POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome

Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG

Predictive factors of urinary tract infections among the oldest old in the general population. a population-based prospective follow-up study

<p>Abstract</p> <p>Background</p> <p>Urinary tract infections (UTI) are common among the oldest old and may lead to a few days of illness, delirium or even to death. We studied the incidence and predictive factors of UTI among the oldest old in the general population.</p> <p>Methods</p> <p>The Leiden 85-plus Study is a population-based prospective follow-up study of 86-year-old subjects in Leiden, The Netherlands. Information on the diagnosis of UTI was obtained annually during four years of follow-up from the medical records and interviews of treating physicians. A total of 157 men and 322 women aged 86 years participated in the study. Possible predictive factors were collected at baseline, including history of UTI between the age of 85 and 86 years, aspects of functioning (cognitive impairment (Mini-Mental State Examination (MMSE) < 19), presence of depressive symptoms (Geriatric Depression Scale (GDS) > 4), disability in activities of daily living (ADL)), and co-morbidities.</p> <p>Results</p> <p>The incidence of UTI from age 86 through 90 years was 11.2 (95% confidence interval (CI) 9.4, 13.1) per 100 person-years at risk. Multivariate analysis showed that history of UTI between the age of 85 and 86 years (hazard ratio (HR) 3.4 (95% CI 2.4, 5.0)), impaired cognitive function (HR 1.9 (95% CI 1.3, 2.9)), disability in daily living (HR 1.7 (95% CI 1.1, 2.5)) and urine incontinence (HR 1.5 (95% CI 1.0, 2.1)) were independent predictors of an increased incidence of UTI from age 86 onwards.</p> <p>Conclusions</p> <p>Within the oldest old, a history of UTI between the age of 85 and 86 years, cognitive impairment, ADL disability and urine incontinence are independent predictors of developing UTI. These predictive factors could be used to target preventive measures to the oldest old at high risk of UTI.</p

Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the <it>NF2 </it>gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient.</p> <p>Case presentation</p> <p>We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing <it>NF2</it>, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including <it>NF2 </it>and <it>MN1 </it>(meningioma 1).</p> <p>Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing <it>NF2 </it>were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed <it>MN1</it>, <it>PITPNB </it>and <it>TTC28</it>. <it>MN1</it>, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (<it>TEL</it>/<it>MN1</it>) in human myeloid leukemias. Interestingly, <it>Mn1</it>-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, <it>Mn1 </it>regulates maturation and function of calvarial osteoblasts and is an upstream regulator of <it>Tbx22</it>, a gene associated with murine and human cleft palate. This suggests that deletion of <it>MN1 </it>in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities.</p> <p>Conclusions</p> <p>Thus, our report describes a <it>NF2</it>-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of <it>MN1 </it>deletion with abnormal craniofacial development and/or cleft palate in humans.</p

Attribution: how is it relevant for loss and damage policy and practice?

Attribution has become a recurring issue in discussions about Loss and Damage (L&D). In this highly-politicised context, attribution is often associated with responsibility and blame; and linked to debates about liability and compensation. The aim of attribution science, however, is not to establish responsibility, but to further scientific understanding of causal links between elements of the Earth System and society. This research into causality could inform the management of climate-related risks through improved understanding of drivers of relevant hazards, or, more widely, vulnerability and exposure; with potential benefits regardless of political positions on L&D. Experience shows that it is nevertheless difficult to have open discussions about the science in the policy sphere. This is not only a missed opportunity, but also problematic in that it could inhibit understanding of scientific results and uncertainties, potentially leading to policy planning which does not have sufficient scientific evidence to support it. In this chapter, we first explore this dilemma for science-policy dialogue, summarising several years of research into stakeholder perspectives of attribution in the context of L&D. We then aim to provide clarity about the scientific research available, through an overview of research which might contribute evidence about the causal connections between anthropogenic climate change and losses and damages, including climate science, but also other fields which examine other drivers of hazard, exposure, and vulnerability. Finally, we explore potential applications of attribution research, suggesting that an integrated and nuanced approach has potential to inform planning to avert, minimise and address losses and damages. The key messages are In the political context of climate negotiations, questions about whether losses and damages can be attributed to anthropogenic climate change are often linked to issues of responsibility, blame, and liability. Attribution science does not aim to establish responsibility or blame, but rather to investigate drivers of change. Attribution science is advancing rapidly, and has potential to increase understanding of how climate variability and change is influencing slow onset and extreme weather events, and how this interacts with other drivers of risk, including socio-economic drivers, to influence losses and damages. Over time, some uncertainties in the science will be reduced, as the anthropogenic climate change signal becomes stronger, and understanding of climate variability and change develops. However, some uncertainties will not be eliminated. Uncertainty is common in science, and does not prevent useful applications in policy, but might determine which applications are appropriate. It is important to highlight that in attribution studies, the strength of evidence varies substantially between different kinds of slow onset and extreme weather events, and between regions. Policy-makers should not expect the later emergence of conclusive evidence about the influence of climate variability and change on specific incidences of losses and damages; and, in particular, should not expect the strength of evidence to be equal between events, and between countries. Rather than waiting for further confidence in attribution studies, there is potential to start working now to integrate science into policy and practice, to help understand and tackle drivers of losses and damages, informing prevention, recovery, rehabilitation, and transformation

Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1.

