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1. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Author

Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., Zorzi, R. de, Payne, K., Henderson, L.B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J.A., Provitera, V., Schuelke, M., Vandrovcova, J., Groppa, S., Karashova, B.M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J.S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M.D., Maagdenberg, A.M.J.M. van den, Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A.M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B.M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E.Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N.N., Atawneh, O., Lim, S.Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y.A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E.G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., Lonlay, P. de, Cantagrel, V., Aguennouz, M., Khorassani, M. el, Schmidts, M., Alkuraya, F.S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., SYNAPS Study Grp, Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., De Zorzi, R., Payne, K., Henderson, L. B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J. A., Provitera, V., Schuelke, M., Vandrovcova, J., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E. G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., De Lonlay, P., Cantagrel, V., Aguennouz, M., El Khorassani, M., Schmidts, M., Alkuraya, F. S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Van Den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratory of Molecular Biophysics, Department of Biochemistry, Department of Biochemistry, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Department of Medical and Molecular Genetics, King‘s College London, Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Fondazione, Leiden University Medical Center (LUMC), Department of Physiology and Cellular Biophysics [New York, NY, USA], Columbia University College of Physicians and Surgeons, Department of Microbiology, Università degli studi di Catania [Catania], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ceinge, centro di Ingegneria Genetica e Biotecnologie Avanzate, Unité des troubles du sommeil, Centre de référence national sur les maladies rares (narcolepsie, hypersomnie idiopathique, syndrome de Kleine-Levin)-Hôpital Gui-de-Chauliac, Muscular and Neurodegenerative Disease Unit, University of Genoa (UNIGE), Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Indiana University, Indiana University [Bloomington], Indiana University System-Indiana University System, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service métabolisme, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Efthymiou S., Salpietro V., Malintan N., Poncelet M., Kriouile Y., Fortuna S., De Zorzi R., Payne K., Henderson L.B., Cortese A., Maddirevula S., Alhashmi N., Wiethoff S., Ryten M., Botia J.A., Provitera V., Schuelke M., Vandrovcova J., Walsh L., Torti E., Iodice V., Najafi M., Karimiani E.G., Maroofian R., Siquier-Pernet K., Boddaert N., De Lonlay P., Cantagrel V., Aguennouz M., El Khorassani M., Schmidts M., Alkuraya F.S., Edvardson S., Nolano M., Devaux J., Houlden H., Groppa S., Karashova B.M., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., Van Den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Kullmann D., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Zollo M., Heimer G., Dauvilliers Y.A., Minetti C., Al-Khawaja I., Al-Mutairi F., Hamed S., Pipis M., Bettencourt C., Rinaldi S., Efthymiou, Stephanie, Salpietro, Vincenzo, Malintan, Nancy, Poncelet, Mallory, Kriouile, Yamna, Fortuna, Sara, De Zorzi, Rita, Payne, Katelyn, Henderson, Lindsay B, Cortese, Andrea, Maddirevula, Sateesh, Alhashmi, Nadia, Wiethoff, Sarah, Ryten, Mina, Botia, Juan A, Provitera, Vincenzo, Schuelke, Marku, Vandrovcova, Jana, Walsh, Laurence, Torti, Erin, Iodice, Valeria, Najafi, Maryam, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Siquier-Pernet, Karine, Boddaert, Nathalie, De Lonlay, Pascale, Cantagrel, Vincent, Aguennouz, Mhammed, El Khorassani, Mohamed, Schmidts, Miriam, Alkuraya, Fowzan S, Edvardson, Simon, Nolano, Maria, Devaux, Jérôme, Houlden, Henry, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Fibers, Myelinated, Gene Frequency, Neurodevelopmental Disorder, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Nerve Growth Factor, Protein Isoforms, Child, ComputingMilieux_MISCELLANEOUS, Myelin Sheath, neurofascin, neurodevelopment, peripheral demyelination, Allele, Demyelinating Disease, Genomics, neurodevelopment, neurofascin, peripheral demyelination, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, Peripheral Nerve, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neuroglia, Human, Adult, Adolescent, Nervous System Malformations, Guillain-Barre Syndrome, Axon, Nervous System Malformation, Ranvier's Nodes, Humans, Nerve Growth Factors, Peripheral Nerves, Alleles, Autoantibodies, Infant, Protein Isoform, Original Articles, Axons, nervous system, Neurodevelopmental Disorders, Cell Adhesion Molecule, Mutation, Cell Adhesion Molecules, Demyelinating Diseases
Abstract

See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres., Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

Published
2019
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2. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Author

