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29 results on '"Bourinaris, Thomas"'

1. Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

Author

de Boni, Laura, Wallis, Amber, Hays Watson, Aurelia, Ruiz-Riquelme, Alejandro, Leyland, Louise-Ann, Bourinaris, Thomas, Hannaway, Naomi, Wüllner, Ullrich, Peters, Oliver, Priller, Josef, Falkenburger, Björn H, Wiltfang, Jens, Bähr, Mathias, Zerr, Inga, Bürger, Katharina, Perneczky, Robert, Teipel, Stefan, Löhle, Matthias, Hermann, Wiebke, Schott, Björn-Hendrik, Brockmann, Kathrin, Spottke, Annika, Haustein, Katrin, Breuer, Peter, Houlden, Henry, Weil, Rimona S, and Bartels, Tim

Published
2024
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5. SORL1 mutation in a Greek family with Parkinson's disease and dementia

Author

Xiromerisiou, Georgia, primary, Bourinaris, Thomas, additional, Houlden, Henry, additional, Lewis, Patrick A., additional, Senkevich, Konstantin, additional, Hammer, Monia, additional, Federoff, Monica, additional, Khan, Alaa, additional, Spanaki, Cleanthe, additional, Hadjigeorgiou, Georgios M., additional, Bonstanjopoulou, Sevasti, additional, Fidani, Liana, additional, Ermolaev, Aleksey, additional, Gan‐Or, Ziv, additional, Singleton, Andrew, additional, Vandrovcova, Jana, additional, and Hardy, John, additional

Published
2021
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7. Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Author

Bourinaris, Thomas, Smedley, Damian, Cipriani, Valentina, Sheikh, Isabella, Athanasiou-Fragkouli, Alkyoni, Chinnery, Patrick, Morris, Huw, Real, Raquel, Harrison, Victoria, Reid, Evan, Wood, Nicholas, Genomics England Research Consortium, Vandrovcova, Jana, Houlden, Henry, Tucci, Arianna, Smedley, Damian [0000-0002-5836-9850], Sheikh, Isabella [0000-0002-3952-371X], Chinnery, Patrick [0000-0002-7065-6617], Morris, Huw [0000-0002-5473-3774], Real, Raquel [0000-0001-8117-742X], Houlden, Henry [0000-0002-2866-7777], Tucci, Arianna [0000-0001-5644-0070], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Phenotype, Adolescent, Spastic Paraplegia, Hereditary, Mutation, Humans, Female, Middle Aged, Carrier Proteins, Child, Aged
Abstract

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Published
2020

10. Expanding the Spectrum ofAP5Z1‐Related Hereditary Spastic Paraplegia ( HSP‐SPG48 ): A Multicenter Study on a Rare Disease

Author

Breza, Marianthi, primary, Hirst, Jennifer, additional, Chelban, Viorica, additional, Banneau, Guillaume, additional, Tissier, Laurène, additional, Kol, Bophara, additional, Bourinaris, Thomas, additional, Said, Samia A., additional, Péréon, Yann, additional, Heinzmann, Anna, additional, Debs, Rabab, additional, Juntas‐Morales, Raul, additional, Martinez, Victoria G., additional, Camdessanche, Jean P., additional, Scherer‐Gagou, Clarisse, additional, Zola, Jean‐Médard, additional, Athanasiou‐Fragkouli, Alkyoni, additional, Efthymiou, Stephanie, additional, Vavougios, George, additional, Velonakis, Georgios, additional, Stamelou, Maria, additional, Tzartos, John, additional, Potagas, Constantin, additional, Zambelis, Thomas, additional, Mariotti, Caterina, additional, Blackstone, Craig, additional, Vandrovcova, Jana, additional, Mavridis, Theodoros, additional, Kartanou, Chrisoula, additional, Stefanis, Leonidas, additional, Wood, Nicholas, additional, Karadima, Georgia, additional, LeGuern, Eric, additional, Koutsis, Georgios, additional, Houlden, Henry, additional, and Stevanin, Giovanni, additional

Published
2021
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11. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Author