Craniofrontonasal syndrome (CFNS) is an X-linked developmental malformation, caused by mutations in the EFNB1 gene, which have only been described since 2004. A genotype-phenotype correlation seems not to be present. As it is of major importance to adequately counsel patients with EFNB1 mutations and their parents, and to improve diagnosis of new patients, more information about the phenotypic features is needed. This study included 23 patients (2 male, 21 female) with confirmed EFNB1 mutations. All patients underwent a thorough physical examination and photographs were taken. If available, radiological images were also consulted. Hypertelorism, longitudinal ridging and/or splitting of nails, a (mild) webbed neck and a clinodactyly of one or more toes were the only consistent features observed in all patients. Frequently observed phenotypic features were bifid tip of the nose (91%), columellar indentation (91%) and low implantation of breasts (90%). In comparison with anthropometric data of facial proportions, patients with CFNS had a significantly different face in multiple respects. An overview of all phenotypic features is shown. Patients with EFNB1 mutations have a clear phenotype. This study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS

Voorbij klimaat - Opties voor verbreding van klimaatpolitiek

In this study ways are explored to increase the policy coherence between the climate regime and a selected number of climate relevant policy areas, by adding a non-climate policy track to national and international climate strategies. The report assesses first the potential, synergies and trade-offs of linking the climate regime to relevant other policy areas, including poverty reduction, land-use, security of energy supply, trade and finance and air quality and health. Next the possibilities to mainstream climate in those policy areas are explored. After this the question is answered how a 'non-climate' policy track can be made part of the current adaptation and mitigation efforts within UNFCCC and its national implementation. Lastly, the question is answered how national and international policies can contribute to the implementation of the non-climate policy track. The reports concludes that the non-climate policy track offers a lot of potential to enhance the implementation of climate beneficial development pathways to decrease the vulnerability of societies for climate change and/or result in less greenhouse gas emissions.Dit onderzoek verkent wegen om de beleidscoherentie tussen het klimaatbeleid en een aantal klimaat relevante beleidsterreinen te versterken. Dit kan worden gerealiseerd door een niet-klimaat beleidsspoor toe te voegen aan nationale en internationale klimaatbeleidstrategieen. Onderzocht zijn het armoedebestrijdingsbeleid, landgebruik en landbouw, de voorzieningszekerheid van energie, handel en financiering, en luchtkwaliteit en gezondheid. Het rapport analyseert het potentieel en de mogelijkheden voor synergie en uitruil van het verbinden van klimaatbeleid met deze beleidsterreinen. Op deze manier is een overzicht gemaakt van de meest veelbelovende opties om klimaat te integreren. Vervolgens is nagegaan hoe een niet-klimaat beleidsspoor onderdeel gemaakt kan worden van het huidige adaptatie en mitigatiebeleid binnen de UNFCCC en nationaal klimaatbeleid. Tot slot is de vraag beantwoord hoe nationaal en internationaal beleid kan bijdragen aan de implementatie van het niet-klimaat beleidsspoor. Het rapport concludeert dat het niet-klimaat beleidsspoor een aanzienlijk potentieel heeft om de implementatie van klimaatveilige en klimaatvriendelijke ontwikkelingspaden te versterken, met als uiteindelijk doel de kwetsbaarheid van samenlevingen voor klimaatveranderingen te verminderen en minder broeikasgasemissies uit te stoten

Voorbij klimaat - Opties voor verbreding van klimaatpolitiek

verkrijgbaar bij/available at: WAB-secretariaat, Postbus 1, 3720 BA Bilthoven, Ottelien Steenis; [email protected] met RIVM en WAB nummerDit onderzoek verkent wegen om de beleidscoherentie tussen het klimaatbeleid en een aantal klimaat relevante beleidsterreinen te versterken. Dit kan worden gerealiseerd door een niet-klimaat beleidsspoor toe te voegen aan nationale en internationale klimaatbeleidstrategieen. Onderzocht zijn het armoedebestrijdingsbeleid, landgebruik en landbouw, de voorzieningszekerheid van energie, handel en financiering, en luchtkwaliteit en gezondheid. Het rapport analyseert het potentieel en de mogelijkheden voor synergie en uitruil van het verbinden van klimaatbeleid met deze beleidsterreinen. Op deze manier is een overzicht gemaakt van de meest veelbelovende opties om klimaat te integreren. Vervolgens is nagegaan hoe een niet-klimaat beleidsspoor onderdeel gemaakt kan worden van het huidige adaptatie en mitigatiebeleid binnen de UNFCCC en nationaal klimaatbeleid. Tot slot is de vraag beantwoord hoe nationaal en internationaal beleid kan bijdragen aan de implementatie van het niet-klimaat beleidsspoor. Het rapport concludeert dat het niet-klimaat beleidsspoor een aanzienlijk potentieel heeft om de implementatie van klimaatveilige en klimaatvriendelijke ontwikkelingspaden te versterken, met als uiteindelijk doel de kwetsbaarheid van samenlevingen voor klimaatveranderingen te verminderen en minder broeikasgasemissies uit te stoten.In this study ways are explored to increase the policy coherence between the climate regime and a selected number of climate relevant policy areas, by adding a non-climate policy track to national and international climate strategies. The report assesses first the potential, synergies and trade-offs of linking the climate regime to relevant other policy areas, including poverty reduction, land-use, security of energy supply, trade and finance and air quality and health. Next the possibilities to mainstream climate in those policy areas are explored. After this the question is answered how a 'non-climate' policy track can be made part of the current adaptation and mitigation efforts within UNFCCC and its national implementation. Lastly, the question is answered how national and international policies can contribute to the implementation of the non-climate policy track. The reports concludes that the non-climate policy track offers a lot of potential to enhance the implementation of climate beneficial development pathways to decrease the vulnerability of societies for climate change and/or result in less greenhouse gas emissions.Wetenschappelijke Assessment en Beleidsanalyse WAB Klimaatverandering = Scientic Assessment and Policy Analyses for Climate Chang