Neuray, C., Maroofian, R., Scala, M., Sultan, T., Pai, G. S., Mojarrad, M., Khashab, H. E., Deholl, L., Yue, W., Alsaif, H. S., Zanetti, M. N., Bello, O., Person, R., Eslahi, A., Khazaei, Z., Feizabadi, M. H., Efthymiou, S., El-Bassyouni, H. T., Soliman, D. R., Tekes, S., Ozer, L., Baltaci, V., Khan, S., Beetz, C., Amr, K. S., Salpietro, V., Jamshidi, Y., Alkuraya, F. S., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Synaps, Group, Di Rosa, G., Aguennouz, M., Goraya, J. S., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Sherifa, H., Neuray C., Maroofian R., Scala M., Sultan T., Pai G.S., Mojarrad M., Khashab H.E., deHoll L., Yue W., Alsaif H.S., Zanetti M.N., Bello O., Person R., Eslahi A., Khazaei Z., Feizabadi M.H., Efthymiou S., El-Bassyouni H.T., Soliman D.R., Tekes S., Ozer L., Baltaci V., Khan S., Beetz C., Amr K.S., Salpietro V., Jamshidi Y., Alkuraya F.S., Houlden H., Mangano S., Dicle Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı, Tekeş, Selahattin, University College of London [London] (UCL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Genoa (UNIGE), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Children's Hospital [Lahore], Institute of Child Health [Lahore], Medical University of South Carolina [Charleston] (MUSC), Mashhad University of Medical Sciences, Ain Shams University (ASU), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Khorasan Razavi Agricultural and Natural Resources Research and Education Center, National Research Centre [Cairo, Egypt], Benha University (BU), Dicle University, CENTOGENE AG, University of London [London], King Faisal Specialist Hospital [Riyadh, Saudi Arabia] (Research Centre), and SYNaPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Gabriella Di Rosa, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D Ferrari, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves A Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa

Subjects
Male, 0301 basic medicine, Glutamate decarboxylase, Malalties cerebrals, Neurotransmissors, Neurodevelopmental delay, Epilepsy, 0302 clinical medicine, MESH: Child, Age of Onset, Child, cleft palate, GAD1, AcademicSubjects/SCI01870, Glutamate Decarboxylase, Glutamate receptor, Muscle weakness, purl.org/becyt/ford/3.1 [https], Neurotransmitters, MESH: Infant, Hypotonia, muscle weakne, Cleft palate, MESH: Epilepsy, Child, Preschool, Muscle Hypotonia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], purl.org/becyt/ford/3 [https], Female, Brain diseases, Abnormalities, medicine.symptom, Multiple, medicine.drug, epilepsy, muscle weakness, neurodevelopmental delay, MESH: Glutamate Decarboxylase, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Age of Onset, Biology, Inhibitory postsynaptic potential, GAD1, cleft palate, epilepsy, muscle weakness, neurodevelopmental delay, gamma-Aminobutyric acid, 03 medical and health sciences, Excitatory synapse, Internal medicine, medicine, Humans, Abnormalities, Multiple, Preschool, Alleles, MESH: Neurodevelopmental Disorders, MESH: Humans, MESH: Muscle Hypotonia, MESH: Alleles, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, Epilèpsia, Editor's Choice, 030104 developmental biology, Endocrinology, Neurodevelopmental Disorders, Mutation, AcademicSubjects/MED00310, Neurology (clinical), MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Reports
Abstract

Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations., Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

Published
2020
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3. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

Author

Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., Silvestri G. (ORCID:0000-0002-1950-1468), Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.

Published
2019

7. Irish Cardiac Society Annual General Meeting and Scientific Sessions held on Friday, 6th December and Saturday, 7th December, 1985