Ebrahimi-Fakhari, Darius, Teinert, Julian, Behne, Robert, Wimmer, Miriam, D'Amore, Angelica, Eberhardt, Kathrin, Brechmann, Barbara, Ziegler, Marvin, Jensen, Dana M., Nagabhyrava, Premsai, Geisel, Gregory, Carmody, Erin, Shamshad, Uzma, Dies, Kira A., Yuskaitis, Christopher J., Salussolia, Catherine L., Ebrahimi-Fakhari, Daniel, Pearson, Toni S., Saffari, Afshin, Ziegler, Andreas, Koelker, Stefan, Volkmann, Jens, Wiesener, Antje, Bearden, David R., Lakhani, Shenela, Segal, Devorah, Udwadia-Hegde, Anaita, Martinuzzi, Andrea, Hirst, Jennifer, Perlman, Seth, Takiyama, Yoshihisa, Xiromerisiou, Georgia, Vill, Katharina, Walker, William O., Shukla, Anju, Gupta, Rachana Dubey, Dahl, Niklas, Aksoy, Ayse, Verhelst, Helene, Delgado, Mauricio R., Pourova, Radka Kremlikova, Sadek, Abdelrahim A., Elkhateeb, Nour M., Blumkin, Lubov, Brea-Fernandez, Alejandro J., Dacruz-Alvarez, David, Smol, Thomas, Ghoumid, Jamal, Miguel, Diego, Heine, Constanze, Schlump, Jan-Ulrich, Langen, Hendrik, Baets, Jonathan, Bulk, Saskia, Darvish, Hossein, Bakhtiari, Somayeh, Kruer, Michael C., Lim-Melia, Elizabeth, Aydinli, Nur, Alanay, Yasemin, El-Rashidy, Omnia, Nampoothiri, Sheela, Patel, Chirag, Beetz, Christian, Bauer, Peter, Yoon, Grace, Guillot, Mireille, Miller, Steven P., Bourinaris, Thomas, Houlden, Henry, Robelin, Laura, Anheim, Mathieu, Alamri, Abdullah S., Mahmoud, Adel A. H., Inaloo, Soroor, Habibzadeh, Parham, Faghihi, Mohammad Ali, Jansen, Anna C., Brock, Stefanie, Roubertie, Agathe, Darras, Basil T., Agrawal, Pankaj B., Santorelli, Filippo M., Gleeson, Joseph, Zaki, Maha S., Sheikh, Sarah, I, Bennett, James T., Sahin, Mustafa, Ebrahimi-Fakhari, Darius, Teinert, Julian, Behne, Robert, Wimmer, Miriam, D'Amore, Angelica, Eberhardt, Kathrin, Brechmann, Barbara, Ziegler, Marvin, Jensen, Dana M., Nagabhyrava, Premsai, Geisel, Gregory, Carmody, Erin, Shamshad, Uzma, Dies, Kira A., Yuskaitis, Christopher J., Salussolia, Catherine L., Ebrahimi-Fakhari, Daniel, Pearson, Toni S., Saffari, Afshin, Ziegler, Andreas, Koelker, Stefan, Volkmann, Jens, Wiesener, Antje, Bearden, David R., Lakhani, Shenela, Segal, Devorah, Udwadia-Hegde, Anaita, Martinuzzi, Andrea, Hirst, Jennifer, Perlman, Seth, Takiyama, Yoshihisa, Xiromerisiou, Georgia, Vill, Katharina, Walker, William O., Shukla, Anju, Gupta, Rachana Dubey, Dahl, Niklas, Aksoy, Ayse, Verhelst, Helene, Delgado, Mauricio R., Pourova, Radka Kremlikova, Sadek, Abdelrahim A., Elkhateeb, Nour M., Blumkin, Lubov, Brea-Fernandez, Alejandro J., Dacruz-Alvarez, David, Smol, Thomas, Ghoumid, Jamal, Miguel, Diego, Heine, Constanze, Schlump, Jan-Ulrich, Langen, Hendrik, Baets, Jonathan, Bulk, Saskia, Darvish, Hossein, Bakhtiari, Somayeh, Kruer, Michael C., Lim-Melia, Elizabeth, Aydinli, Nur, Alanay, Yasemin, El-Rashidy, Omnia, Nampoothiri, Sheela, Patel, Chirag, Beetz, Christian, Bauer, Peter, Yoon, Grace, Guillot, Mireille, Miller, Steven P., Bourinaris, Thomas, Houlden, Henry, Robelin, Laura, Anheim, Mathieu, Alamri, Abdullah S., Mahmoud, Adel A. H., Inaloo, Soroor, Habibzadeh, Parham, Faghihi, Mohammad Ali, Jansen, Anna C., Brock, Stefanie, Roubertie, Agathe, Darras, Basil T., Agrawal, Pankaj B., Santorelli, Filippo M., Gleeson, Joseph, Zaki, Maha S., Sheikh, Sarah, I, Bennett, James T., and Sahin, Mustafa

