BackgroundInborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.MethodsWe ...designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.ResultsIn 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause.ConclusionNGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.
Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent ...episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non‐episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.
SYNOPSIS
This work describes the first confirmed pathogenic variant in UQCRH in two children presenting with recurrent episodes of metabolic crisis. A mouse model harbouring the equivalent variant in Uqcrh shared similar biochemical phenotypes of impaired CIII activity and abnormal OXPHOS supercomplex structures, but with more severe manifestation.
A 2.2 kb homozygous deletion of exons 2 and 3 of UQCRH (chr1:g.46,774,245‐46,776,461) was identified through WES in two cousins that presented with episodes of lactic acidosis, hyperammonaemia and impaired glucose homeostasis.
A viable mouse model carrying the equivalent two‐exon deletion in Uqcrh was generated and systematically phenotyped, displaying important characteristics of human CIII disorders.
CIII activity and assembly in both patient fibroblasts and Uqcrh−/− mice were impaired by Uqcrh/UQCRH absence. Its lack of expression, however, still allows dimerisation.
Aberrant assemblies of respiratory supercomplexes including an increase of a large supercomplex (SXL) were revealed by complexome profiling in both patient fibroblasts and Uqcrh−/− mouse tissue.
This work describes the first confirmed pathogenic variant in UQCRH in two children presenting with recurrent episodes of metabolic crisis. A mouse model harbouring the equivalent variant in Uqcrh shared similar biochemical phenotypes of impaired CIII activity and abnormal OXPHOS supercomplex structures, but with more severe manifestation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ancient Muses Jameson Jr, John H; Gibb, James G; Anderson, David G ...
2003
eBook
Known widely in Europe as interpretive narrative archaeology, the practice of using creative methods to interpret and present current knowledge of the past is gaining popularity in North America. ...This book is the first compilation of international case studies of the various artistic methods used in this new form of education—one that makes archaeology come alive for the nonprofessional. Plays, opera, visual art, stories, poetry, performance dance, music, sculpture, digital imagery—all can effectively communicate archaeological processes and cultural values to public audiences. The 23 contributors to this volume are a diverse group of archaeologists, educators, and artisans who have direct experience in schools, museums, and at archaeological sites. Citing specific examples, such as the film The English Patient , science fiction mysteries, and hypertext environments, they explain how creative imagination and the power of visual and audio media can personalize, contextualize, and demystify the research process. A 16-page color section illuminates their examples, and an accompanying CD includes relevant videos, music, web sites, and additional color images. In their Introduction, the editors invoke the ancient muses to inspire the modern presenters and interpreters of archaeological research. They aptly quote George Santayana, from his poem The Power of Art: . . . may our hands immortalize the day When life was sweet, and save from utter death The sacred past that should not pass away. John H. Jameson Jr. is an archaeologist and John E. Ehrenhard is Director at the National Park Service's Southeast Archeological Center in Tallahassee, Florida. Christine A. Finn is research associate at the Institute of Archaeology at the University of Oxford in England.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation with an incidence in the UK of more than 1:10,000. The majority of patients are ...homozygous for a missense mutation c.985A > G. Newborn screening for this condition was implemented in England and Northern Ireland in 2009 in Scotland in 2010 and in Wales in 2012. Patients with MCADD are at risk during periods of fasting stress, particularly during intercurrent infections, of developing an encephalopathy associated with hypoketotic hypoglycaemia. These episodes can be prevented by giving high calorie drinks (the emergency regimen) during periods of illness but hospital admission is required for intravenous dextrose if the emergency regimen is not tolerated. No specific treatment is required at other times. This review highlights the pathogenesis, the presentation and management of MCADD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation with an incidence in the UK of more than 1:10,000. The majority of patients ...are homozygous for a missense mutation c.985A > G. Newborn screening for this condition was implemented in England and Northern Ireland in 2009 in Scotland in 2010 and in Wales in 2012. Patients with MCADD are at risk during periods of fasting stress, particularly during intercurrent infections, of developing an encephalopathy associated with hypoketotic hypoglycaemia. These episodes can be prevented by giving high calorie drinks (the emergency regimen) during periods of illness but hospital admission is required for intravenous dextrose if the emergency regimen is not tolerated. No specific treatment is required at other times. This review highlights the pathogenesis, the presentation and management of MCADD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The rate of local recurrence of osteosarcoma after limb-sparing surgery in dogs and humans has been reported up to 28%. The primary purpose of this study was to determine whether a biodegradable ...cisplatin-containing implant (OPLA-Pt), inserted into the limb-sparing surgery site at the time of surgery, would decrease the rate of local recurrence. Secondary aims included evaluation of systemic toxicity associated with the release of cisplatin from the implant and identification of prognostic factors associated with limb-sparing surgery for osteosarcoma in dogs.
Eighty dogs with spontaneously occurring osteosarcoma were treated with limb-sparing surgery. They were randomized to receive the biodegradable implant either without cisplatin (control group) or with cisplatin (OPLA-Pt group) and were targeted to receive four doses of an adjuvant cisplatin chemotherapy protocol.
Although this was not statistically significant (P =.071), dogs in the OPLA-Pt group were 53.5% less likely to develop local recurrence than dogs in the control group. There were no significant differences in systemic toxicity between treatment arms. Incomplete surgical resection, absence of infection, and fewer than four doses of adjuvant chemotherapy had a significant correlation with local recurrence and survival according to univariate analyses, although only incomplete surgical resection remained significant for local recurrence after multivariate analysis.
Local tumor recurrence may be decreased after limb-sparing surgery by use of biodegradable implants impregnated with chemotherapeutic agents.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Out of the Blue Jameson, John H; Scott-Ireton, Della A
2007
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While there are several books in the field of preservation and heritage protection for terrestrial archaeology, there are very few resources for archaeologists working with maritime and submerged ...cultural heritage. This book brings together state-of-the-art ideas, research and scholarship associated with maritime public education and interpretation. It will add to a limited body of knowledge in a field that is steadily growing.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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