Author

Buchalter, M. B., Quigley, P. J., Erwin, J. E., Maurer, B. J., Walsh, M. J., Gearty, G. F., Griffin, B., Timmis, A., Crick, J. C. P., Sowton, E., McGovern, E., Wood, A. E., Shaw, K. M., Crean, Peter A., Waters, David D., Theroux, Pierre, Armstrong, N., Chadwick, E., Nugent, T., Toner, Paula, Varma, M. P. S., Richardson, S. G., Morton, Patricia, Murtagh, J. G., Scott, M. E., O’Keeffe, D. B., Allen, D. C., Richardson, S. G., O’Keeffe, D. B., Morton, Patricia, Murtagh, J. G., Scott, M. E., Richardson, S. G., Morton, Patricia, Murtagh, J. G., Scott, M. E., O’Keeffe, D. B., O’Keeffe, D. B., Morton, Patricia, Murtagh, J. G., Scott, M. E., Buchalter, M. B., Quigley, P. J., Maurer, B. J., Walsh, M., Gearty, G. F., Murray, D. P., Rafiqi, E., Murray, R. G., Littler, W. A., Branagan, J. P., McCafferty, D., Kelleher, A., Walsh, M. J., Donnelly, M. D. I., Mcllwaine, W. F., Duff, D., Hussain, A., Devane, S., Hickey, M. St. J., Wood, A. E., Neligan, M. C., Mulholland, H. C., Shields, M. D., Griffin, B., Sowton, E., Clements, Ian P., Nelson, Martin A., Gibbon, Raymond J., Brown, Manuel L., Daly, L., Conroy, R., Hickey, N., Mulcahy, R., Lee, J. E., Knight, J. A., Campbell, N. P. S., Adgey, A. A. J., O’Hara, M. J., Jones, R. I., Lahira, A., B-Raftery, E., Walsh, K. P., Ingram, A., Kenny, R. A., Vardas, P. E., Sutton, R., Walsh, K. P., Ingram, A., Kenny, R. A., Vardas, P. E., Sutton, R., Erwin, J., McWilliams, E., Gearty, G., Maurer, B., Holt, P., Boyd, E., O’Keeffe, D. B., Pringle, T. H., O’Keeffe, D. B., Morton, Patricia, Murtagh, J. G., Scott, M. E., Aherne, T., Yee, E. S., Tcholakoff, D., Finkbeiner, W., Higgins, C. B., Conray, R., Robinson, K., Mulcahy, R., Murray, D. P., Salih, M., Tan, L. B., Derry, S., Murray, R. G., Littler, W. A., Moriarty, A. J., Nelson, S. D., Balnave, K., Graham, I., Bourke, S., Hurley, G., Nunes, D., Stafford, F., Al-Khawaja, I., Caruana, M., Lahiri, A., Raftery, E. B., Pringle, T. H., McCullough, F. W., McNair, S. W., Campbell, N. P. S., Horgan, J. J., O’Callaghan, D., Webb, Hilary, Walsh, K. P., Kelly, P., Brangan, J. P., Collins, W. C., McCafferty, D., Walsh, M. J., Mulcahy, R., Robinson, K., Conroy, R., Robinson, K., Conroy, R., Mulcahy, R., Robinson, K., Conroy, R., Madden, B., Mulcahy, R., Moriarty, A. J., Nelson, S. D., Balnave, K., McCafferty, D., Branagan, J. P., Walsh, M. J., Moriarty, A. J., Nelson, S. D., Balnave, K., Jamidar, H. A., Crooks, S. W., Adgey, A. A. J., Griffin, B., Timmis, A., Crick, J., Sowton, E., Halligan, A., Harkin, K., Gearty, G. F., Collins, W. C. J., Cullen, M. J., Feely, J., Crean, Peter A., Waters, David D., McCans, John L., Kohli, R. S., Kardash, M. M., Rodrigues, E. A., Khurmi, N. S., Lahiri, A., RafteryKhurmi, E. B., Lahiri, A., Raftery, E. B., Gearty, G. F., O’Hara, M. J., Jones, R. I., Lahiri, A., Raftery, E. B., Sullivan, P. A., Daly, Bertie, O’Connor, Raymond, Freyne, Ml., Dineen, Mary, Mulcahy, D. A., Shapiro, L. M., Westgate, Caroline, Ross, D. N., Donaldson, R., Ohman, E. M., Teo, K. K., Johnson, A., Collins, P., Horgan, J. H., Jack, C. M., Hunter, E., Pringle, T. H., Wilson, T., Anderson, J., Adgey, A. A. J., Horgan, J. H., O’Callaghan, D., Webb, Hilary, Teo, K. K., Lahiri, A., Caruana, M., Brigden, G., Cashman, P., Raftery, E. B., Ohman, E. M., Mulcahy, D., Johnson, A., Colins, P., Horgan, J. H., Sherani, Tariq M., McGovern, Eilis, Tarief, Habib-Al, Neligan, Maurice C., Mulcahy, D., Mulcahy, R., Reardon, B., Graham, I., Kenny, R. A., Ingram, A., Mitsuoka, T., Walsh, K., Sutton, R., Bourke, J., Gold, R. G., Jameson, S., and Steen, Heather

Published
1987
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10. 24 h blood pressure control with the once daily calcium antagonist, amlodipine.

Author

Heber, ME, Brigden, G., Al-Khawaja, I., and Raftery, EB

Abstract

1. Amlodipine is a novel calcium antagonist which, although pharmacologically similar to other dihydropyridine calcium antagonists, has a long plasma half-life, permitting steady state blood levels to be achieved with a once-daily dose regimen. 2. We have performed a study to examine the effects of this drug on the blood pressure of hypertensive patients over a 24 h period. After a placebo run-in, the drug was administered to 11 patients at a starting dose of 5 mg, and increased to 10 mg after 2 weeks of treatment if the cuff diastolic blood pressure response was unsatisfactory. Cuff measurements were made at entry, after 2 weeks treatment with placebo, after 2 weeks on amlodipine 5 mg once daily, and after a further 4 weeks on amlodipine 5 mg or 10 mg once daily. Intraarterial blood pressure recordings were made at the end of the placebo phase and at completion of the study. 3. Mean supine blood pressure measured sphygmomanometrically was 168/103 (n = 11) mm Hg at entry, 169/104 (n = 11) mm Hg at the end of the placebo phase, 153/95 (n = 11) mm Hg after 2 weeks of treatment and 146/92 (n = 11) mm Hg at the end of the study. Blood pressure curves plotted for each phase of the study revealed an effective 24 h duration of action. Mean daytime blood pressure was reduced from 165/103 to 147/89 mm Hg (P less than 0.05, n = 10), and mean night-time blood pressure was reduced from 137/79 to 121/69 mm Hg (P less than 0.05, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Published
1989
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11. Nicardipine and verapamil in essential hypertension.

Author

AL-KHAWAJA, I. M., CARUANA, M. P., LAHIRI, A., WHITTINGTON, J. R., LEWIS, J. G., and RAFTERY, E. B.