Abstract

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined th

Published
2020
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12. Spastic paraplegia preceding PSEN1 ‐related familial Alzheimer's disease

Author

Chelban, Viorica, primary, Breza, Marianthi, additional, Szaruga, Maria, additional, Vandrovcova, Jana, additional, Murphy, David, additional, Lee, Chia‐Ju, additional, Alikhwan, Sondos, additional, Bourinaris, Thomas, additional, Vavougios, George, additional, Ilyas, Muhammad, additional, Halim, Sobia Ahsan, additional, Al‐Harrasi, Ahmed, additional, Kartanou, Chrisoula, additional, Ronald, Coras, additional, Blumcke, Ingmar, additional, Alexoudi, Athanasia, additional, Gatzonis, Stylianos, additional, Stefanis, Leonidas, additional, Karadima, Georgia, additional, Wood, Nicholas W., additional, Chávez‐Gutiérrez, Lucía, additional, Hardy, John, additional, Houlden, Henry, additional, and Koutsis, Georgios, additional

Published
2021
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13. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Author

Ebrahimi-Fakhari, Darius, primary, Teinert, Julian, additional, Behne, Robert, additional, Wimmer, Miriam, additional, D'Amore, Angelica, additional, Eberhardt, Kathrin, additional, Brechmann, Barbara, additional, Ziegler, Marvin, additional, Jensen, Dana M, additional, Nagabhyrava, Premsai, additional, Geisel, Gregory, additional, Carmody, Erin, additional, Shamshad, Uzma, additional, Dies, Kira A, additional, Yuskaitis, Christopher J, additional, Salussolia, Catherine L, additional, Ebrahimi-Fakhari, Daniel, additional, Pearson, Toni S, additional, Saffari, Afshin, additional, Ziegler, Andreas, additional, Kölker, Stefan, additional, Volkmann, Jens, additional, Wiesener, Antje, additional, Bearden, David R, additional, Lakhani, Shenela, additional, Segal, Devorah, additional, Udwadia-Hegde, Anaita, additional, Martinuzzi, Andrea, additional, Hirst, Jennifer, additional, Perlman, Seth, additional, Takiyama, Yoshihisa, additional, Xiromerisiou, Georgia, additional, Vill, Katharina, additional, Walker, William O, additional, Shukla, Anju, additional, Dubey Gupta, Rachana, additional, Dahl, Niklas, additional, Aksoy, Ayse, additional, Verhelst, Helene, additional, Delgado, Mauricio R, additional, Kremlikova Pourova, Radka, additional, Sadek, Abdelrahim A, additional, Elkhateeb, Nour M, additional, Blumkin, Lubov, additional, Brea-Fernández, Alejandro J, additional, Dacruz-Álvarez, David, additional, Smol, Thomas, additional, Ghoumid, Jamal, additional, Miguel, Diego, additional, Heine, Constanze, additional, Schlump, Jan-Ulrich, additional, Langen, Hendrik, additional, Baets, Jonathan, additional, Bulk, Saskia, additional, Darvish, Hossein, additional, Bakhtiari, Somayeh, additional, Kruer, Michael C, additional, Lim-Melia, Elizabeth, additional, Aydinli, Nur, additional, Alanay, Yasemin, additional, El-Rashidy, Omnia, additional, Nampoothiri, Sheela, additional, Patel, Chirag, additional, Beetz, Christian, additional, Bauer, Peter, additional, Yoon, Grace, additional, Guillot, Mireille, additional, Miller, Steven P, additional, Bourinaris, Thomas, additional, Houlden, Henry, additional, Robelin, Laura, additional, Anheim, Mathieu, additional, Alamri, Abdullah S, additional, Mahmoud, Adel A H, additional, Inaloo, Soroor, additional, Habibzadeh, Parham, additional, Faghihi, Mohammad Ali, additional, Jansen, Anna C, additional, Brock, Stefanie, additional, Roubertie, Agathe, additional, Darras, Basil T, additional, Agrawal, Pankaj B, additional, Santorelli, Filippo M, additional, Gleeson, Joseph, additional, Zaki, Maha S, additional, Sheikh, Sarah I, additional, Bennett, James T, additional, and Sahin, Mustafa, additional

