A5006344644- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- ATP Synthase and ATPases Research
- Cancer Genomics and Diagnostics
- BRCA gene mutations in cancer
- Genomics and Rare Diseases
- Genetic factors in colorectal cancer
- Multiple and Secondary Primary Cancers
- Cancer Risks and Factors
- Statistics Education and Methodologies
- Cardiomyopathy and Myosin Studies
- Prenatal Screening and Diagnostics
- Muscle Physiology and Disorders
- Mesenchymal stem cell research
- Connective tissue disorders research
- RNA Research and Splicing
- Religion, Society, and Development
- Neonatal Respiratory Health Research
- Ubiquitin and proteasome pathways
- Innovations in Educational Methods
- Fetal and Pediatric Neurological Disorders
- Colorectal Cancer Screening and Detection
- Metalloenzymes and iron-sulfur proteins
- African cultural and philosophical studies
National Cancer Registration Service
2022-2025
National Health Service
2024
NHS England
2023-2024
Government of the United Kingdom
2024
NHS Digital
2022-2023
Quinnipiac University
2021
Institute of Cancer Research
2021
St George’s University Hospitals NHS Foundation Trust
2021
Wellcome Centre for Mitochondrial Research
2014-2020
Newcastle University
2013-2020
Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine 235, skeletal muscle 77) represents mutation load mitochondrial DNA (mtDNA) copy number most strongly burden progression. levels are correlated in blood, (R2 0.61-0.73). Blood heteroplasmy declines by ~2.3%/year; have extended previously...
Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions brainstem basal ganglia. can result from mutations affecting many different mitochondrial proteins. French-Canadian variant COX-deficient syndrome unique to Saguenay-Lac-Saint-Jean region...
BackgroundSecond primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets.MethodsThe included 581,403 female 3562 male survivors diagnosed between 1995 2019. estimated standardized incidence ratios (SIRs) for combined site-specific SPCs...
The acetylation polymorphism may affect rates of activation or detoxification common carcinogens, thereby influencing cancer risk. Our aim was to define the ethnic distribution major slow acetylator mutations in polymorphic N-acetyltransferase gene, order provide background data for epidemiological studies. results contain new analyses on 803 individuals, including 365 specimens and 438 that had been partly characterized an earlier study. Tests were done establish specificity reproducibility...
Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease date. Mutations three them, NFU1, BOLA3, IBA57, affect assembly [4Fe-4S] proteins leading an impairment diverse metabolic pathways ATP production. Patients these present lactic acidosis, hyperglycinemia, reduced activities respiratory chain...
Titin gene (TTN) mutations have been described in eight families with hereditary myopathy early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar (MFM), arguing that TTN could be a much more common cause inherited muscle disease, especially presence involvement.We studied 127 undiagnosed clinical presentation compatible MFM. Sanger sequencing for two previously HMERF (p.C30071R 119th fibronectin-3 (FN3) domain, and p.R32450W kinase domain) was...
Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification APOPT1 mutations two Italian sisters and third Turkish individual presenting severe COX deficiency. All three subjects presented distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly posterior region cerebral hemispheres. We then found additional...
Research Article10 September 2018Open Access Source DataTransparent process OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect Kyle Thompson Wellcome Centre for Mitochondrial Research, Newcastle University, upon Tyne, UK Search more papers by this author Nicole Mai Monika Oláhová Filippo Scialó Institute Cell Molecular Biosciences, University Ageing, Luke E Formosa Department of Biochemistry Biology, Monash Biomedicine Discovery Institute,...
Mutations in the m.13094T>C MT-ND5 gene have been previously described three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at time analysis (median age death was 10 years (range: 5·4 months−37 years, IQR = 17·9 years). Nine manifested with LS, one mitochondrial encephalomyopathy, lactic acidosis stroke-like episodes (MELAS), Leber...
Abstract It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued 2017 state all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation agreed diagnostic pathway at baseline point 2 years post-publication official guidelines. Using real-world data collected and curated by...
To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for cardiac management patients with most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring m.3243A>G mutation died suddenly unexpectedly. The is present in ∼1 400 population, although recognized incidence (mtDNA) disease 5000. Pathological including histochemistry molecular genetic analyses performed on...