Abstract

Nicardipine 30 mg three times daily and verapamil 160 mg twice daily have been compared in 30 patients with essential hypertension using a two-period crossover clinical trial with 6 week treatment periods., Blood pressure, heart rate and radionuclide left ventricular function were measured before and after exercise on both treatments. In addition to ejection fraction and ejection time, the left ventricular pressure volume ratio (P/V ratio) and left ventricular circumferential fibre shortening (VcF) were determined from the radionuclide scans., Two patients were withdrawn from the trial during each of the treatment periods because of possible side-effects of therapy. Three patients were not analysed because of early crossover due to side-effects, leaving 23 completed studies., Both treatments resulted in similar reductions in blood pressure, which were statistically significant with respect to the placebo-treated baseline. There was a significant difference between the effect of the two treatments on heart rate; both at rest and peak exercise, verapamil produced significant falls in heart rate but nicardipine produced little change. Neither treatment altered exercise capacity., Both treatments produced similar increases in resting ejection fraction. Nicardipine resulted in a small decrease in ejection time and verapamil in a small increase ( P < 0.001 between treatments)., Neither treatment produced significant change in resting P/V ratio. However, VcF improved significantly with nicardipine but was virtually unchanged with verapamil., Nicardipine has a similar hypotensive efficacy to that of verapamil, but may be safer in the treatment of patients with depressed or compromised cardiac function. [ABSTRACT FROM AUTHOR]

Published
1986
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12. Calcium antagonist treatment and its effects on left ventricular function in patients with ischaemic heart disease.

Author

RODRIGUES, E. A., AL-KHAWAJA, I. M., LAHIRI, A., and RAFTERY, E. B.

Abstract

A double-blind, cross-over protocol was used to study the effects of chronic therapy with nicardipine and verapamil on left ventricular function in 21 patients with chronic stable angina. Rest and exercise radionuclide angiography was performed before and after each 4 week treatment period., Resting and exercise heart rates were significantly lower on verapamil than on nicardipine. Rest and exercise systolic blood pressures were not significantly altered by either drug, but peak exercise time increased on both nicardipine and verapamil compared with placebo., Left ventricular ejection fraction and ejection time were comparable on both drugs. Resting ejection rate was unaltered but resting ejection rate index was greater on verapamil than on nicardipine., On exercise, however, ejection rate was significantly higher on nicardipine than on verapamil suggesting improved exercise systolic left ventricular function on nicardipine. [ABSTRACT FROM AUTHOR]

Published
1986
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13. The effects of long-acting pinacidil on intra-arterial blood pressure.

Author

Caruana, MP, Al-Khawaja, I., Royston, P., and Raftery, EB

Abstract

We have tested the efficacy of a new long-acting preparation of pinacidil, an arterial vasodilator, using continuous intra-arterial ambulatory blood pressure recording. An acute dose produced a measurable effect lasting for 12 h. The duration of this effect was less during chronic twice daily drug administration. Side effects were common, causing two out of nine patients to withdraw from the study. Tilt testing produced no postural hypotension and there was no evidence of rebound hypertension on the withdrawal day. [ABSTRACT FROM AUTHOR]

Published
1985
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14. Radionuclide measurements of diastolic function for assessing early left ventricular abnormalities in the hypertensive patient.

Author

Caruana, M, Al-Khawaja, I, Lahiri, A, Lewis, J, and Raftery, E B

Abstract

Three measurements of diastolic filling were compared in 29 patients with essential hypertension and 27 age matched normotensive controls. Systolic function was normal in all but one of the patients. The mean (1SD) first one third filling fraction (a measurement of early diastolic filling) was significantly lower in the hypertensive groups (0.27 (0.24] than in the control group (0.45 (0.16)). The hypertensive group was subdivided into those with electrocardiographic abnormalities and those without. In the subgroup with a normal electrocardiogram the mean (1SD) first one third filling fraction measurement (0.28 (0.16)) was significantly lower than in the control group. In the subgroup with an abnormal electrocardiogram, the first one third filling fraction was even lower (0.24 (0.9)). In addition, the time to peak filling rate (213 (56) ms) was significantly longer in the subgroup with the abnormal electrocardiogram than in the control group (164 (45) ms). However, the interobserver reproducibility of the time to peak filling measurement was poor. The peak filling rate was low in the subgroup with an abnormal electrocardiogram, but not significantly different from the normal controls. The discriminatory value of the three diastolic measurements did not improve with exercise. These results showed an early diastolic filling abnormality in essential hypertension that did not appear to be caused by disease of the large coronary vessels as it was present in patients with normal wall motion and a normal exercise electrocardiogram. The occurrence of diastolic abnormalities when systolic function is still normal may mark an early stage in the development of hypertensive heart failure, at a time when the process is still potentially reversible. [ABSTRACT FROM PUBLISHER]

Published
1988
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15. Radionuclide left ventricular ejection fraction: a comparison of three methods.

