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Epilepsy: HELP
Articles by Charlotte L. Alston
Based on 6 articles published since 2010
(Why 6 articles?)
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Between 2010 and 2020, C. L. Alston wrote the following 6 articles about Epilepsy.
 
+ Citations + Abstracts
1 Article Three families with 'de novo' m.3243A > G mutation. 2016

de Laat, Paul / Janssen, Mirian C H / Alston, Charlotte L / Taylor, Robert W / Rodenburg, Richard J T / Smeitink, Jan A M. ·Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands. · Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands; Radboud University Medical Center, Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands. · Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK. ·BBA Clin · Pubmed #27331024.

ABSTRACT: The m.3243A > G mutation is the most prevalent, disease-causing mitochondrial DNA (mtDNA) mutation. In a national cohort study of 48 families harbouring the m.3243A > G mutation, we identified three families in which the mutation appeared to occur sporadically within these families. In this report we describe these three families. Based on detailed mtDNA analysis of three different tissues using two different quantitative pyrosequencing assays with sensitivity to a level of 1% mutated mtDNA, we conclude that the m.3243A > G mutation has arisen de novo in each of these families. The symptomatic carriers presented with a variety of symptoms frequently observed in patients harbouring the m.3243A > G mutation. A more severe phenotype is seen in the de novo families compared to recent cohort studies, which might be due to reporting bias. The observation that de novo m.3243A > G mutations exist is of relevance for both diagnostic investigations and genetic counselling. Firstly, even where there is no significant (maternal) family history in patients with stroke-like episodes, diabetes and deafness or other unexplained organ dysfunction, the m.3243A > G mutation should be screened as a possible cause of the disease. Second, analysis of maternally-related family members is highly recommended to provide reliable counselling for these families, given that the m.3243A > G mutation may have arisen de novo.

2 Article A novel de novo STXBP1 mutation is associated with mitochondrial complex I deficiency and late-onset juvenile-onset parkinsonism. 2015

Keogh, Michael J / Daud, D / Pyle, A / Duff, J / Griffin, H / He, L / Alston, C L / Steele, H / Taggart, S / Basu, A P / Taylor, R W / Horvath, R / Ramesh, V / Chinnery, Patrick F. ·Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. ·Neurogenetics · Pubmed #25418441.

ABSTRACT: Mutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens. A de novo mutation in STXBP1 (c.416C>T, p.(Pro139Leu)) was detected with exome sequencing together with profound impairment of complex I of the mitochondrial respiratory chain on muscle biopsy. These findings implicate a secondary impairment of mitochondrial function in the progressive nature of the disease phenotype.

3 Article The urinary proteome and metabonome differ from normal in adults with mitochondrial disease. 2015

Hall, Andrew M / Vilasi, Annalisa / Garcia-Perez, Isabel / Lapsley, Marta / Alston, Charlotte L / Pitceathly, Robert D S / McFarland, Robert / Schaefer, Andrew M / Turnbull, Doug M / Beaumont, Nick J / Hsuan, Justin J / Cutillas, Pedro R / Lindon, John C / Holmes, Elaine / Unwin, Robert J / Taylor, Robert W / Gorman, Grainne S / Rahman, Shamima / Hanna, Michael G. ·Institute of Anatomy, University of Zurich, Zurich, Switzerland. · Laboratory of Mass Spectrometry and Proteomics, Institute of Protein Biochemistry-CNR, Naples, Italy. · Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK. · South West Thames Institute for Renal Research, St Helier University Hospitals, Surrey, UK. · Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK. · Medical Research Council Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, UK. · Division of Medicine, Institute for Liver & Digestive Health, University College London, London, UK. · Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary, University of London, London, UK. · UCL Centre for Nephrology, Royal Free Hospital, London, UK. · UCL Institute of Child Health, London, UK. ·Kidney Int · Pubmed #25207879.

ABSTRACT: We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.

4 Article Distal weakness with respiratory insufficiency caused by the m.8344A > G "MERRF" mutation. 2014

Blakely, Emma L / Alston, Charlotte L / Lecky, Bryan / Chakrabarti, Biswajit / Falkous, Gavin / Turnbull, Douglass M / Taylor, Robert W / Gorman, Grainne S. ·Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK. · The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK. · Aintree Chest Centre, University Hospital Aintree, Liverpool L9 7AL, UK. · Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne NE2 2HH, UK. Electronic address: grainne.gorman@ncl.ac.uk. ·Neuromuscul Disord · Pubmed #24792523.

ABSTRACT: The m.8344A>G mutation in the mt-tRNA(Lys) gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A>G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A>G 'MERRF' mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A>G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A>G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative.

5 Article Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency. 2014

Almalki, Abdulraheem / Alston, Charlotte L / Parker, Alasdair / Simonic, Ingrid / Mehta, Sarju G / He, Langping / Reza, Mojgan / Oliveira, Jorge M A / Lightowlers, Robert N / McFarland, Robert / Taylor, Robert W / Chrzanowska-Lightowlers, Zofia M A. ·Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: abdulraheem.almalki@newcastle.ac.uk. ·Biochim Biophys Acta · Pubmed #24161539.

ABSTRACT: Mitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNA(Phe) transcript. Functional analysis of the recombinant mutant p. Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNA(Phe) as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the p.Asp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNA(Phe).

6 Article Near-identical segregation of mtDNA heteroplasmy in blood, muscle, urinary epithelium, and hair follicles in twins with optic atrophy, ptosis, and intractable epilepsy. 2013

Spyropoulos, Achilles / Manford, Mark / Horvath, Rita / Alston, Charlotte L / Yu-Wai-Man, Patrick / He, Langping / Taylor, Robert W / Chinnery, Patrick F. ·Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, England. · Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, England. · Wellcome Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle Upon Tyne, England. ·JAMA Neurol · Pubmed #24126373.

ABSTRACT: IMPORTANCE: Mitochondrial DNA (mtDNA) disorders have emerged as major causes of inherited neurologic disease. Despite being well recognized for more than 2 decades, the clinical presentation continues to broaden. The phenotypic heterogeneity is partly owing to different percentage levels of mutant mtDNA heteroplasmy in different tissues, but the factors influencing this are poorly understood. OBSERVATIONS: This case report describes monozygotic male twins with ptosis, optic atrophy, and recent-onset intractable myoclonic epilepsy. The assessment of respiratory chain enzyme activities in the muscle from 1 twin revealed a severe and isolated defect involving mitochondrial complex I. Mitochondrial DNA sequencing revealed a pathogenic m.14487T>C MTND6 mutation, which was present at very high levels of heteroplasmy in muscle (84%) and lower levels in blood (15%), urinary epithelium (75%), and buccal mucosa (58%). Of particular interest, his identical twin was found to harbor very similar levels of the m.14487T>C mutation in his blood, urine, buccal mucosa, and hair follicle DNA samples, while the presence of low levels in the mother's tissues confirmed maternal transmission. CONCLUSIONS AND RELEVANCE: It was shown that m14487T>C can also cause the unusual combination of optic atrophy, ptosis, and encephalomyopathy leading to intractable seizures. Near-identical heteroplasmy levels in different tissues in both siblings support a nuclear genetic mechanism controlling the tissue segregation of mtDNA mutations.