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109 results on '"J. A. Morgan-Hughes"'

1. Blood loss following tonsillectomy in children

Author

J. Thiagarajan, J. O. Morgan-Hughes, S. Bates, and M. Hitchcock

Subjects
Chemotherapy, medicine.medical_specialty, business.industry, medicine.medical_treatment, Incidence (epidemiology), Papaveretum, Tonsillectomy, Surgery, stomatognathic diseases, Anesthesiology and Pain Medicine, Diclofenac, El Niño, Blood loss, Anesthesia, medicine, business, Intramuscular injection, medicine.drug
Abstract

Summary One hundred and ninety-eight children, aged 3 to 12 years, who were scheduled for tonsillectomy were randomly allocated to receive either diclofenac 1.0 mg.kg−1 or papaveretum 0.2 mg.kg−1 by intramuscular injection after induction of anaesthesia. There were no significant differences between the treatment groups in operating theatre blood loss, the frequency of bleeding on the ward, or the need for operative haemostasis. However, the incidence of above average bleeding in the recovery room was significantly higher in the diclofenac group (p < 0.05). Similarly, marked restlessness in the recovery room was more frequent in the diclofenac group (p < 0.01). In both treatment groups there was an association between bleeding and restlessness during recovery so the increased bleeding in the diclofenac group may not be a direct effect.

Published
2007
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2. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS

Author

L. H. Eunson, J. A. Morgan-Hughes, Teeratorn Pulkes, Asra Siddiqui, I.P. Nelson, Nicholas W. Wood, Michael G. Hanna, and Victor Patterson

Subjects
Genetics, Mitochondrial encephalomyopathy, Mitochondrial DNA, Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, Overlap syndrome, Biology, medicine.disease, MELAS syndrome, Heteroplasmy, Neurology, Mitochondrial myopathy, Lactic acidosis, medicine, Neurology (clinical)
Abstract

We report on 4 male patients with clinical, radiological, and muscle biopsy findings typical of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. Skeletal muscle mitochondrial DNA (mtDNA) analysis showed that all patients harbored a heteroplasmic G13513A mutation in the ND5 subunit gene. One of these cases (Patient 1) presented with symptoms characteristic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode. Quantitative analysis in several postmortem tissue sections showed that the relative proportions of mutant mtDNA were generally lower than those reported with other pathogenic mtDNA mutations. Single-fiber polymerase chain reaction studies demonstrated significantly higher amounts of mutant mtDNA in ragged red fibers (RRFs) compared with non-RRFs. This study indicates that the G13513A transition is likely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more frequent cause of MELAS than previously recognized.

Published
1999
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3. Cytochrome c Oxidase Deficiency Associated with the First Stop-Codon Point Mutation in Human mtDNA

Author

I.P. Nelson, J. Land, Sjr Heales, Russell J.M. Lane, M.J. Cooper, S. Rahman, Anthony H.V. Schapira, J. A. Morgan-Hughes, Nicholas W. Wood, and Michael G. Hanna

Subjects
Adult, Mitochondrial DNA, Mitochondrial disease, Molecular Sequence Data, Cytochrome-c Oxidase Deficiency, Biology, DNA, Mitochondrial, Stop codon, Electron Transport Complex IV, Kearns–Sayre syndrome, Mitochondrial myopathy, Genetics, medicine, Humans, Point Mutation, Cytochrome c oxidase, Genetics(clinical), Amino Acid Sequence, Muscle, Skeletal, Myopathy, Genetics (clinical), Histocytochemistry, mtDNA, Point mutation, Mitochondrial Myopathies, Sequence Analysis, DNA, medicine.disease, Immunohistochemistry, Molecular biology, Heteroplasmy, Codon, Terminator, biology.protein, Female, medicine.symptom, Research Article
Abstract

Summary We have identified the first stop-codon point mutation in mtDNA to be reported in association with human disease. A 36-year-old woman experienced episodes of encephalopathy accompanied by lactic acidemia and had exercise intolerance and proximal myopathy. Histochemical analysis showed that 90% of muscle fibers exhibited decreased or absent cytochrome c oxidase (COX) activity. Biochemical studies confirmed a severe isolated reduction in COX activity. Muscle immunocytochemistry revealed a pattern suggestive of a primary mtDNA defect in the COX-deficient fibers and was consistent with either reduced stability or impaired assembly of the holoenzyme. Sequence analysis of mtDNA identified a novel heteroplasmic G→A point mutation at position 9952 in the patient's skeletal muscle, which was not detected in her leukocyte mtDNA or in that of 120 healthy controls or 60 additional patients with mitochondrial disease. This point mutation is located in the 3′ end of the gene for subunit III of COX and is predicted to result in the loss of the last 13 amino acids of the highly conserved C-terminal region of this subunit. It was not detected in mtDNA extracted from leukocytes, skeletal muscle, or myoblasts of the patient's mother or her two sons, indicating that this mutation is not maternally transmitted. Single-fiber PCR studies provided direct evidence for an association between this point mutation and COX deficiency and indicated that the proportion of mutant mtDNA required to induce COX deficiency is lower than that reported for tRNA-gene point mutations. The findings reported here represent only the second case of isolated COX deficiency to be defined at the molecular genetic level and reveal a new mutational mechanism in mitochondrial disease.

Published
1998
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4. A rapidly progressive adolescent-onset oculopharyngeal somatic syndrome with rimmed vacuoles in two siblings

Author

Alex Papadimitriou, J. A. Morgan-Hughes, Michael R. Rose, and David N. Landon

Subjects
Male, Pathology, medicine.medical_specialty, Adolescent, Somatic cell, Biopsy, Diagnostico diferencial, Muscular Dystrophies, Oculopharyngeal muscular dystrophy, Tubulofilamentous inclusions, Humans, Medicine, Age of Onset, Adolescent onset, medicine.diagnostic_test, business.industry, Muscles, Rimmed vacuoles, Syndrome, medicine.disease, Microscopy, Electron, Neurology, Oculomotor Muscles, Pharyngeal Muscles, Female, Neurology (clinical), Age of onset, business
Abstract

We describe 2 Greek siblings who developed a rapidly progressive oculopharyngeal somatic syndrome, at the ages of 11 and 14 years, with muscle biopsies showing rimmed vacuoles and, in 1 case, cytoplasmic and intranuclear tubulofilamentous inclusions 25 nm in diameter. Although a similar pattern of muscle involvement with rimmed vacuoles is described in autosomal dominant oculopharyngeal muscular dystrophy, the age of onset, the rapid progression of the symptoms, and the nature of the tubulofilaments distinguish this as a separate entity.

Published
1997
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5. Bilateral oculomotor nerve palsy due to dolichoectasia of the basilar artery

Author

J A Morgan-Hughes, G T Plant, R A Wright, and D N Landon

Subjects
Diplopia, Weakness, Muscle biopsy, genetic structures, medicine.diagnostic_test, business.industry, Anatomy, Neurological disorder, medicine.disease, Ophthalmoparesis, Ophthalmology, Nemaline myopathy, Ptosis, medicine, Neurology (clinical), medicine.symptom, Oculomotor nerve palsy, business
Abstract

Ophthalmoparesis and ptosis are extremely rare in nemaline myopathy. A 45-year-old man with a long history of bilateral ptosis and a 1-year history of diplopia is reported. Leg and arm weakness and wasting had been present since childhood, with a very slow deterioration over time. On examination, there was nonfatigueable bilateral ptosis that was more marked on the right. There was diplopia on left gaze. Extraocular movements showed limitation of elevation and adduction of the right eye. There was bilateral facial weakness, as well as proximal and distal wasting and weakness in the arms and legs. Electromyography (EMG) showed a combination of myopathic and neurogenic changes. Triceps muscle biopsy showed small multiple collections of rod-like structures in > 50% of fibers. This patient presented with a clinical picture that did not primarily suggest nemaline myopathy. This case illustrates the heterogeneity of this disorder and the need for muscle biopsy to make an accurate diagnosis in patients with ptosis and progressive external ophthalmoparesis.

Published
1997
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6. Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological features

Author

M. Brockington, B.R.F Lecky, A. E. Harding, J. A. Morgan-Hughes, R.S Howard, and R.M Chalmers

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Mitochondrial DNA, Biology, DNA, Mitochondrial, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Retinitis pigmentosa, medicine, Humans, Aged, Family Health, Nerve biopsy, medicine.diagnostic_test, Parkinsonism, Multiple mitochondrial DNA deletions, Middle Aged, medicine.disease, Pedigree, Micrographia, Blotting, Southern, Peripheral neuropathy, nervous system, Neurology, Female, Neurology (clinical), medicine.symptom, Gene Deletion
Abstract

A mitochondrial myopathy associated with multiple deletions of mitochondrial DNA has been identified in pedigrees showing an autosomal dominant mode of inheritance. We report the first two British kindreds with this disorder, and two sporadic cases. The families exhibited some unusual clinical features, including pigmentary retinopathy and tremor; the latter was levodopa-responsive and associated with rigidity and micrographia in one family. Members of one pedigree and both sporadic patients had a peripheral neuropathy and nerve biopsy showed marked axonal degeneration. Post-mortem examination of one patient without parkinsonism showed severe neuronal loss in the substantia nigra.

Published
1996
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7. Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype

Author

JM Cooper, Hammans, Anthony H.V. Schapira, J. A. Morgan-Hughes, John B. Clark, Mary G. Sweeney, A. E. Harding, and M. Brockington

Subjects
Adult, Male, Mitochondrial DNA, Ataxia, RNA, Transfer, Leu, Adolescent, Genotype, Biopsy, Respiratory chain, Biology, Mitochondrion, MELAS syndrome, DNA, Mitochondrial, Electron Transport Complex IV, 03 medical and health sciences, Electron Transport Complex III, 0302 clinical medicine, Mitochondrial Encephalomyopathies, MELAS phenotype, medicine, MELAS Syndrome, NAD(P)H Dehydrogenase (Quinone), Humans, Point Mutation, Age of Onset, Child, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Genetics, 0303 health sciences, Middle Aged, medicine.disease, Cytochrome b Group, Heteroplasmy, 3. Good health, mtDNA disease, Phenotype, Molecular Medicine, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.