Author

Hains, A D, Al-Khawaja, I, Hinge, D A, Lahiri, A, and Raftery, E B

Abstract

Three commercially available computer programs (a semiautomatic method, a manual method, and a regional method) were used to calculate left ventricular ejection fraction from the equilibrium multiple gated radionuclide ventriculograms obtained from 24 normal male subjects and 20 men with heart failure. In the normal subjects the ejection fraction values calculated by each method were significantly different (mean SD) difference between semiautomatic and manual 3.3 (5.8); between semiautomatic and regional 12.0 (6.3); and between manual and regional 8.7 (6.9]. In the patients with heart failure the ejection fraction values calculated by the semiautomatic method differed significantly from those calculated by the manual and regional methods (mean (SD) difference between semiautomatic and manual 3.4 (4.7); between semiautomatic and regional 4.9 (4.9); and between manual and regional 1.5 (6.2]. The ejection fraction values obtained by the semiautomatic method were generally higher and more consistent than those derived from the manual and regional methods. An ejection fraction of greater than or equal to 50% with the semiautomatic method would be regarded as normal but if the same normal range was applied to the regional method nine (38%) of the 24 normal subjects would appear to have an abnormal left ventricular function. Clinicians should be aware that the method used to generate a time-activity curve is an important consideration in the calculation of ejection fraction. Each centre should establish its own range and reproducibility for the method it uses to measure ejection fraction. These values should not be assumed to apply to any other method. [ABSTRACT FROM PUBLISHER]

Published
1987
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19. Calcium antagonist treatment and its effects on left ventricular function in patients with ischaemic heart disease

Author

Rodrigues, E. A., Al-Khawaja, I. M., Lahiri, A., and Raftery, E. B.

Subjects
Calcium Antagonists in the Treatment of Angina, cardiovascular diseases
Abstract

1 A double-blind, cross-over protocol was used to study the effects of chronic therapy with nicardipine and verapamil on left ventricular function in 21 patients with chronic stable angina. Rest and exercise radionuclide angiography was performed before and after each 4 week treatment period.

33. The effect of body weight and age on frequency of repairs in lower-limb prostheses.

Author

Haboubi NHJ, Heelis M, Woodruff R, and Al-Khawaja I

Abstract

INTRODUCTION: Overweight patients sometimes present a practical problem for provision of lower-limb prostheses. Most information about the effect of body weight on the endurance of prostheses is based on laboratory tests. This is a retrospective study based on an audit to study the effect of body weight and age on the frequency of repairs. SUBJECTS: One hundred and sixteen patients were involved (98 male), age 16-96 years, mean=58.7 years; weight 47-140 kg, mean=88 kg; 68 were transtibial amputees and 48 were transfemoral amputees. Causes of amputation were trauma (49), peripheral vascular disease (29), and others (38). Amputation was done 1-66 years prior to assessment, mean=13.66 years. Period of use of current prostheses was 0.5-28 years, mean=3.5 years. RESULTS: One hundred and one repairs were done in a period of 6 months. The number of repairs was found to correlate significantly with weight (P value<0.001) and inversely with age (P value=0.003). No significant correlation was found between repairs and gender, cause of amputation, or level of amputation. CONCLUSION: Body weight and age of amputee are determining factors in the frequency of repairs of lower-limb prostheses. However, a larger study for a longer period will be needed to confirm our finding. [ABSTRACT FROM AUTHOR]