Published
2020
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14. Screening for the C9ORF72 Expansion in Greek Huntington Disease Phenocopies and Controls and Meta-analysis of Current Data

Author

Rikos, Dimitrios, primary, Marogianni, Chrysoula, additional, Provatas, Antonios, additional, Bourinaris, Thomas, additional, Arnaoutoglou, Marianthi, additional, Stathis, Pantelis, additional, Patrinos, George P., additional, Dardiotis, Efthimios, additional, Hadjigeorgiou, George M., additional, and Xiromerisiou, Georgia, additional

Published
2020
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15. A homozygous GDAP2 loss-of-function variant in a patient with adult-onset cerebellar ataxia

Author

Breza, Marianthi, primary, Bourinaris, Thomas, primary, Efthymiou, Stephanie, primary, Maroofian, Reza, primary, Athanasiou-Fragkouli, Alkyoni, primary, Tzartos, John, primary, Velonakis, Georgios, primary, Karavasilis, Efstratios, primary, Angelopoulou, Georgia, primary, Kasselimis, Dimitrios, primary, Potagas, Constantin, primary, Stefanis, Leonidas, primary, Karadima, Georgia, primary, Koutsis, Georgios, primary, and Houlden, Henry, primary

Published
2020
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16. Prevalence of C9orf72 hexanucleotide repeat expansion in Greek patients with sporadic ALS

Author

Sokratous, Maria, primary, Lucia, Schottlaender, additional, Bourinaris, Thomas, additional, Marogianni, Chrysoula, additional, Arnaoutoglou, Marianthi, additional, Patrikiou, Eleni, additional, Ralli, Styliani, additional, Markou, Aikaterini, additional, Dardiotis, Efthimios, additional, Houlden, Henry, additional, Hadjigeorgiou, Georgios M., additional, and Xiromerisiou, Georgia, additional

Published
2020
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17. Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking

Author

Behne, Robert, primary, Teinert, Julian, additional, Wimmer, Miriam, additional, D’Amore, Angelica, additional, Davies, Alexandra K, additional, Scarrott, Joseph M, additional, Eberhardt, Kathrin, additional, Brechmann, Barbara, additional, Chen, Ivy Pin-Fang, additional, Buttermore, Elizabeth D, additional, Barrett, Lee, additional, Dwyer, Sean, additional, Chen, Teresa, additional, Hirst, Jennifer, additional, Wiesener, Antje, additional, Segal, Devorah, additional, Martinuzzi, Andrea, additional, Duarte, Sofia T, additional, Bennett, James T, additional, Bourinaris, Thomas, additional, Houlden, Henry, additional, Roubertie, Agathe, additional, Santorelli, Filippo M, additional, Robinson, Margaret, additional, Azzouz, Mimoun, additional, Lipton, Jonathan O, additional, Borner, Georg H H, additional, Sahin, Mustafa, additional, and Ebrahimi-Fakhari, Darius, additional

Published
2020
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19. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, Tucci Arianna, Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, and Tucci Arianna

Published
2019

21. Expanding the Spectrum of AP5Z1‐Related Hereditary Spastic Paraplegia (HSP‐SPG48): A Multicenter Study on a Rare Disease.