Published
1995
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8. The mitochondrial DNA transfer RNA Leu(UUR) A→G(3243) mutation: A clinical and genetic study

Author

Simon Hammans, J. A. Morgan-Hughes, Mary G. Sweeney, Michael G. Hanna, Martin Brockington, and A. E. Harding

Subjects
Adult, Male, Mitochondrial DNA, RNA, Transfer, Leu, DNA Mutational Analysis, Cytochrome-c Oxidase Deficiency, Biology, MELAS syndrome, DNA, Mitochondrial, Electron Transport Complex IV, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, medicine, Humans, Point Mutation, Genetic Testing, Age of Onset, Child, Codon, Muscle, Skeletal, Myopathy, Aged, Neurologic Examination, Genetics, Point mutation, MERRF syndrome, Middle Aged, medicine.disease, Pedigree, Phenotype, Female, Neurology (clinical), medicine.symptom, Chronic progressive external ophthalmoplegia
Abstract

The mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.

Published
1995
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9. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author

H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. Chavdarov, J. P. Willmer, C. H. Hawkes, Th. Naegele, E. Ellie, E. Dartigues, M. J. Guardiola, S. Hesse, Z. Levic, Marco Rovaris, P. Saugeir-Veber, B. A. Yaqub, H. F. Durwen, R. Larumbe, J. Ballabrina, M. Sendtner, J. Röther, M. Horstink, C. Kluglein, M.P. Montesi, H. Apaydin, J. Montoya, E. Waubant, Ch. Verellen-Dunoulin, A. Nicolai, J. Lopez-Delval, R. Lemon, G. Cantinho, E. Granieri, A. Zeviani, Wolfgang H. Oertel, U. Ficola, V. Di Piero, V. Fragola, K. Sabev, M. V. Guitera, I. Turki, F. Bolgert, P. Ingrand, J. M. Gobernado, L. M. E. Grimaldi, S. Baybas, B. Eymard, Y. Rolland, Y. Robitaille, Ta. Pampols, P. J. Koehler, A. Carroacedo, J. Vilchez, S. Di Vittorio, I. R. Rise, T. Nagy, M. Kuffner, E. Palazzini, A. Ott, J. Pruim, T. X. Arbizu, E. Manetti, C. Cervera, S. Felber, G. Gursoy, J. Scholz, G. A. Buscaino, M. S. Chen, A. Pascual, J. Hazan, J. U. Gajda, J. G. Cea, G. Bottini, G. Damalik, F. Le Doze, G. Bonaldi, J. M. Hew, C. Messina, A. M. Kennedy, J. M. Carney, N. M. F. Murray, M. Parent, M. Koepp, V. Dimova, D. De Leo, K. Jellinger, G. Salemi, S. Mientus, M. L. Hansen, F. Mazzucchelli, J. Vieth, M. Mauri, E. Bartels, L. Johannsen, C. Humphreys, J. Emile, D. N. Landon, E. Kansu, R. Sanchez-Pernaute, Rsj Frackowiak, M. Gonzalez Torres, L. Oller, C. Machedo, J. Kother, M. Billiard, H. Durak, T. Schindler, A. Frank, A. Uncini, A. Sbriccoli, C. Farinas, D. W. Paty, N. Fast, A. T. Zangaladze, A. Kerkhofs, J. M. Pino Garcia, I. De la Fuente, B. Marini, L. Gomez, I. Rubio, Alessandra Bardoni, C. Brodie, P. Acin, U. Sliwka, S. A. Hawkins, S. Tardieu, F. Vitullo, J. M. Pereira Monteino, R. Gagliardi, T. Jezewski, A. Cano, T. Lempert, F. Abad Alegria, G. Rotondo, D. Ince, C. Martinez Parra, Y. Huang, H. Luders, Y. Steinvil, F. G. A. Van Der Meche, R. Bianchi, A. Sanchez, T. Sevilla, J. M. Ketelslegers, A. Domzal-Stryga, M. Pandolfo, M. O. Josse, K. W. Neff, I. Blanco, G. W. Bruyn, O. W. Witte, J. L. Thibault, G. Andersen, J. Pariset, A. Marcone, R. J. M. Lane, A. Hofman, M. Verin, T. Matilla, P. Bedoucha, J. Roche, M. Lai, M. Collard, A. Ugarte, F. Gallecho, D. Silbersweig, C. Kennard, J. P. Azulay, T. W. Ho, P. L. I. Dellemijn, R. Girardello, F. Baas, B. Voss, F. Rozenberg, E. M. Brocker, V. Stanev, A. A. J. Soeterboek, A. Marra, A. Rey, E. Ertem, M. Sawradewicz-Rybak, J. De Keyser, P. Cavallari, F. Proust, Y. Chevalier, H. C. Hansen, D. Leys, C. A. Davie, K. Hoang-Xuan, C. Bairati, H. van Crevel, Thomas T. Warner, B. Bompais, A. Dobbeleir, T Campbell, C. Macko, C. J. M. Klijn, M. Dussallant, T. P. Berlit, W. Rozenbaum, M. J. van den Bent, W. A. Rocca, M. Muller, H. Hundemer, U. Zifko, M. Campera, F. Drislane, D. Ranoux, T. M. Kloss, Anil Kumar, I. Ruolt, C. Bargnani, B. Marescau, N. A. Losseff, S. Notermans, B. Kint, E. T. Burke, C. Aykut, J. Matias Guiu, P. Maquet, T. Drogendijk, M. Leone, K. von Ammon, M. Pepeliarska, C. Prados, L. DiGiamberardino, T. Logtenberg, G. Lenoir, I. Castaldo, Damhaut, M. Radionova, G. Sirabian, R. Navon, Giovanni Antonini, K. Al Moutaery, E. Chamas, R. Schönhuber, M. Giannini, B. Debilly, I. Labatut, H. Henon, J. A. Egido, M. Baudrimont, J. N. Lorenzo, J. E. C. Bromberg, R. Antonacci, J. J. Vilchez, T. Moulin, B. Rautenstrauss, Giovanni Meola, J. Noth, S Mammi, P. Laforet, F. Lopez, C. Gehring, S. Bort, G. Rancurel, D. Decamps, S. Kostadinova, Y. Shapira, B. Neundoerfer, D. Chavrot, M. Solimena, J. P. Salier, W. Deberdt, R. Hoff-Jörgensen, A. Messina, S. Meairs, G. Rosoklija, E. Nelis, I. Bertran, C. Ertekin, J. Lohmeyer, Mitermayer Galvao dos Reis, L. Calo, E. Maccagnano, A. P. Hays, J. Verlooy, M. G. Forno, T. Blanco, L. Bail, Gabriella Silvestri, J. Montero, F. Bertrand, R. T. Ghnassia, C. Besses, T. Sereghy, F. Shalit, G. Bogliun, S. Braghi, St. Baykouchev, C. Franke, A. Lasa, L. C. Archard, J. Kriebel, S. Shaunak, M. Nocito, Alexander Tsiskaridze, E. Manfredini, T. Seigal, David G. Gadian, M. Barlas, J. D. Degos, C. Seeber, J. Caemert, J. L. Mas, R. B. Pepinsky, M. G. D'Angelo, N. Baumann, S. Yorifuji, H. P. Endtz, M. A. Cassatella, R. A. C. Hughes, V. Golzi, A. Bittencourt, A. Ferreira, M. Sanson, C. Alper, M. Vermeulen, M. A. A. van Walderveen, E. Alexiou, C. H. Lucas, M. Fiorelli, Y. N. Debbink, R. Gil, S. Congia, T. Banerjee, J. M. Bouchard, A. N. Pinto, A. Ceballos-Baumann, G. Grollier, P. I. M. Schmitz, M. D. Catata, N. Lahat, N. S. Rao, P. Papathanasopoulos, J. Valls-Solé, D. Claus, G. Schroter, A. Castro, C. Videbaek, R. Martinez Dreke, A. D. Platts, M. Hermesl, A. C. PeÇanha-Martins, M. Cardoso Silva, P. Masnou, M. J. A. Tanner, Ch. Confavreux, B. Mishu, H. Rasmussen, L. Valenciano, Carlo Pozzilli, S. W. Li, V. Salzman, Y. Vashtang, Massimo Franceschi, M. Severo, G. Deuschl, S. Setien, G. Mariani, A. Protti, J. Castillo, M. J. B. Taphoorn, M. Frontali, I. Milonas, D. Decoq, J. A. Navarro, S. Castellvi-Pel, C. Ertikin, M. Urtasun, Y. Lajat, B. E. Kendall, E. Verdu, B. Gueguen, E. Boisen, R. Couderc, A Danek, JM Stevens, F. Nicoli, L. 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Brizioli, J. Calleja, L. Publio, M. Desi, R. Soffietti, P. Cortinovis-Tourniaire, E. F. Gonano, G. Cavaletti, S. Uselli, K. Westerlind, H. Betuel, C. O. Dhiver, H. Guggenheim, M. Hamon, R. Fazio, P. Lehikoinen, A. Esser, B. Sadzot, G. Fink, Angelo Antonini, D. Bendahan, V. Di Carlo, G. Galardi, A. F. Boller, M. Aksenova, Del Fiore, V. de la Sayette, H. Chabriat, A. Nicoletti, A. Dilouya, M. L. Harpin, E. Rouillet, J. Stam, A. Wolters, M. R. Delgado, Eduardo Tolosa, G. Said, A. J. Lees, L. Rinaldi, A. Schulze-Bonhage, MA Ron, C. Lefebvre, E. W. Radü, R. Alvarez, M. L. Bots, P. Reganati, S. Palazzi, A. Poggi, N. J. Scolding, V. Sazdovitch, T. Moreau, E. Maes, M. A. Estelies, P. Petkova, Jose-Felix Marti-Masso, G De La Meilleure, N. Mullatti, M. Rodegher, N. C. Notermans, T. A. T. Warner, S. Aktan, J. P. Louboutin, L. Volpe, C. Scheidt, W. Aust, C. M. Wiles, U. Schneider, S. K. Braekken, W. R. Willems, K. Usuku, Peter M. Rothwell, C. Talamon, M. L. Sacchetti, A. Codina, M. H. Marion, A. Santoro, J. Roda, A. Bordoni, D. J. Taylor, S. Ertas, H. H. Emmen, J. Vichez, V. BesanÇon, R. E. Passingham, M. L. Malosio, A. Vérier, M. Bamberg, A. W. Hansen, E. Mostacero, G. Gaudriault, Marie Vidailhet, B. Birebent, K. Strijckmans, F. Giannini, T. Kammer, I. Araujo, J. Nowicki, E. Nikolov, A. Hutzelmann, R. Gherardi, J. Verroust, L. Austoni, A. Scheller, A. Vazquez, S. Matheron, H. Holthausen, J. M. Gerard, M. Bataillard, S. Dethy, V. H. Patterson, V. Ivanez, N. P. Hirsch, F. Ozer, M. Sutter, C. Jacomet, M. Mora, Bruno Colombo, A. Sarropoulos, T. H. Papapetropoulos, M. Schwarz, D. S. Dinner, N. Acarin, B. Iandolo, J. O. Riis, P. R. J. Barnes, F. Taroni, J. Kazenwadel, L. Torre, A. Lugaresi, I. L. Henriques, S. Pauli, S. Alfonso, Pedro Quesada, A. S. T. Planting, J. M. Castilla, Thomas Gasser, M. Van der Linden, A. Alfaro, E. Nobile-Orazio, G. Popova, W. Vaalburg, F. G. A. van der Mech, L. Williams, F. Medina, J. P. Vernant, J. Yaouanq, B. Storch-Hagenlocher, A. Potemkowski, R. Riva, M. H. Mahagne, M. Ozturk, Ve. Drory, N. Konic, C. Jungreis, A. Pou Serradell, J. L. Gauvrit, G. J. Chelune, S. Hermandez, T. Dingus, L. Hewer, Ch. Koch, M. N. Metz-Lutz, G. Parlato, M. Sinaki, Charles Pierrot-Deseilligny, H. C. Diener, J. Broeckx, J. Weill-Fulazza, M. L. Villar, M. Rizzo, O. Ganslandt, C. Duran, N. A. Fletcher, G. Di Giovacchino, Susan T. Iannaccone, C. Kolig, N. Fabre, H. A. Crockard, Rita Bella, M. Tazir, E. Papagiannuli, K. Overgaard, Emma Ciafaloni, I. Lorenzetti, F. Viader, P. A. H. Millac, I. Montiel, L. H. Visser, M. Palomar, P. L. Murgia, H. Pedersen, Rafael Blesa, S. Seddigh, W. O. Renier, I. Lemahieu, H. M. L. Jansen, L. Rosin, J. Galofre, K. Mattos, M. Pondal, G. M. Hadjigeorgiou, D. Francis, L. Cantin, D. Stegeman, M. Rango, A. B. M. F. Karim, S. Schraff, B. Castellotti, I. Iriarte, E. Laborde, T. J. Tjan, R. Mutani, D. Toni, B. Bergaasco, J. G. Young, C. Klotzsch, A. Zincone, X. Ducrocq, M. Uchuya, O. J. Kolar, A. Quattrone, T. Bauermann, Nereo Bresolin, J. Vallée, B. C. Jacobs, A. Campos, Werner Poewe, J. A. Villanueva, A. W. Kornhuber, A. Malafosse, E. Diez-Tejedor, G. Jungreia, M. J. A. Puchner, A. Komiyama, O. Saribas, V. Volpini, L. Geremia, S. Bressi, A. Nibbio, Timothy E. Bates, T. z. Tzonev, E. Ideman, G. A. Damlacik, G. Martino, G. Crepaldi, T. Martino, Kjell Någren, E. Idiman, D. Samuel, J. M. Perez Trullen, Y. van der Graaf, J. O. Thorell, M. J. M. Dupuis, E. Sieber, R. D'Alessandro, C. Cazzaniga, J. Faiss, A. Tanguy, A. Schick, I. Hoksergen, A. Cardozo, R. Shakarishvili, G. K. Wennlng, J. L. Marti-Vilalta, J. Weissenbach, I. L. Simone, Amalia C. Bruni, Darius J. Adams, C. Weiller, A. Pietrangeli, F. Croria, C. Vigo-Pelfrey, Patricia Limousin, A. Ducros, G. Conti, O. Lindvall, E. Richter, M. Zuffi, A. Nappo, T. Riise, J. Wijdenes, M. J. Fernandez, J. Rosell, P. Vermersh, S. Servidei, M. S. C. Verdugo, F. Gouttiere, W. Solbach, M. Malbezin, I. S. Watanabe, A. Tumac, W. I. McDonald, D. A. Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg

Subjects
Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published
1994
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10. Mitochondrial DNA mutation underlying Leigh's syndrome: Clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy

Author

B.D. Youl, JM Cooper, A. E. Harding, S.R. Hammans, Anthony H.V. Schapira, J.M. Jacobs, J. A. Morgan-Hughes, Mary G. Sweeney, Colin R. Kennedy, and L.W. Duchen

Subjects
Male, Mitochondrial DNA, Pathology, medicine.medical_specialty, Ataxia, Adolescent, Molecular Sequence Data, Respiratory chain, Epilepsies, Myoclonic, Progressive myoclonus epilepsy, Biology, DNA, Mitochondrial, Degenerative disease, medicine, Humans, Leigh disease, Muscle biopsy, Base Sequence, medicine.diagnostic_test, Brain, medicine.disease, Magnetic Resonance Imaging, Neurology, Mutation, Myoclonic epilepsy, Neurology (clinical), Leigh Disease, medicine.symptom
Abstract

An 18-year-old male patient presented with clinical and radiological evidence of Leigh's syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy. Biochemical studies showed reduced activity of complexes I and IV of the respiratory chain in mitochondria from heart, liver and kidney. The mutation of mitochondrial DNA (mtDNA) at position 8344, commonly associated with the syndrome of myoclonic epilepsy and ragged red fibres, was detected in the patient's blood and was present in muscle, brain, liver, heart, and kidney in uniformly high amounts. It is clear that LS is genetically heterogeneous and represents one of the most severe phenotypes of a number of different mtDNA defects.

Published
1994
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11. A tandem duplication in the D–loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies

Author

J. A. Morgan-Hughes, Hammans, Martin Brockington, A. E. Harding, and Mary G. Sweeney

Subjects
Genetics, Mitochondrial DNA, Base Sequence, Muscles, Molecular Sequence Data, Mitochondrial Myopathies, Kearns-Sayre Syndrome, Biology, medicine.disease, DNA, Mitochondrial, Molecular biology, Human mitochondrial genetics, Heteroplasmy, D-loop, Mitochondrial myopathy, Transcription (biology), Multigene Family, Gene duplication, medicine, Humans, Female, Tandem exon duplication, Aged, Sequence Deletion
Abstract

About 40 per cent of patients with mitochondrial myopathies have two populations of mitochondrial DNA (mtDNA) in muscle, one of which is deleted. All patients with single mtDNA deletions and neurological disease are sporadic cases, suggesting that deletions arise as fresh mutational events. We have detected a low abundance heteroplasmic tandem duplication involving the displacement loop of mtDNA in 18 of 58 patients with deletions and 5/5 of their mothers, but not in normal subjects. The location of the duplication to a region that controls both replication and transcription of mtDNA could explain features suggesting mild mitochondrial dysfunction in the muscle biopsies of three patients' mothers, and a predisposition to deletion.

Published
1993
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12. The mitochondrial DNA transfer RNALysA→G[8344] mutation and the syndrome of myoclonic epilepsy with ragged red fibres [MERRF]

Author

C. R. Kennedy, G. G. Lennox, Martin Brockington, Mary G. Sweeney, A. E. Harding, Simon Hammans, J. A. Morgan-Hughes, and N. F. Lawton

Subjects
Adult, Male, Mitochondrial DNA, Ataxia, Molecular Sequence Data, Biology, DNA, Mitochondrial, Mitochondrial myopathy, Genotype, medicine, Humans, Amino Acid Sequence, Leigh disease, Child, Aged, Genetics, Muscles, MERRF syndrome, Middle Aged, medicine.disease, MERRF Syndrome, Pedigree, Phenotype, Mutation, RNA, Transfer, Lys, Myoclonic epilepsy, Female, Neurology (clinical), medicine.symptom, Myoclonus
Abstract

The mitochondrial DNA (mtDNA) transfer RNA (tRNA)Lys A-->G(8344) mutation was identified in seven patients. These patients and their relatives were assessed clinically; in one family the mutation was deduced to be present in four generations. The phenotype in index cases was consistent with the syndrome of myoclonic epilepsy with ragged red fibres, with the core clinical features of myoclonus, ataxia and seizures. Amongst other features, progressive external ophthalmoplegia, Leigh's syndrome and stroke-like episodes were observed, well recognized in mitochondrial myopathies but novel manifestations of this genotype. Samples of blood and muscle were analysed for the proportion of mutant mtDNA using an oligonucleotide hybridization technique. The proportion of mutant mtDNA in blood was significantly greater in symptomatic than asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. Study of disease associated with the tRNA(Lys) A-->G(8344) mutation provides further insight into the pathogenesis and transmission of mitochondrial diseases. Quantification of the proportion of mtDNA in tissues demonstrates that this is a major factor determining the course of disease, but other, as yet unidentified factors are also likely to play a role.