Published
2001

34. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Author

Chelban, Viorica, Wilson, Matthew P., Warman Chardon, Jodi, Vandrovcova, Jana, Zanetti, M. Natalia, Zamba‐Papanicolaou, Eleni, Efthymiou, Stephanie, Pope, Simon, Conte, Maria R., Abis, Giancarlo, Liu, Yo‐Tsen, Tribollet, Eloise, Haridy, Nourelhoda A., Botía, Juan A., Ryten, Mina, Nicolaou, Paschalis, Minaidou, Anna, Christodoulou, Kyproula, Kernohan, Kristin D., Eaton, Alison, Osmond, Matthew, Ito, Yoko, Bourque, Pierre, Jepson, James E. C., Bello, Oscar, Bremner, Fion, Cordivari, Carla, Reilly, Mary M., Foiani, Martha, Heslegrave, Amanda, Zetterberg, Henrik, Heales, Simon J. R., Wood, Nicholas W., Rothman, James E., Boycott, Kym M., Mills, Philippa B., Clayton, Peter T., Houlden, Henry, Kriouile, Yamna, Khorassani, Mohamed El, Aguennouz, Mhammed, Groppa, Stanislav, Marinova Karashova, Blagovesta, Van Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez‐Dueñas, Belen, Di Rosa, Gabriella, Goraya, Jatinder S., Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda‐Marfa, Mercedes, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M J M, Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García‐Silva, Mayte, Ruiz, Alfons Macaya, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Sanchez, Benigno Monteagudo, Boles, Richard, Papacostas, Savvas, Vikelis, Michail, Rothman, James, Giunti, Paola, Salpietro, Vincenzo, Oconnor, Emer, Kullmann, Dimitri, Kaiyrzhanov, Rauan, Sullivan, Roisin, Khan, Alaa Matooq, Yau, Wai Yan, Hostettler, Isabel, Papanicolaou, Eleni Zamba, Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat Noureen, Atawneh, Osama, Lim, Shen‐Yang, Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Torti, Erin, Zollo, Massimi, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al‐Khawaja, Issam, Al‐Mutairi, Fuad, Alkuraya, Fowzan S, Sherifa, Hamed, Rizig, Mie, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Oguntunde, Olapeju, Pchelina, Sofya, Senkevich, Konstantin, Haridy, Nourelhoda, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Bourinaris, Thomas, Xiromerisiou, Georgia, Fidani, Liana, Spanaki, Cleanthe, Tucci, Arianna, University College London Hospitals (UCLH), Université d'Ottawa [Ontario] (uOttawa), King‘s College London, University College of London [London] (UCL), University of Cyprus [Nicosia], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, National Yang Ming University (NYMU), Department of Information and Communications Engineering [Murcia], Universidad de Murcia, Guy's Hospital [London], Cyprus Institute of Neurology and Genetics, University of Ottawa [Ottawa], The Ottawa Hospital, University of British Columbia (UBC), Ottawa Hospital Research Institute [Ottawa] (OHRI), Institute of Neurology, Queen Square, London, Sahlgrenska University Hospital, Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Department of Medical and Surgical Pediatrics, University Hospital, Fondazione, Departments of Human Genetics & Neurology, Leiden University Medical Center (LUMC), University of Laquila, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Yale University School of Medicine, Department of Microbiology, Università degli studi di Catania [Catania], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gene Dx, Partenaires INRAE, Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universita degli studi di Genova, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], UCL Institute of neurology, UCL Institute of Neurology, Chelban V., Wilson M.P., Warman Chardon J., Vandrovcova J., Zanetti M.N., Zamba-Papanicolaou E., Efthymiou S., Pope S., Conte M.R., Abis G., Liu Y.-T., Tribollet E., Haridy N.A., Botia J.A., Ryten M., Nicolaou P., Minaidou A., Christodoulou K., Kernohan K.D., Eaton A., Osmond M., Ito Y., Bourque P., Jepson J.E.C., Bello O., Bremner F., Cordivari C., Reilly M.M., Foiani M., Heslegrave A., Zetterberg H., Heales S.J.R., Wood N.W., Rothman J.E., Boycott K.M., Mills P.B., Clayton P.T., Houlden H., Kriouile Y., Khorassani M.E., Aguennouz M., Groppa S., Marinova Karashova B., Van Maldergem L., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Di Rosa G., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., van den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Giunti P., Salpietro V., Oconnor E., Kullmann D., Kaiyrzhanov R., Sullivan R., Khan A.M., Yau W.Y., Hostettler I., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Torti E., Zollo M., Heimer G., Dauvilliers Y.A., Striano P., Al-Khawaja I., Al-Mutairi F., Alkuraya F.S., Sherifa H., Rizig M., Okubadejo N.U., Ojo O.O., Oshinaike O.O., Wahab K., Bello A.H., Abubakar S., Obiabo Y., Nwazor E., Ekenze O., Williams U., Iyagba A., Taiwo L., Komolafe M., Oguntunde O., Pchelina S., Senkevich K., Haridy N., Shashkin C., Zharkynbekova N., Koneyev K., Manizha G., Isrofilov M., Guliyeva U., Salayev K., Khachatryan S., Rossi S., Silvestri G., Bourinaris T., Xiromerisiou G., Fidani L., Spanaki C., and Tucci A.

Subjects
0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LOCAL TRANSLATION, Medizin, medicine.disease_cause, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, polineuropathy, Cinètica enzimàtica, Gene Regulatory Networks, Pyridoxal phosphate, Child, Pyridoxal Kinase, Adenosine triphosphate (ATP), Research Articles, Aged, 80 and over, Mutation, Gene Regulatory Network, PLASMA, Autosomal recessive axonal polyneuropathy, Disease gene identification, Pyridoxal kinase, 3. Good health, Settore MED/26 - NEUROLOGIA, Neuropaties perifèriques, Treatment Outcome, Polyneuropathie, Neurology, Child, Preschool, Pyridoxal Phosphate, RELIABILITY, Vitamin B Complex, Female, Life Sciences & Biomedicine, Polyneuropathy, Human, Research Article, Adult, Adolescent, PDXK, Clinical Neurology, CHARCOT-MARIE-TOOTH, CHARCOT-MARIE-TOOTH, CMT NEUROPATHY SCORE, LOCAL TRANSLATION, DISEASE, RELIABILITY, MECHANISMS, DISCOVERY, FRAMEWORK, KINASE, PLASMA, MECHANISMS, 03 medical and health sciences, Polyneuropathies, Atrophy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], KINASE, medicine, Humans, CMT NEUROPATHY SCORE, PDXK mutations, Pyridoxal, Dietary Supplement, Aged, Peripheral neuropathies, Science & Technology, [SCCO.NEUR]Cognitive science/Neuroscience, Enzyme kinetics, Neurosciences, FRAMEWORK, medicine.disease, Molecular biology, 030104 developmental biology, chemistry, DISCOVERY, Dietary Supplements, Neurosciences & Neurology, Neurology (clinical), Adenosine triphosphate, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240. ispartof: ANNALS OF NEUROLOGY vol:86 issue:2 pages:225-240 ispartof: location:United States status: published

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35. The Barthel Index and its relationship to nursing dependency in rehabilitation.

