysis revealed the presence of abnormal pattern of cholesterol precursors in blood. The increased level of 8-dehydrocholesterol (42.2 µmol/l, controls < 1) and 7-dehydrocholesterol (25.5 µmol/l, controls < 1) recognised with GC/MS suggested an endogenous defect of cholesterol biosynthesis. The diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) was confirmed by the molecular analysis. Sequencing of the EBP gene encoding for 3ß-hydroxysteroid-?8, ?7-isomerase revealed the presence of “de novo” heterozygous mutation c.327C>T (p.Arg110Stop). High cholesterol diet normalized cholesterol level (3.28 mmol/l) but it had no influence on the unfavourable prognosis of the disease. Low level of cholesterol with abnormal sterol profile in a child with congenital development anomalies represent an important laboratory marker suggesting an inherited defect of cholesterol biosynthesis.
- MeSH
- cholesterol biosyntéza nedostatek škodlivé účinky MeSH
- chondrodysplasia punctata diagnóza etiologie MeSH
- dehydrocholesteroly izolace a purifikace škodlivé účinky MeSH
- diagnostické zobrazování metody využití MeSH
- finanční podpora výzkumu jako téma MeSH
- ichtyóza komplikace MeSH
- kojenec MeSH
- spektrofotometrie využití MeSH
- Check Tag
- kojenec MeSH
- Publikační typ
- kazuistiky MeSH
Křivice je onemocnění rostoucího organismu, které vzniká v důsledku poruchy homeostázy vápníku a fosfátů, což má za následek narušení apoptózy hypertrofických chondrocytů v růstové ploténce. Hypofosfatemie vázaná na chromosom X (X-linked hypophosphatemia, XLH) je vzácná dědičná porucha skeletu charakterizovaná nadměrnou produkcí fibroblastového růstového faktoru 23 (fibroblast growth factor 23, FGF23), což vede k renálním ztrátám fosfátů, hypofosfatemii a defektní mineralizaci kostí, která způsobuje křivici, osteomalacii, deformity skeletu, nízký vzrůst, bolest, snížený lineární růst a sníženou fyzickou funkčnost. Konvenční léčba XLH spočívá v podávání fosfátových solí a aktivního vitaminu D a může být spojena se špatnou tolerancí a vznikem komplikací. Burosumab je plně humánní monoklonální protilátka typu imunoglobulinu podtřídy 1 (IgG1) anti-FGF23, která inhibuje nadměrnou aktivitu intaktního FGF23 (iFGF23), čímž zvyšuje renální reabsorpci fosfátů, sérových koncentrací fosfátů a vede ke zlepšení známek křivice. Uvádíme kazuistiku chlapce s XLH, který byl po nedostatečně účinné konvenční terapii fosfáty a kalcitriolem převeden na léčbu burosumabem s dobrým účinkem na ústup známek křivice a zlepšení kvality života.
Rickets is a disease of the growing organism that results from a disturbance of calcium and phosphate homeostasis, which leads to impaired apoptosis of hypertrophic chondrocytes in the growth plate. X chromosome-linked hypophosphatemia (XLH) is a rare inherited skeletal disorder characterized by excessive production of fibroblast growth factor 23 (FGF23), leading to renal phosphate loss, hypophosphatemia and defective bone mineralisation, causing rickets, osteomalacia, skeletal deformities, short stature, pain, reduced linear growth and reduced physical function. Conventional treatment of XLH involves the administration of phosphate salts and active vitamin D and may be associated with poor tolerance and the development of complications. Burosumab is a fully human IgG1 anti-FGF23 monoclonal antibody that inhibits the excessive activity of intact FGF23 (iFGF23), thereby increasing renal phosphate reabsorption, increasing serum phosphate levels and improving rickets symptoms. We present a case report of a boy with XLH who was switched to treatment with burosumab after insufficiently effective conventional phosphate and caLcitrioL therapy, with a good effect on rickets remission and improved quality of life.
Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.
- Publikační typ
- časopisecké články MeSH
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