Published
1993
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13. TREATMENT OF EXPERIMENTAL NADH UBIQUINONE REDUCTASE DEFICIENCY WITH MENADIONE

Author

D. J. Hayes, J. B. Clark, JM Cooper, R. A. J. Challiss, and J. A. Morgan-Hughes

Subjects
medicine.medical_specialty, business.industry, viruses, animal diseases, Metabolite, virus diseases, Stimulation, Isometric exercise, Phosphocreatine, Biphenyl compound, chemistry.chemical_compound, Gastrocnemius muscle, Endocrinology, Menadione, chemistry, Internal medicine, parasitic diseases, medicine, Neurology (clinical), Intramuscular injection, business
Abstract

Chronic administration of diphenylene iodonium (DPI) to rats has been shown to model the characteristics of mitochondrial myopathy. Using this model the efficacy of menadione therapy has been assessed. Menadione treatment of rats injected with DPI was associated with improved weight gain and increased survival rate. This was accompanied by an improvement in muscle function as judged by analysis of isometric twitch tension of the gastrocnemius muscle (1 Hz for 20 min). The decline in phosphocreatine (PCr) levels in the gastrocnemius muscle during stimulation and delayed recovery in PCr after stimulation were similar in the menadione treated and untreated models. Menadione treatment of the DPI model resulted in a resting intramuscular pH significantly lower than control or untreated DPI rats, but a similar decline in intramuscular pH to the DPI rats during stimulation. The changes in metabolite levels were broadly similar in both the menadione treated and untreated DPI models following stimulation, although the changes, except for increased lactate concentration, were generally less marked in the menadione-treated DPI model.

Published
1992
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14. The diagnosis of carnitine palmitoyltransferase II deficiency is now possible in small skeletal muscle biopsies

Author

Iain P. Hargreaves, Simon E. Olpin, J. A. Morgan-Hughes, S. J. R. Heales, and John M. Land

Subjects
Adult, Male, medicine.medical_specialty, Biopsy, Lipid Metabolism, Inborn Errors, Internal medicine, Genetics, medicine, Humans, Carnitine palmitoyltransferase II, Carnitine O-palmitoyltransferase, Muscle, Skeletal, Myopathy, Genetics (clinical), Carnitine O-Palmitoyltransferase, business.industry, Myoglobinuria, Skeletal muscle, Acute Kidney Injury, medicine.disease, Endocrinology, Mitochondrial respiratory chain, medicine.anatomical_structure, Carnitine palmitoyltransferase II deficiency, medicine.symptom, business, Rhabdomyolysis
Abstract

Carnitine palmitoyltransferase II (CPT II) converts acylcarnitine esters to the corresponding acyl-CoA derivatives within mitochondria prior to β-oxidation. CPT II deficiency (McKusick 255110) may present early in life, with patients displaying hypoketonaemia, hypoglycaemia, cardiomyopathy or multiorgan failure (Hug et al 1994). A neonatal case with a lethal myopathy has also been described (Land et al 1995). However, the most common presentation of CPT II deficiency is in adulthood, invariably characterized by exercise-included rhabdomyolysis and myoglobinuria, especially in the fasted state. In our laboratory we routinely measure mitochondrial respiratory chain enzyme (MRCE) activities in small skeletal muscle biopsies (50-100 mg). However, once the diagnosis of MRCE deficiency has been excluded, the ability to measure CPT activity in the muscle biopsies of patients suspected of having MRCE/β-oxidation defects would improve the differential diagnosis. We describe the contribution made by enzymatic measurement in skeletal muscle homogenates to the diagnosis of CPT II deficiency.

Published
2000
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15. Behaviour of small children before induction. The effect of parental presence and EMLA and premedication with triclofos or a placebo

Author

J. O. Morgan-Hughes and B. Page

Subjects
Parents, Triclofos, Dorsum, Pediatrics, medicine.medical_specialty, Time Factors, medicine.drug_class, Child Behavior, Anesthesia, General, Placebo, Hypnotic, medicine, Humans, Hypnotics and Sedatives, Anesthetics, Local, Lidocaine, Prilocaine Drug Combination, business.industry, Age Factors, Small children, Infant, Lidocaine, Parental presence, Organophosphates, Prilocaine, Drug Combinations, Anesthesiology and Pain Medicine, Child, Preschool, Anesthesia, Sedative, Premedication, business, Preanesthetic Medication, medicine.drug
Abstract

The effect of the prescription of triclofos 70 mg/kg orally 90 minutes before operation on the behaviour of 263 children aged 1 to 5 years was studied in a blind, randomised, placebo-controlled trial. EMLA was applied to the dorsum of one hand when the premedication was administered, and all the children were accompanied by a parent during induction of anaesthesia. The frequency of satisfactory behaviour was significantly higher in the triclofos group (p less than 0.02), but the time spent in the recovery ward was increased.

Published
1990
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16. Mitochondrial Myopathy with a Defect of Mitochondrial-Protein Transport

Author

J. M. Cooper, J. B. Clark, D. N. Landon, Anthony H.V. Schapira, and J. A. Morgan-Hughes

Subjects
Iron-Sulfur Proteins, Muscle ultrastructure, Muscle metabolism, Pathology, medicine.medical_specialty, Adolescent, Mitochondrion, Electron Transport Complex III, Muscular Diseases, Mitochondrial myopathy, Multienzyme Complexes, Metalloproteins, Electron transport complex III, NAD(P)H Dehydrogenase (Quinone), medicine, Humans, Quinone Reductases, Mitochondrial protein, business.industry, Electron Transport Complex II, Biological Transport, General Medicine, medicine.disease, Mitochondria, Muscle, Cell biology, Succinate Dehydrogenase, Female, Oxidoreductases, business
Abstract

The clinical and biochemical heterogeneity of the mitochondrial myopathies is now well established.1 , 2 Recent work has focused on identifying the molecular basis of these disorders and has demons...

Published
1990
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17. Pre-induction behaviour of children A review of placebo-controlled trials of sedatives

Author

J. O. Morgan-Hughes and J. A. Bangham

Subjects
Clinical Trials as Topic, medicine.drug_class, business.industry, Child Behavior, Infant, Placebo, Placebos, Hypnotic, Clinical trial, Route of administration, Anesthesiology and Pain Medicine, El Niño, Preanesthetic Medication, Child, Preschool, Anesthesia, Sedative, medicine, Humans, Hypnotics and Sedatives, Premedication, Child, business
Abstract

Placebo-controlled trials of sedative premedication in children are reviewed in an attempt to determine which drugs have been shown to reduce the frequency with which children cry or appear apprehensive. Small samples and inappropriate statistical methods limit the value of many of the studies. Most of the drugs tested will, in sufficient dose, increase the proportion of children who are asleep. Only intramuscular opioid analgesics, either alone or in combination with other drugs, have been shown repeatedly to increase the frequency of calm behaviour in those who are awake. There is some evidence, however, that intramuscular placebo controls have a lower frequency of calm behavior than oral placebo controls.

Published
1990
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18. A MITOCHONDRIAL ENCEPHALOMYOPATHY WITH SPECIFIC DEFICIENCIES OF TWO RESPIRATORY CHAIN POLYPEPTIDES AND A CIRCULATING AUTOANTIBODY TO A MITOCHONDRIAL MATRIX PROTEIN

Author

J. B. Clark, J. M. Cooper, L. Manneschi, Anthony H.V. Schapira, J. A. Morgan-Hughes, and C. Vital

Subjects
Male, Mitochondrial encephalomyopathy, Adolescent, Protein subunit, Respiratory chain, Muscle Proteins, Biology, Mitochondrion, Oxygen Consumption, Muscular Diseases, Mitochondrial myopathy, medicine, Humans, Antigens, Mitochondrial Encephalomyopathies, Autoantibodies, Brain Diseases, Liver Cirrhosis, Biliary, Immune Sera, Autoantibody, medicine.disease, Mitochondria, Muscle, Biochemistry, Mitochondrial matrix, Neurology (clinical), Peptides, Tomography, X-Ray Computed
Abstract

A 15-yr-old boy with mitochondrial encephalomyopathy and NADH CoQ reductase (Complex I) deficiency is presented. Immunoblotting demonstrated specific deficiencies of the 24 kDa FeS protein of Complex I and subunit II of Complex IV. The patient's serum contained an antibody to a specific mitochondrial matrix polypeptide of apparent Mr 41 kDa. The specific polypeptide deficiencies involve products of nuclear (24 kDa FeS protein) and mitochondrial (subunit II) genes and suggest some intergenomic regulation. The relevance of the circulating antibody to the pathogenesis of the patient's Complex I deficiency is discussed.

Published
1990
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19. New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation

Author

A.G. Debono, D.N. Landon, D.R. Marchington, J. A. Morgan-Hughes, Teeratorn Pulkes, Danae Liolitsa, Joanna Poulton, Michael G. Hanna, I.P. Nelson, S Rahman, Michael R. Rose, and L. H. Eunson

Subjects
Proband, Adult, Electrophoresis, Male, Adolescent, DNA Mutational Analysis, Respiratory chain, Biology, Gene mutation, medicine.disease_cause, DNA, Mitochondrial, Electron Transport Complex IV, Mitochondrial Proteins, Microscopy, Electron, Transmission, Mitochondrial Encephalomyopathies, medicine, Serine, Humans, Myopathy, Muscle, Skeletal, Genetics (clinical), RNA, Transfer, Ser, Genetics, Mutation, Transition (genetics), Cerebellar ataxia, Molecular biology, Phenotype, Mitochondria, Muscle, Neurology, Pediatrics, Perinatology and Child Health, Nucleic Acid Conformation, Female, Neurology (clinical), medicine.symptom
Abstract

We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.