Author

al-Khawaja I, Wade DT, and Turner F

Subjects
Activities of Daily Living, Adolescent, Adult, Aged, Central Nervous System Diseases physiopathology, Central Nervous System Diseases rehabilitation, Chronic Disease, Female, Humans, Male, Middle Aged, Prospective Studies, Regression Analysis, Sensitivity and Specificity, Spinal Cord Diseases nursing, Spinal Cord Diseases physiopathology, Spinal Cord Diseases rehabilitation, United Kingdom, Central Nervous System Diseases nursing, Rehabilitation Nursing
Abstract

Objectives: To investigate the clinical application of the Barthel Index as an indicator of nursing dependency in a younger disabled unit., Design: A prospective study of 132 patients (mean age 49) with chronic neurological problems., Setting: A younger disabled unit at a District General Hospital, Oxford., Main Outcome Measures: The Barthel Index, and total nursing hours., Results: The Median Barthel Index was 7 (95% confidence interval 6-9). The mean nursing hours were 2.7 +/- 1.7 (CI 2.41-2.99). Spearman rank order correlation coefficient between the Barthel Index and nursing hours was r = -0.69 (CI -0.79 to -0.59)., Conclusions: Regression analysis showed that it was possible to use the Barthel Index as an indicator of nursing dependency particularly in physical care, and that it was independent of age and diagnosis.

Published
1997
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36. Bedside screening for aphasia: a comparison of two methods.

Author

Al-Khawaja I, Wade DT, and Collin CF

Subjects
Aphasia psychology, Female, Humans, Linear Models, Male, Memory physiology, Middle Aged, Prospective Studies, Psychiatric Status Rating Scales, Aphasia physiopathology, Point-of-Care Systems
Abstract

A prospective study was carried out in 50 consecutive patients referred with suspected aphasia in order to compare the Frenchay Aphasia Screening Test (FAST) with the Sheffield Screening Test for Acquired Language Disorders (SST). The study included 32 men and 18 women with a mean (SEM) age 53.9 (2) years. The comprehension scores on the FAST were correlated with receptive skills on the SST r = 0.74 (P < 0.001). For expression, the correlation coefficient was r = 0.92 (P < 0.001) and the total scores of the two tests correlated closely r = 0.89 (P < 0.001). There was a positive correlation between total score on the FAST and the Short Orientation, Memory and Concentration test (SOMC) r = 0.86 (P < 0.001), and the total scores on the SST and SOMC r = 0.91 (P < 0.001). The Barthel index also correlated positively with the FAST r = 0.59 (P < 0.001) and SST r = 0.63 (P < 0.001). The study demonstrated that the two tests are simple, short and similar in their predictive value for the screening and diagnosis of aphasia. The SST was found to have additional advantages, as it does not require any special equipment or stimulus cards, and it was not affected by visual neglect.

Published
1996
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38. Intra-arterial monitoring of the antihypertensive effects of once-daily amlodipine.

Author

Broadhurst P, Heber ME, Brigden G, al-Khawaja I, and Raftery EB

Subjects
Amlodipine administration & dosage, Amlodipine adverse effects, Antihypertensive Agents administration & dosage, Antihypertensive Agents adverse effects, Blood Pressure drug effects, Blood Pressure physiology, Blood Pressure Determination instrumentation, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Single-Blind Method, Time Factors, Amlodipine therapeutic use, Antihypertensive Agents therapeutic use, Blood Pressure Monitors, Hypertension drug therapy
Abstract

Amlodipine is a dihydropyridine calcium antagonist with a long elimination half life making it suitable for once-daily dosing. This study used sphygmomanometric and intra-arterial ambulatory blood pressure (BP) monitoring to confirm the antihypertensive effect of a once-daily dose of amlodipine over the dosing interval. After a 2-week single-blind placebo run in, amlodipine was administered to 11 patients at a starting dose of 5 mg daily for 2 weeks increasing to 10 mg daily for a further 4 weeks if diastolic blood pressure (DBP) measured sphygmomanometrically was not < 90 mmHg or decreased by > 10 mmHg from baseline values. Intra-arterial blood pressure recordings for 24-hour periods were made at the end of the placebo run in and on completion of the active treatment phase. The effects of isometric and dynamic exercise and head-up tilting (60 degrees) on BP and heart rate were measured during ambulatory monitoring. Mean supine cuff BP was 169/104 mmHg (n = 11) at the end of the placebo treatment period and was reduced to 153/95 mmHg (n = 11) after 2 weeks of amlodipine treatment and 146/92 mmHg (n = 11) after 6 weeks of amlodipine treatment. There was no significant change in heart rate. Intra-arterial ambulatory monitoring showed that BP was controlled for the whole dosing interval with once-daily doses of amlodipine. The normal circadian pattern of BP changes was not altered. BP was reduced by amlodipine during exercise and physiological tests, but there was no postural hypotension and the BP and heart rate responses to exercise were not blunted.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1992

39. Measurement of absolute left ventricular volume by radionuclide angiography: a technical review.

Author

Al-Khawaja IM, Lahiri A, and Raftery EB

Subjects
Heart Diseases diagnostic imaging, Heart Ventricles, Humans, Reference Values, Cardiac Volume, Heart diagnostic imaging, Radionuclide Angiography
Abstract

Absolute left ventricular volumes have important clinical implications in the evaluation of cardiac performance. Several invasive and noninvasive techniques have been reported, none of which can be considered ideal for this purpose. Contrast angiography, echocardiography and radionuclide ventriculography are open to criticism. Different radioisotopic approaches are described with emphasis on the importance of accurate separation of left ventricular activity, the selection of background activity, and the correction for photon attenuation by body tissues. Improper use of statistics and validation techniques have obscured the value of these techniques. In the absence of a 'gold standard' there should be a 'radioisotopic' left ventricular volume with established independent characteristics, repeatability and reproducibility by which new approaches can be judged.