In England, through the Genomic Medicine Service Alliances (GMSAs), a national transformation project aims to embed robust pathways deliver universal Lynch syndrome (LS) testing for patients with colorectal and endometrial cancers. Prior commencement of project, there was evidence variation low levels in eligible which is consistent other health systems; however, we believe this amenable systematic improvement responsibility delivery by local cancer teams supported regional infrastructure. A...
To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer. We used data on diagnosed invasive cancer 1995 2019 from National Cancer Registration Dataset (NCRD) England. The were linked to Hospital Episode Statistics-Admitted Patient Care dataset identify BSO delivery. Long-term selected both datasets. Multivariable Cox regression was examine associations, modelled as time-dependent covariate....
Summary The implementation of whole genome sequencing and large somatic gene panels in haematological malignancies is identifying an increasing number individuals with either potential or confirmed germline predisposition to malignancy. There are currently no national international best practice guidelines respect management carriers such variants their at‐risk relatives. To address this gap, the UK Cancer Genetics Group (UKCGG), CanGene‐CanVar NHS England Haematological Oncology Working...
BRAF V600E mutation has been reported to show a high specificity for papillary thyroid carcinoma (PTC). Using this marker upgrade 'indeterminate' or 'suspicious' fine needle aspiration (FNA) cytology 'malignant' could potentially allow one-stage therapeutic total thyroidectomy.For 14-month period, FNA specimens in the Thy3-5 categories, which are UK equivalents of indeterminate (Thy3a, atypical; Thy3f, follicular), suspicious malignancy (Thy4) and malignant (Thy5) Bethesda System, underwent...
Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. comprises 44 structural subunits at least 10 ancillary proteins; mutations in 29 of these have so far been but there are limited genotype-phenotype correlations to guide clinicians correct genetic diagnosis.Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping affected individuals was...
<h3>Importance</h3> Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive<i>RTN4IP1</i>gene mutations have been shown to cause and syndromic optic neuropathies. <h3>Objective</h3> To define the spectrum of clinical phenotypes associated in<i>RTN4IP1</i>encoding a quinone oxidoreductase. <h3>Design, Setting, Participants</h3> This study involved 12 individuals from 11 families severe central nervous system...
A 2-year-old patient with a neuroblastoma developed haemolytic uraemic syndrome (HUS) following treatment cisplatin and carboplatin. Following eculizumab, there was substantial improvement in renal function the recovery of platelet count cessation haemolysis. Subsequent investigations showed novel, heterozygous CD46 splice site mutation reduced peripheral blood neutrophil expression. Withdrawal eculizumab followed by recurrence disease activity, which resolved re-introduction therapy....
Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients isolated myopathy owing to novel mt-tRNAAla variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically...
Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary DNA (mtDNA)-related disease despite accounting for only 5%–10% the genome.1,2 Although some common mt-tRNA mutations, such as m.3243A>G mutation, exist, majority are rare and have been reported in small number cases.3 The MT-TP gene, encoding mt-tRNAPro, is one less polymorphic genes, 5 muscle to date (table e-1 at [Neurology.org/ng][1], P6–10). We report patients with myopathic phenotypes, each...
Abstract Mitochondrial diseases collectively represent one of the most heterogeneous group metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple‐organ involvement. Advances in next‐generation sequencing strategies have greatly enhanced diagnosis patients mitochondrial disease, particularly where a aetiology is strongly suspected yet OXPHOS activities biopsied tissue samples appear normal. We used whole exome (WES) to identify molecular basis an...
Introduction Prenatal exome sequencing (pES) can enhance genetic diagnosis of fetuses with structural anomalies and has recently been introduced as a national service in England. We aimed to examine outcomes such diagnostic yield (definite final diagnosis), referral rate, sources referral, explore variation pES by individual or level factors between 01 October 2021 30 June 2022. Methods testing results from the National Health Service laboratories performing were linked Congenital Anomaly...
Background: Mitochondrial diseases due to deficiencies in the mitochondrial oxidative phosphorylation system (OXPHOS) can be associated with nuclear genes involved translation, causing heterogeneous early onset and often fatal phenotypes. Case report: The authors describe clinical features diagnostic workup of an infant who presented severe encephalopathy, spastic-dystonic tetraparesis, failure thrive, seizures persistent lactic acidemia. Brain imaging revealed thinning corpus callosum...