Published
2004

20. Late onset Leber's optic neuropathy: a case confused with ischaemic optic neuropathy

Author

M. D. Sanders, François-Xavier Borruat, M G Sweeney, J A Morgan-Hughes, E M Graham, and W T Green

Subjects
Male, Pathology, medicine.medical_specialty, genetic structures, Eye disease, Late onset, Fundus (eye), DNA, Mitochondrial, Diagnosis, Differential, Optic neuropathy, Cellular and Molecular Neuroscience, Optic Atrophies, Hereditary, medicine, Humans, Fluorescein Angiography, medicine.diagnostic_test, business.industry, Optic Nerve, Magnetic resonance imaging, Middle Aged, medicine.disease, Fluorescein angiography, Magnetic Resonance Imaging, eye diseases, Sensory Systems, Optic Atrophy, Ophthalmology, Optic nerve, sense organs, Differential diagnosis, business, Research Article
Abstract

A case is reported of a 63-year-old man with progressive central visual loss in one eye followed 11 months later by involvement of the fellow eye. A diagnosis of chronic ischaemic optic neuropathy was considered. However, despite a negative family history, the absence of electrocardiographic abnormalities, and minimal fundus changes a diagnosis of Leber's optic neuropathy was made on the basis of magnetic resonance imaging findings and the mitochondrial DNA mutation at base pair 11778.

Published
1992
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21. The Neuropsychological Features of Mitochondrial Myopathies and Encephalomyopathies

Author

J. A. Morgan-Hughes, A. E. Harding, L. D. Kartsounis, and D. D. Troung

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Encephalopathy, Neuropsychological Tests, Audiology, Electroencephalography, Cognition, Muscular Diseases, Arts and Humanities (miscellaneous), Mitochondrial myopathy, medicine, Cerebral function, Humans, Cerebral dysfunction, Brain Diseases, medicine.diagnostic_test, Cognitive disorder, Neuropsychology, Middle Aged, medicine.disease, Mitochondria, Muscle, Female, Neurology (clinical), Psychology, Neuroscience
Abstract

Detailed testing of higher cerebral function was performed in 36 patients with mitochondrial myopathies and encephalomyopathies. Fourteen of these patients were thought to be cognitively impaired on clinical grounds. The assessments included tests of general intellectual ability and focal tests of memory, language, and perception. Twenty-one (58%) of the 36 patients who were tested had evidence of general intellectual deterioration, with focal cognitive deficits of variable degree. Of the remaining 15 patients in whom there was no evidence of general intellectual decline, five displayed focal cognitive deficits. In only 10 patients was there evidence of cerebral dysfunction. The range and extent of cognitive deficits in mitochondrial myopathies are greater than predicted by their clinical presentations.

Published
1992
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22. A novel mutation in the mitochondrial tRNA(TYr) gene associated with exercise intolerance

Author

Teeratorn Pulkes, Michael G. Hanna, J. A. Morgan-Hughes, and A. Siddiqui

Subjects
Genetics, Adult, medicine.medical_specialty, Exercise Tolerance, Point mutation, Exercise intolerance, Biology, Mitochondrion, DNA, Mitochondrial, Pedigree, RNA, Transfer, Tyr, Endocrinology, Germline mutation, RNA, Transfer, Coenzyme Q – cytochrome c reductase, Internal medicine, Transfer RNA, Mutation (genetic algorithm), medicine, Humans, Point Mutation, Female, Neurology (clinical), medicine.symptom, Myopathy
Abstract

Article abstract The authors report a novel A5874G mutation in the mitochondrial tRNA tyrosine (tRNA Tyr ) gene associated with exercise intolerance, limb weakness, and complex III deficiency. The mutation was absent in blood from the patient and all maternal family members, indicating that it may be a spontaneous somatic mutation in muscle. This is the first point mutation in the tRNA Tyr gene associated with human disease and is further evidence that exercise intolerance associated with complex III deficiency is genetically heterogeneous.

Published
2000

23. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples

Author

M. Brockington, S.R. Hammans, A. E. Harding, J. A. Morgan-Hughes, and Mary G. Sweeney

Subjects
Adult, Mitochondrial DNA, Pathology, medicine.medical_specialty, Adolescent, Encephalopathy, Epilepsies, Myoclonic, Biology, medicine.disease_cause, DNA, Mitochondrial, medicine, Humans, Child, Brain Diseases, Mutation, Muscle biopsy, medicine.diagnostic_test, Muscles, Point mutation, Syndrome, General Medicine, medicine.disease, Mitochondria, Muscle, Cerebrovascular Disorders, Child, Preschool, Lactic acidosis, Myoclonic epilepsy, Acidosis, Lactic, Ataxia, medicine.symptom, Myoclonus
Abstract

Point mutations of mitochondrial DNA have been described in the muscle of patients with syndromes of myoclonic epilepsy and ragged red fibres (MERRF) and of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). We have found the MERRF mutation in members of 6 British kindreds; 2 of these had unusual phenotypes but all index patients had myoclonus. The MELAS mutation was detected in 17 patients from 16 families, who had a wide range of clinical features that particularly affected the central nervous system; stroke-like episodes were observed in 10.3 patients with mitochondrial DNA mutations did not have ragged red fibres on muscle biopsy, generally considered to be the morphological hallmark of mitochondrial diseases. In all 6 patients with the MERRF mutation, and 10 of 11 with the MELAS mutation, the genetic defect was easily detected in blood cells as well as muscle (blood samples were not available in 6 patients with MELAS mutations in muscle). Molecular genetic analysis of blood samples represents an inexpensive and reliable screening test for mitochondrial encephalopathies, and use of such techniques could influence diagnosis and genetic counselling in patients with seizure disorders and young-onset stroke.

Published
1991
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24. A case of progressive encephalomyelitis with rigidity and positive antiglutamic acid decarboxylase antibodies [corrected]

Author

P O Behan, A J Lees, David J. Burn, J A Morgan-Hughes, and J Ball

Subjects
biology, Glutamate Decarboxylase, Encephalomyelitis, Middle Aged, medicine.disease, Autoimmune Diseases, Muscle Rigidity, Pathogenesis, Psychiatry and Mental health, Cerebrospinal fluid, Immunopathology, Immunology, biology.protein, medicine, Humans, Female, Surgery, Neurology (clinical), Antibody, Autoantibodies, Research Article
Abstract

A 50 year old woman developed progressive encephalomyelitis with rigidity over a three year period. Her CSF contained oligoclonal bands and both her serum and CSF contained antibodies directed against GABA-ergic synapses (antiglutamic acid decarboxylase [corrected] antibodies). These antibodies have recently been described in cases of stiff man syndrome. Both disorders may be part of a clinical spectrum that has an underlying autoimmune basis.

Published
1991
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25. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS

Author

T, Pulkes, L, Eunson, V, Patterson, A, Siddiqui, N W, Wood, I P, Nelson, J A, Morgan-Hughes, and M G, Hanna

Subjects
Adult, Male, Electron Transport Complex I, DNA, Mitochondrial, Polymerase Chain Reaction, Mitochondria, Muscle, Electron Transport Complex IV, Optic Atrophies, Hereditary, MELAS Syndrome, Humans, Point Mutation, Female, Genetic Predisposition to Disease, NADH, NADPH Oxidoreductases, Muscle, Skeletal
Abstract

We report on 4 male patients with clinical, radiological, and muscle biopsy findings typical of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. Skeletal muscle mitochondrial DNA (mtDNA) analysis showed that all patients harbored a heteroplasmic G13513A mutation in the ND5 subunit gene. One of these cases (Patient 1) presented with symptoms characteristic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode. Quantitative analysis in several postmortem tissue sections showed that the relative proportions of mutant mtDNA were generally lower than those reported with other pathogenic mtDNA mutations. Single-fiber polymerase chain reaction studies demonstrated significantly higher amounts of mutant mtDNA in ragged red fibers (RRFs) compared with non-RRFs. This study indicates that the G13513A transition is likely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more frequent cause of MELAS than previously recognized.

Published
1999

26. Biochemical and molecular aspects of human mitochondrial respiratory chain disorders

Author

Anthony H.V. Schapira, J. A. Morgan-Hughes, I. J. Holt, A. E. Harding, JM Cooper, A. Toscano, and John B. Clark

Subjects
Respiratory chain, macromolecular substances, Oxidative phosphorylation, In Vitro Techniques, Biochemistry, Electron Transport Complex III, Oxygen Consumption, Quinone Reductases, Multienzyme Complexes, Immunochemistry, NAD(P)H Dehydrogenase (Quinone), Humans, biology, Chemistry, Electron Transport Complex II, Succinate dehydrogenase, Neuromuscular Diseases, Mitochondria, Muscle, Molecular Weight, Succinate Dehydrogenase, Mitochondrial respiratory chain, biology.protein, Oxidoreductases
Abstract

Functional mitochondrial respiratory chain and oxidative phosphorylation systems are obligate requirements for the normal function of most eukaryotic cells. When a defect of one of these systems occurs in humans, it results in a variety of clinical symptoms according to the severity of the defect and the tissues involved. Defects of all five multisubunit complcxes comprising the respiratory chain and oxidative phosphorylation systems have been reported [ 1-51, with some patterns emerging [ 61. but generally no clear picture correlating. the clinical symptoms and the biochemical or molecular

Published
1990
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27. Mitochondrial encephalomyopathies: the enigma of genotype versus phenotype

Author

Michael G. Hanna and J. A. Morgan-Hughes

Subjects
Mitochondrial encephalomyopathy, Genotype, Biophysics, Oxidative phosphorylation, Biology, Biochemistry, Human mitochondrial genetics, DNA, Mitochondrial, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, RNA, Transfer, medicine, Humans, Mitochondrial Encephalomyopathies, 030304 developmental biology, Genetics, Gene Rearrangement, 0303 health sciences, Brain Diseases, Proteins, Cell Biology, medicine.disease, Phenotype, Mitochondria, mitochondrial fusion, Protein Biosynthesis, Mutation, 030217 neurology & neurosurgery
Abstract

Over the past decade a large body of evidence has accumulated implicating defects of human mitochondrial DNA in the pathogenesis of a group of disorders known collectively as the mitochondrial encephalomyopathies. Although impaired oxidative phosphorylation is likely to represent the final common pathway leading to cellular dysfunction in these diseases, fundamental issues still remain elusive. Perhaps the most challenging of these is to understand the mechanisms which underlie the complex relationship between genotype and phenotype. Here we examine this relationship and discuss some of the factors which are likely to be involved.

