Publications by authors named "Charlotte Knowles"

5 Publications

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Early impact of the coronavirus disease (COVID-19) pandemic and physical distancing measures on routine childhood vaccinations in England, January to April 2020.

Euro Surveill 2020 05;25(19)

Immunisation and Countermeasures Division, Public Health England, Colindale, United Kingdom.

Using electronic health records, we assessed the early impact of coronavirus disease (COVID-19) on routine childhood vaccination in England by 26 April 2020. Measles-mumps-rubella vaccination counts fell from February 2020, and in the 3 weeks after introduction of physical distancing measures were 19.8% lower (95% confidence interval: -20.7 to -18.9) than the same period in 2019, before improving in mid-April. A gradual decline in hexavalent vaccination counts throughout 2020 was not accentuated by physical distancing.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.19.2000848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238742PMC
May 2020

Camptocormia and shuffling gait due to a novel mutation: Diagnostic pitfalls.

Neurol Genet 2017 Jun 5;3(3):e147. Epub 2017 Apr 5.

Department of Neurology (J.R., C.K.), Department of Epileptology (W.S.K.), Life and Brain Centre (W.S.K.), and Centre for Rare Diseases Bonn (ZSEB) (C.K.), University Hospital of Bonn, Germany; Department of Neurology (D.L.), University of Halle/S., Germany; and Wellcome Trust Centre for Mitochondrial Research (D.L., S.A.H., G.F., C.V.Y.K., R.L.J., R.W.T.), Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1212/NXG.0000000000000147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384303PMC
June 2017

Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.

JAMA Neurol 2017 06;74(6):686-694

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.

Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders.

Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant.

Design, Setting, And Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015.

Main Outcome And Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants.

Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes.

Conclusions And Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.
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http://dx.doi.org/10.1001/jamaneurol.2016.4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822212PMC
June 2017

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome.

BMC Med Genet 2017 03 16;18(1):29. Epub 2017 Mar 16.

Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.

Background: Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations.

Methods: MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.

Results: We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.

Conclusion: The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.
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http://dx.doi.org/10.1186/s12881-017-0387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356238PMC
March 2017

De novo mtDNA point mutations are common and have a low recurrence risk.

J Med Genet 2017 02 22;54(2):73-83. Epub 2016 Jul 22.

Department of Clinical Genetics, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.

Background: Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations.

Methods: Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. 'De novo' based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included.

Results: In our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism.

Conclusions: De novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.
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http://dx.doi.org/10.1136/jmedgenet-2016-103876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502310PMC
February 2017