Published
1988

40. Effects of a new vasodilating beta-blocking drug, carvedilol, on left ventricular function in stable angina pectoris.

Author

Lahiri A, Rodrigues EA, Al-Khawaja I, and Raftery EB

Subjects
Adrenergic beta-Antagonists adverse effects, Aged, Blood Pressure drug effects, Carbazoles adverse effects, Carvedilol, Electrocardiography, Exercise Test, Female, Heart Rate drug effects, Heart Ventricles diagnostic imaging, Heart Ventricles drug effects, Humans, Male, Middle Aged, Radionuclide Imaging, Vasodilator Agents adverse effects, Adrenergic beta-Antagonists pharmacology, Angina Pectoris physiopathology, Carbazoles pharmacology, Heart drug effects, Propanolamines, Vasodilator Agents pharmacology
Abstract

The effects of a new vasodilating beta-blocking drug, carvedilol, were studied in 20 patients with chronic stable angina using a single-blind, placebo-controlled protocol. Two doses of carvedilol, 25 mg twice daily and 50 mg twice daily, were compared with placebo using analysis of variance. The study design consisted of 2 weekly phases of initial placebo followed by carvedilol, 25 mg twice daily and then 50 mg twice daily, and a second placebo period. Supine rest and exercise radionuclide ventriculography was performed at the end of each phase. Carvedilol produced a significant dose-related reduction in rest and exercise heart rate and blood pressure (p less than 0.01 to less than 0.0001). Ejection fraction at rest increased significantly, from a mean (+/- standard error) of 53 +/- 3% with placebo to 58 +/- 3% with carvedilol, 50 mg twice daily, but no improvement was noted in ejection fraction on exercise. Relative, counts-based end-systolic and end-diastolic volumes were significantly reduced at rest (p less than 0.001). Rest peak filling rate index, first-third filling fraction and ejection rate index increased significantly with carvedilol. A dose-related change was observed with rest ejection fraction, peak filling rate index and ejection rate index. Exercise-induced ST-segment depression improved significantly with both doses of carvedilol compared with placebo. Carvedilol was well tolerated and produced significant hemodynamic improvement. This salutary effect on left ventricular function may confer advantages in long-term treatment of patients with chronic stable angina.

Published
1987
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41. A comparison of single doses of lisinopril and enalapril in hypertension.

Author

Dews I, Wiseman WT, al-Khawaja I, Stephens J, and VandenBurg M

Subjects
Adult, Aged, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Blood Pressure drug effects, Double-Blind Method, Enalapril administration & dosage, Heart Rate drug effects, Humans, Hypertension enzymology, Lisinopril, Middle Aged, Peptidyl-Dipeptidase A blood, Random Allocation, Renin blood, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Enalapril analogs & derivatives, Enalapril therapeutic use, Hypertension drug therapy
Abstract

Sixteen patients with mild to moderate hypertension were studied in a double-blind crossover comparison of single oral doses of lisinopril 10 mg and enalapril 10 mg. Both drugs caused a marked fall in blood pressure (BP) with a clinically useful effect persisting for 24 h postdose and with no significant difference between treatments in this respect. The time to minimum systolic BP was 2 h (95% confidence limits 0-19 h) longer for lisinopril. The fall in ACE activity at 24 h was 18.5 (8.2-28.8) U/l greater for lisinopril. We conclude that, within the limits of this small study, lisinopril appears to be as effective as enalapril in lowering BP and that it may have a slower onset of action that could be clinically valuable.

Published
1989

42. Once- and twice-daily bevantolol for systemic hypertension using 24-hour ambulatory intraarterial blood pressure recording.

Author

Al-Khawaja IM, Caruana MP, Prince H, Whittington J, and Raftery EB

Subjects
Adrenergic beta-Antagonists adverse effects, Adult, Aged, Blood Pressure Determination methods, Circadian Rhythm, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Monitoring, Physiologic methods, Propanolamines adverse effects, Adrenergic beta-Antagonists administration & dosage, Hypertension drug therapy, Propanolamines administration & dosage
Abstract

The antihypertensive efficacy of bevantolol, a selective beta 1-adrenoreceptor antagonist, was evaluated in 17 patients with essential hypertension, using continuous ambulatory intraarterial blood pressure (BP) monitoring. The study compared a twice-daily regimen (titrated dose of 200 to 600 mg/day) with the same amount given in a single daily dose. Within-patient comparisons of mean hourly systolic and diastolic BPs and heart rate showed a highly significant effect with twice-daily therapy (p less than 0.001) for all of the 24 hours. Similar significant results were obtained with a single morning dose. There was no difference between the pattern or extent of BP reduction with the 2 regimens. The decrease in BP after bevantolol persisted during the physiologic tests (rest, tilt, isometric and dynamic exercise). Four patients developed minor side effects with the single morning dose, and only 1 patient with the twice-daily regimen. These effects included tiredness, fatigue and dizziness. Unlike pure beta-blocking agents, bevantolol controlled the early morning increase in BP, lending support to the belief that it possesses vasodilatory properties in addition to beta blockade. These results suggest that bevantolol may be useful as first-line therapy in a once-daily dosage for the treatment of essential hypertension.

Published
1986
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