Published
1999

28. MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity

Author

Nicholas W. Wood, I.P. Nelson, J. A. Morgan-Hughes, and Michael G. Hanna

Subjects
Adult, Male, Mitochondrial DNA, Phenylalanine, Biology, medicine.disease_cause, MELAS syndrome, DNA, Mitochondrial, Polymerase Chain Reaction, Mitochondrial myopathy, medicine, MELAS Syndrome, Humans, Point Mutation, Gene, DNA Primers, Genetics, Mutation, Genetic heterogeneity, Point mutation, Middle Aged, RNA, Transfer, Amino Acid-Specific, medicine.disease, Heteroplasmy, Psychiatry and Mental health, Phenotype, Papers, Surgery, Female, Neurology (clinical)
Abstract

OBJECTIVES—To define the molecular genetic basis of the MELAS phenotype in five patients without any known mutation of mitochondrial DNA. METHODS—Systematic automated mitochondrial DNA sequencing of all mitochondrial transfer RNA and cytochrome c oxidase genes was undertaken in five patients who had the MELAS phenotype. RESULTS— A novel heteroplasmic mitochondrial DNA mutation was identified in the transfer RNA gene for phenylalanine in one case (patient 3). This mutation was not detected in the patient's blood or in her mother's blood. No pathogenic mutations were identified in the other four patients. CONCLUSIONS—This is the first point mutation in the transfer RNA gene for phenylalanine to be associated with MELAS. The absence of mutations in the remaining four patients suggests that there is further genetic heterogeneity associated with this mitochondrial phenotype.

Published
1998

29. Growth hormone therapy may benefit protein metabolism in mitochondrial encephalomyopathy

Author

Peter H. Sönksen, E Albany, Anne Umpleby, Nicola Jackson, David Russell-Jones, Paul V. Carroll, and J. A. Morgan-Hughes

Subjects
Mitochondrial encephalomyopathy, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Protein metabolism, High-protein diet, Biology, medicine.disease_cause, chemistry.chemical_compound, Endocrinology, Mitochondrial myopathy, Weight loss, Mitochondrial Encephalomyopathies, Internal medicine, medicine, Humans, Insulin-Like Growth Factor I, Muscle, Skeletal, Wasting, Protein turnover, Proteins, Middle Aged, medicine.disease, Combined Modality Therapy, Protein catabolism, chemistry, Growth Hormone, Body Composition, Dietary Proteins, medicine.symptom
Abstract

Mitochondrial encephalomyopathy is a genetic disorder for which there is at present no cure. Conventional treatment regimes may not be effective in preventing weight loss and muscle wasting in many patients. Recombinant human GH has been shown to have anabolic effects on protein metabolism and to reduce muscle wasting in various diseases. We have treated a patient known to have myoclonus, epilepsy with ragged red fibres (MERRF) with a high protein diet for 1 month followed by a high protein diet and GH therapy for 1 month. To assess the benefit of these treatments the patient underwent whole body protein turnover, myometric and body composition studies at baseline, following the high protein diet (100 g/day) and following GH therapy. Whole body protein synthesis (and protein breakdown) increased following a high protein intake and was further enhanced by treatment with GH and in a high protein diet. Body composition did not change significantly following treatment with either the high protein diet or GH but there was an improvement in muscle performance following GH treatment. Mitochondrial encephalomyopathy, a wasting disorder, may be a disease in which the known protein anabolic effect of GH may have a therapeutic benefit.

Published
1997

30. Effect of timing of ketorolac administration on patient-controlled opioid use

Author

K. C. Macintosh, J. E. G. Rogers, B. G. Fleming, J. O. Morgan-Hughes, and B. Johnston

Subjects
Adult, medicine.medical_specialty, Nausea, medicine.medical_treatment, Analgesic, Blood Loss, Surgical, Hysterectomy, Drug Administration Schedule, Double-Blind Method, medicine, Humans, Tolmetin, Aged, Chemotherapy, Pain, Postoperative, Patient-controlled analgesia, business.industry, Analgesia, Patient-Controlled, Analgesics, Non-Narcotic, Middle Aged, Confidence interval, Surgery, body regions, Ketorolac, Analgesics, Opioid, Heroin, Anesthesiology and Pain Medicine, Anesthesia, Vomiting, Female, medicine.symptom, business, Preanesthetic Medication, medicine.drug
Abstract

In order to investigate the analgesic effect of timing of administration of ketorolac 10 mg i.v., we recorded patient-controlled use of diamorphine at 2, 4 and 12 h after abdominal hysterectomy. In a randomized, double-blind trial, 30 patients received ketorolac before skin incision and 28 after skin closure. A control group of 32 patients did not receive ketorolac. We measured operative blood loss and assessed nausea, vomiting and pruritus. After 2 h of patient-controlled analgesia, the median cumulative diamorphine dose in the group given ketorolac before operation was less than that of the control group (95% confidence interval 8-66 micrograms kg-1; P = 0.01). There were no other statistically significant differences in diamorphine consumption between the groups. The frequency of nausea and vomiting was similar in all groups Median blood loss in the group given ketorolac before operation exceeded that of the patients who did not receive ketorolac before operation (95% confidence interval 20-149 ml; P = 0.01). We conclude that the diamorphine-sparing effect of ketorolac attributable to timing of administration was small, conferred no clinical benefit and was accompanied by increased bleeding. No patient given ketorolac complained of pruritus.

Published
1995

31. Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study

Author

A. E. Harding, M. Brockington, J. A. Morgan-Hughes, Mary G. Sweeney, N. Alsanjari, and Francesco Scaravilli

Subjects
Adult, Male, Mitochondrial DNA, Cerebellum, Adolescent, Spleen, Kearns-Sayre Syndrome, Biology, DNA, Mitochondrial, Basal Ganglia, Kearns–Sayre syndrome, chemistry.chemical_compound, Gene duplication, medicine, Humans, Genetics, Brain Chemistry, Skeletal muscle, Brain, medicine.disease, Blot, Blotting, Southern, medicine.anatomical_structure, Neurology, chemistry, Spinal Cord, Multigene Family, Female, Neurology (clinical), DNA, Gene Deletion
Abstract

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leigh's syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion, rearranged mtDNA was undetectable in blood, spleen, and testis, and present in highest amounts in muscle and the brain, but relatively low in cerebellum, reflecting the ratio seen, albeit in much smaller amounts, in normal aged brains. MtDNA rearrangements in this patient were largely deletions or deletion dimers; duplicated mtDNA was present in only trace amounts in some tissues and there was none in skeletal muscle. The patient with a predominant duplication of mtDNA had higher amounts of rearranged mtDNA in blood (mainly duplicated) than muscle (mainly deleted). Correlation of these data with tissue dysfunction is probably complicated by the replicative behaviour of deleted, duplicated and normal mtDNA.

Published
1995

32. Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A--G (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA

Author

A. E. Harding, Michael G. Hanna, J. A. Morgan-Hughes, and I.P. Nelson

Subjects
Male, Mitochondrial DNA, Mutant, Respiratory chain, Epilepsies, Myoclonic, Mitochondrion, DNA, Mitochondrial, medicine, Cytochrome c oxidase, Humans, Point Mutation, Cells, Cultured, Genetics, biology, Point mutation, Lysine, Muscles, MERRF syndrome, Middle Aged, medicine.disease, Blotting, Northern, Mitochondria, Muscle, Phenotype, Neurology, Protein Biosynthesis, Transfer RNA, biology.protein, Autoradiography, RNA, Transfer, Lys, Neurology (clinical)
Abstract

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) phenotype. The molecular pathogenesis of disease associated with this mutation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied these processes in cloned primary human myoblast cultures containing different proportions of mutant mtDNA. No abnormality of transcription was observed. However, there was a progressive decrease in mitochondrially encoded protein synthesis as the proportion of mutant mtDNA increased. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunits with relatively low proportions of mutant mtDNA.

Published
1995

33. A new mitochondrial DNA mutation associated with progressive dementia and chorea: a clinical, pathological, and molecular genetic study

Author

I.P. Nelson, Michael G. Hanna, N. Alsanjari, A. E. Harding, Francesco Scaravilli, and J. A. Morgan-Hughes

Subjects
Adult, Male, Mitochondrial DNA, Pathology, medicine.medical_specialty, Cerebellar Ataxia, Biopsy, Biology, Deafness, DNA, Mitochondrial, Fatal Outcome, Chorea, mental disorders, medicine, Humans, Point Mutation, Myopathy, Muscle, Skeletal, Muscle biopsy, medicine.diagnostic_test, Cerebellar ataxia, Point mutation, Brain, Peripheral Nervous System Diseases, Syndrome, medicine.disease, Peripheral neuropathy, Neurology, Gliosis, Dementia, Neurology (clinical), medicine.symptom
Abstract

A novel mitochondrial DNA transfer RNA mutation at position 5549 was identified in a patient with dementia, chorea, cerebellar ataxia, deafness, and peripheral neuropathy in the absence of clinical myopathy. Muscle biopsy specimens showed ragged red and cytochrome oxidase-negative fibers, and reduced complex I activity on polarography. There was diffuse neuronal loss and gliosis throughout the brain on postmortem examination. The heteroplasmic mutation had a widespread distribution in autopsy tissues.

Published
1995

34. Mitochondrial DNA transfer RNA mutation LEU(UUR)A→G 3260: a second family with myopathy and cardiomyopathy

Author

Weston Mj, J. A. Morgan-Hughes, Brockington M, Mary G. Sweeney, and A. E. Harding

Subjects
Genetics, Mitochondrial DNA, Mutation, Point mutation, RNA, General Medicine, Biology, medicine.disease_cause, Heteroplasmy, Transfer RNA, medicine, medicine.symptom, Myopathy, Gene
Abstract

A family with maternally inherited myopathy and cardiomyopathy is described. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 3260 in the leucine transfer RNA gene, previously reported in a large Italian family with a similar phenotype. This observation confirms pathogenicity of this mutation and suggests phenotypic specificity.

Published
1993
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35. Mitochondrial DNA transfer RNA mutation Leu(UUR)A--G 3260: a second family with myopathy and cardiomyopathy

Author

M G, Sweeney, M, Brockington, M J, Weston, J A, Morgan-Hughes, and A E, Harding

Subjects
Adult, Electrophoresis, Agar Gel, Heart Failure, Male, RNA, Transfer, Leu, Muscular Diseases, Mutation, Humans, Female, DNA, Mitochondrial, Pedigree
Abstract

A family with maternally inherited myopathy and cardiomyopathy is described. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 3260 in the leucine transfer RNA gene, previously reported in a large Italian family with a similar phenotype. This observation confirms pathogenicity of this mutation and suggests phenotypic specificity.

Published
1993

36. Treatment of experimental NADH ubiquinone reductase deficiency with menadione

Author

J M, Cooper, D J, Hayes, R A, Challiss, J A, Morgan-Hughes, and J B, Clark

Subjects
Male, Electron Transport Complex I, Magnetic Resonance Spectroscopy, Vitamin K, Phosphocreatine, Muscles, Biphenyl Compounds, Mitochondrial Myopathies, Hindlimb, Phosphates, Rats, Adenosine Diphosphate, Electron Transport, Adenosine Triphosphate, Onium Compounds, Animals, Drug Therapy, Combination, NADH, NADPH Oxidoreductases, Rats, Wistar
Abstract

Chronic administration of diphenylene iodonium (DPI) to rats has been shown to model the characteristics of mitochondrial myopathy. Using this model the efficacy of menadione therapy has been assessed. Menadione treatment of rats injected with DPI was associated with improved weight gain and increased survival rate. This was accompanied by an improvement in muscle function as judged by analysis of isometric twitch tension of the gastrocnemius muscle (1 Hz for 20 min). The decline in phosphocreatine (PCr) levels in the gastrocnemius muscle during stimulation and delayed recovery in PCr after stimulation were similar in the menadione treated and untreated models. Menadione treatment of the DPI model resulted in a resting intramuscular pH significantly lower than control or untreated DPI rats, but a similar decline in intramuscular pH to the DPI rats during stimulation. The changes in metabolite levels were broadly similar in both the menadione treated and untreated DPI models following stimulation, although the changes, except for increased lactate concentration, were generally less marked in the menadione-treated DPI model.

Published
1992

37. A molecular genetic study of focal histochemical defects in mitochondrial encephalomyopathies

Author

D. A. G. Wicks, A. E. Harding, Mary G. Sweeney, Simon Hammans, and J. A. Morgan-Hughes

Subjects
Mitochondrial DNA, Pathology, medicine.medical_specialty, Molecular Sequence Data, Biology, MELAS syndrome, DNA, Mitochondrial, Mitochondrial myopathy, Muscular Diseases, medicine, Humans, RNA RIBOSOMAL 16S, Mitochondrial Encephalomyopathies, Genetics, Brain Diseases, Base Sequence, Histocytochemistry, MERRF syndrome, Nucleic Acid Hybridization, medicine.disease, Drug or chemical Tissue Distribution, Mitochondria, Mitochondria, Muscle, Mutation, Neurology (clinical), Chromosome Deletion, Oligonucleotide Probes
Abstract

Using in situ hybridization and histochemistry we have studied muscle biopsy samples from eight patients with mitochondrial encephalomyopathies and known defects of mitochondrial DNA (mtDNA). In four patients with heteroplasmic mtDNA deletions there were focal accumulations of deleted mtDNA and its transcripts within ragged red fibres (RRF). In one of these, a probe designed specifically to detect deleted mtDNA identified abundant deleted mtDNA and its fusion transcript in RRF and lesser accumulations in non-ragged red cytochrome oxidase (COX) deficient fibres. A further patient with a deletion involving the heavy strand promoter region showed accumulation of deleted mtDNA and light strand transcripts in RRF, but concomitant depletion of all heavy strand transcripts. In all patients with deletions, normal mtDNA transcripts were depleted in COX deficient fibres irrespective of ragged red change. Deleted mtDNA was rare or absent in normal fibres. Within RRF, COX activity was more profoundly impaired in patients with deletions involving COX subunits. In two patients heteroplasmic for the base pair (bp) 3243 mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS), RRF contained a great excess of mtDNA and transcripts of all species. Some RRF showed excess COX activity. Non-ragged red COX deficient fibres showed equal increases of ribosomal RNA (rRNA) and messenger RNA, suggesting that focal biochemical defects were not associated with a quantitative defect of transcription termination at the 3' end of the 16S rRNA which might be predicted. A patient heteroplasmic for the bp 8344 mutation (associated with myoclonic epilepsy and ragged red fibres: MERRF) showed subnormal COX activity within RRF, although the tissue distribution of mtDNA and its transcripts was similar to that seen with the bp 3243 mutation. Within mitochondrial encephalomyopathies, the relationships between the distribution and expression of abnormal mtDNA and the focal biochemical consequences are complex and heterogeneous.

Published
1992

38. Evidence for intramitochondrial complementation between deleted and normal mitochondrial DNA in some patients with mitochondrial myopathy

Author

I. J. Holt, John B. Clark, Mary G. Sweeney, A. E. Harding, Antonio Toscano, J. A. Morgan-Hughes, S.R. Hammans, and JM Cooper

Subjects
Mitochondrial DNA, Molecular Sequence Data, Restriction Mapping, Respiratory chain, Mitochondrion, medicine.disease_cause, DNA, Mitochondrial, Kearns–Sayre syndrome, Electron Transport Complex IV, Mitochondrial myopathy, Muscular Diseases, medicine, Cytochrome c oxidase, Humans, Deletion mapping, Mutation, biology, Base Sequence, Histocytochemistry, DNA, medicine.disease, Molecular biology, Mitochondria, Muscle, Neurology, biology.protein, Neurology (clinical)
Abstract

Twenty-three patients with mitochondrial myopathies and mitochondrial DNA deletions in muscle were studied by means of deletion mapping and sequencing, histochemistry and polarography. Histochemistry showed significantly less focal cytochrome oxidase deficiency relative to number of ragged red fibres when the deletion did not involve reading frames for cytochrome oxidase subunits. Polarography in such patients showed defects exclusively involving complex I, in contrast to the others with larger deletions who generally had more diffuse respiratory chain defects. Analysis of other published histochemical data showed similar findings to our own. It is concluded that translation of a proportion of deleted mitochondrial DNAs occurs in at least some patients with mitochondrial DNA deletions, implying that deleted and normal mitochondrial genomes share transfer RNAs within mitochondria in such cases.

Published
1992

39. Mitochondrial myopathies: clinical defects

Author

Anthony H.V. Schapira, J. A. Morgan-Hughes, J. M. Cooper, Holt Ij, Harding Ae, and J. B. Clark

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Ophthalmoplegia, Adolescent, Chemistry, Muscles, Middle Aged, medicine.disease, Biochemistry, DNA, Mitochondrial, Mitochondria, Muscle, Electron Transport, Mitochondrial myopathy, Muscular Diseases, Central Nervous System Diseases, medicine, Humans, Female, Chromosome Deletion, Exercise, Retinitis Pigmentosa
Published
1990

40. Mitochondrial myopathies: genetic defects

Author

Ian J. Holt, A. E. Harding, Mary G. Sweeney, J. B. Clark, Anthony H.V. Schapira, J. A. Morgan-Hughes, and J. M. Cooper

Subjects
Muscle metabolism, Base Sequence, Molecular Sequence Data, Chromosome Mapping, Mitochondrion, Biology, medicine.disease, Biochemistry, DNA, Mitochondrial, Mitochondria, Muscle, chemistry.chemical_compound, Mitochondrial myopathy, chemistry, Muscular Diseases, medicine, Humans, Base sequence, Amino Acid Sequence, Chromosome Deletion, Peptide sequence, DNA
Published
1990

41. The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies

Author

J. M. Cooper, A. E. Harding, J. A. Morgan-Hughes, A. H. V. Schapira, J. B. Clark, and I. J. Holt

Subjects
Male, Mitochondrial DNA, Protein subunit, Immunoblotting, Biophysics, Respiratory chain, Kearns-Sayre Syndrome, Mitochondrion, Biology, Biochemistry, Electron Transport, Electron Transport Complex IV, Electron Transport Complex III, Mitochondrial myopathy, Muscular Diseases, medicine, NAD(P)H Dehydrogenase (Quinone), Humans, Quinone Reductases, Mitochondrial Encephalomyopathies, Autoantibodies, Molecular pathology, Cell Biology, DNA, medicine.disease, Molecular biology, Mitochondria, Muscle, Cytosol, Immunology, Female, Chromosome Deletion
Abstract

Some of the different molecular pathologies of respiratory-chain dysfunction in human mitochondrial myopathies will be reviewed in relation to the findings in 58 cases. Deletions of mitochondrial DNA were identified in 21 cases [36%]. There was some correlation between the sites of the deletion and the mitochondrial biochemistry in patients with defects of Complex I but not in cases with more extensive loss of respiratory chain activity. Complex I and Complex IV polypeptides were usually normal in deleted cases. Non-deleted cases, however, often showed specific subunit deficiencies which involved the products of both nuclear and mitochondrial genes. Immunoblots of respiratory-chain polypeptides in one case pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The pathogenic role of circulating autoantibodies to specific matrix proteins and the nature of the target antigens in two patients with mitochondrial encephalomyopathies and respiratory-chain dysfunction will also be discussed.

Published
1990

42. Movement disorders in mitochondrial myopathies. A study of nine cases with two autopsy studies

Author

Daniel Dung Truong, C. D. Marsden, S. J. M. Smith, J. A. Morgan-Hughes, A. E. Harding, and F. Scaravilli

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, Ataxia, Movement disorders, Olivopontocerebellar atrophy, Mitochondrial myopathy, Muscular Diseases, mental disorders, otorhinolaryngologic diseases, medicine, Humans, Aged, Dystonia, Movement Disorders, business.industry, Parkinsonism, Brain, Chorea, Anatomy, Middle Aged, medicine.disease, nervous system diseases, Mitochondria, Muscle, Neurology, Female, Neurology (clinical), medicine.symptom, business, Myoclonus
Abstract

Of 85 consecutive patients with mitochondrial myopathy, 29 had clinically significant central nervous system involvement. Nine of these had movement disorders that included dystonia, chorea, parkinsonism, and myoclonus. Autopsy studies of one patient with ataxia, dementia, and parkinsonism followed by dystonia showed the features of olivopontocerebellar atrophy with additional degenerative changes in the basal ganglia. Postmortem in a further case with myoclonus, deafness, muscle weakness, retinopathy, and ataxia showed symmetrical mineralisation of the striatopallidodentatal system.

Published
1990

43. Cytochrome c oxidase deficiency linked to a new stop codon point mutation in mitochondrial DNA

Author

Nicholas W. Wood, I.P. Nelson, J.M. Cooper, Michael G. Hanna, S Rahman, Anthony H.V. Schapira, and J. A. Morgan-Hughes

Subjects
Mitochondrial DNA, Neurology, biology, Cytochrome b, Chemistry, Point mutation, Pediatrics, Perinatology and Child Health, biology.protein, Cytochrome c oxidase, Neurology (clinical), Molecular biology, Genetics (clinical), Stop codon
Published
1997
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44. Erratum to 'Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A → G (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA'

Author

I.P. Nelson, J. A. Morgan-Hughes, Michael G. Hanna, and A. E. Harding

Subjects
Genetics, Mutation, Mitochondrial DNA, Impaired mitochondrial translation, Mutant, Lysine, Biology, medicine.disease_cause, Molecular biology, Neurology, Transfer RNA, medicine, Myocyte, Neurology (clinical)
Published
1995
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45. Drug points: Exacerbation of idiopathic Parkinson's disease by naproxen

Author

S Shaunak, J A Morgan-Hughes, and P S Brown

Subjects
Levodopa, medicine.medical_specialty, Naproxen, Neurology, Exacerbation, business.industry, Selegiline, General Engineering, General Medicine, Propranolol, medicine.disease, Surgery, Central nervous system disease, Anesthesia, medicine, General Earth and Planetary Sciences, Neurosurgery, business, General Environmental Science, medicine.drug
Abstract

Drs S SHAUNAK, P BROWN, and J A MORGAN-HUGHES (National Hospital for Neurology and Neurosurgery, London WC1N 3BG) write: A 74 year old woman with a 10 year history of idiopathic Parkinson's disease was prescribed naproxen 250 mg three times a day for musculoskeletal pain. Her symptoms had previously been well controlled with co-beneldopa (levodopa and benserazide hydrochloride) 375 mg a day, selegiline 10 mg a day, and propranolol 60 mg a day. Shortly after starting naproxen treatment she became immobile …

Published
1995
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46. A mitochondrial myopathy with a deficiency of respiratory chain NADH-CoQ reductase activity

Author

J. A. Morgan-Hughes, John B. Clark, J. M. Land, P. Darveniza, and D. N. Landon

Subjects
Adult, medicine.medical_specialty, Weakness, Chemical Phenomena, Ubiquinone, Physical Exertion, Respiratory chain, Exercise intolerance, Biology, Reductase, Electron Transport, Lesion, Quinone Reductases, Muscular Diseases, Mitochondrial myopathy, Internal medicine, medicine, Humans, NADH, NADPH Oxidoreductases, Respiratory system, Cytochrome Reductases, medicine.disease, Mitochondria, Muscle, Chemistry, Endocrinology, Neurology, Biochemistry, Female, Neurology (clinical), medicine.symptom
Abstract

This paper presents data on two sisters with a mitochondrial myopathy characterised by weakness, marked exercise intolerance and a fluctuating lactic acidaemia. Both patients also experienced episodes of increased weakness which could be brought on by unaccustomed activity, going without food or by taking small quantities of alcohol. Metabolic studies during exercise showed a marked and sudden rise in blood lactate and pyruvate levels. Biochemical studies in one case showed that mitochondrial respiratory rates were markedly decreased with all NAD-linked substrates tested but were normal with succinate and with TMPD + ascorbate. The mitochondrial cytochrome components were normal as determined by low temperature spectroscopy and the addition of uncoupler did not enhance state 3 respiratory rates utilising NAD-linked substrates. It was concluded, therefore, that the mitochondrial lesion was located at the level of the NADH-CoQ reductase complex.

Published
1979
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47. Myoadenylate deaminase deficiency or not?

Author

D. J. Hayes, Beatrice A. Summers, and J. A. Morgan-Hughes

Subjects
Adenosine monophosphate, Inosine monophosphate, medicine.medical_specialty, Red Cell, business.industry, AMP deaminase, macromolecular substances, Periodic acid–Schiff stain, Adenylate deaminase activity, chemistry.chemical_compound, Endocrinology, Myoadenylate deaminase activity, Neurology, chemistry, Internal medicine, Medicine, Neurology (clinical), Younger sibling, business
Abstract

This paper describes 2 brothers with increasingly severe exercise-induced muscle pain and stiffness, beginning in adolescence. Histochemical studies showed that myoadenylate deaminase activity was absent in the propositus, but present in his younger brother. Biochemical examination of muscle homogenates confirmed these findings, with enzyme activity approximately 60% of the mean control value in the younger sibling. Red cell adenylate deaminase activity was normal in both cases. The possible relationship between the clinical and biochemical findings in these patients is discussed.

Published
1982
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48. ALTERATIONS IN THE NUMBER AND AFFINITY OF JUNCTIONAL ACETYLCHOLINE RECEPTORS IN A MYOPATHY WITH TUBULAR AGGREGATES

Author

J. A. Morgan-Hughes, B. R. F. Lecky, N. M. F. Murray, and D. N. Landon

Subjects
Adult, Male, Weakness, Pathology, medicine.medical_specialty, Neuromuscular Junction, Electromyography, Synaptic Transmission, Muscular Diseases, Ptosis, Myasthenia Gravis, Muscarinic acetylcholine receptor M5, otorhinolaryngologic diseases, medicine, Humans, Receptors, Cholinergic, Receptor, Myopathy, Acetylcholine receptor, medicine.diagnostic_test, Chemistry, Muscles, Microscopy, Electron, Cholinergic, Neurology (clinical), medicine.symptom
Abstract

This paper reports the findings in a 32-year-old man who presented in adult life with a myasthenic syndrome characterized by dysphagia, dysphonia, fluctuating ptosis, episodic diplopia and a variable weakness of the limbs and trunk. Electromyography showed a small decremental response, increased neuromuscular jitter and blocking of some components. Histochemical and electron microscopic studies revealed changes in end-plate morphology and prominent tubular aggregations within the muscle fibres. Radiochemical investigations using di-iodinated 125I-alpha-bungarotoxin demonstrated a reduction in the number of AChR and alterations in receptor affinity which suggested an abnormality of the AChR macromolecule.

Published
1981
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49. Mitochondrial DNA polymorphism in mitochondrial myopathy

Author

J. A. Morgan-Hughes, A. E. Harding, and I. J. Holt

Subjects
Genetics, Mutation, Mitochondrial DNA, Polymorphism, Genetic, Biology, Mitochondrion, medicine.disease_cause, medicine.disease, DNA, Mitochondrial, Human mitochondrial genetics, Molecular biology, Mitochondria, Muscle, Restriction fragment, Muscular Diseases, Mitochondrial myopathy, medicine, biology.protein, Humans, Restriction fragment length polymorphism, medicine.symptom, Myopathy, Polymorphism, Restriction Fragment Length, Genetics (clinical)
Abstract

In order to test the hypothesis that mitochondrial myopathy may be caused by mutation of the mitochondrial (mt) genome, restriction fragment length polymorphism in leucocyte mt DNA has been studied in 38 patients with mitochondrial myopathy, 44 of their unaffected matrilineal relatives, and 35 normal control subjects. Previously unreported mt DNA polymorphisms were identified in both patients and controls. No differences in restriction fragment patterns were observed between affected and unaffected individuals in the same maternal line, and there was no evidence of major deletion of mt DNA in patients. This study provides no positive evidence of mitochondrial inheritance in mitochondrial myopathy, but this has not been excluded.

Published
1988
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50. ACID MALTASE DEFICIENCY IN ADULTS

Author

A. D. Patrick, C. M. Wiles, P. St J. Trend, G. T. Spencer, J. A. Morgan-Hughes, and B. D. Lake

Subjects
Adult, Male, medicine.medical_specialty, Gastroenterology, chemistry.chemical_compound, Internal medicine, Glycogen storage disease type II, medicine, Humans, Diaphragmatic weakness, Respiratory system, Gluteal muscles, Positive end-expiratory pressure, Muscle biopsy, Pelvic girdle, medicine.diagnostic_test, Glycogen, business.industry, Muscles, Middle Aged, Glycogen Storage Disease, medicine.disease, Respiration, Artificial, Surgery, medicine.anatomical_structure, chemistry, Female, Neurology (clinical), Tracheotomy, Respiratory Insufficiency, business
Abstract

Five patients with adult onset acid maltase deficiency are described. All patients had developed their initial pelvic girdle symptoms late in the second or early in the third decade and some years later developed signs of respiratory insufficiency. Typically they were tall, had weak and wasted paraspinal and gluteal muscles with lower limb weakness. All were orthopnoeic with marked diaphragmatic weakness. In all patients characteristic glycogen vacuoles were seen in peripheral blood lymphocytes. Muscle biopsy was characteristic in only 1 out of 4 cases and showed minimal or nonspecific features in 3. The diagnosis was confirmed by enzyme assay in muscle and cultured fibroblasts. Long-term domiciliary ventilatory support (25 patient-years) using a rocking bed or intermittent positive pressure respiration with a tracheostomy has allowed a return to work in all patients, with their clinical condition remaining stable.

Published
1985
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