Author

Breza, Marianthi, Hirst, Jennifer, Chelban, Viorica, Banneau, Guillaume, Tissier, Laurène, Kol, Bophara, Bourinaris, Thomas, Said, Samia A., Péréon, Yann, Heinzmann, Anna, Debs, Rabab, Juntas‐Morales, Raul, Martinez, Victoria G., Camdessanche, Jean P., Scherer‐Gagou, Clarisse, Zola, Jean‐Médard, Athanasiou‐Fragkouli, Alkyoni, Efthymiou, Stephanie, Vavougios, George, and Velonakis, Georgios

Published
2021
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22. Additional file 1: FigureS1. of Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Author

Bettencourt, Conceição, Salpietro, Vincenzo, Efthymiou, Stephanie, Chelban, Viorica, Hughes, Deborah, Pittman, Alan, Federoff, Monica, Bourinaris, Thomas, Spilioti, Martha, Deretzi, Georgia, Kalantzakou, Triantafyllia, Houlden, Henry, Singleton, Andrew, and Xiromerisiou, Georgia

Subjects
nervous system
Abstract

Expression of the AP4M1 gene in several regions of the human brain throughout development and aging. Note the higher expression levels during fetal development (birth is marked with a vertical solid line). Data from the Human Brain Transcriptome (HBT) project ( http://hbatlas.org ). CBC - cerebellar cortex, MD - mediodorsal nucleus of the thalamus, STR - striatum, AMY - amygdala, HIP - hippocampus, and NCX – neocortex. (PDF 68 kb)

Published
2017
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23. Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Author

Bettencourt, Conceição, Salpietro, Vincenzo, Efthymiou, Stephanie, Chelban, Viorica, Hughes, Deborah, Pittman, Alan M., Federoff, Monica, Bourinaris, Thomas, Spilioti, Martha, Deretzi, Georgia, Kalantzakou, Triantafyllia, Houlden, Henry, Singleton, Andrew B., and Xiromerisiou, Georgia

Subjects
Male, AP4 complex, Cerebellar hypoplasia, Epilepsy, Spastic Paraplegia, Hereditary, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Research, lcsh:R, Hereditary spastic paraplegia, Whole exome sequencing, RNA-Binding Proteins, lcsh:Medicine, Pedigree, DNA-Binding Proteins, Hereditary, Mutation, Humans, Spastic Paraplegia, Female, Genetic Association Studies
Abstract

Background Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients. Methods We investigated a Greek HSP family using whole exome sequencing (WES). Results A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI. Conclusions We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission. Electronic supplementary material The online version of this article (10.1186/s13023-017-0721-2) contains supplementary material, which is available to authorized users.

Published
2017

24. Neuronal intranuclear inclusion disease is genetically heterogeneous.

Author

Chen, Zhongbo, Yan Yau, Wai, Jaunmuktane, Zane, Tucci, Arianna, Sivakumar, Prasanth, Gagliano Taliun, Sarah A., Turner, Chris, Efthymiou, Stephanie, Ibáñez, Kristina, Sullivan, Roisin, Bibi, Farah, Athanasiou‐Fragkouli, Alkyoni, Bourinaris, Thomas, Zhang, David, Revesz, Tamas, Lashley, Tammaryn, DeTure, Michael, Dickson, Dennis W., Josephs, Keith A., and Gelpi, Ellen

Subjects
EAST Asians, NEURODEGENERATION
Abstract

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases. [ABSTRACT FROM AUTHOR]

Published
2020
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25. Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia

Author

Bettencourt, Conceição, primary, Salpietro, Vincenzo, additional, Efthymiou, Stephanie, additional, Chelban, Viorica, additional, Hughes, Deborah, additional, Pittman, Alan M., additional, Federoff, Monica, additional, Bourinaris, Thomas, additional, Spilioti, Martha, additional, Deretzi, Georgia, additional, Kalantzakou, Triantafyllia, additional, Houlden, Henry, additional, Singleton, Andrew B., additional, and Xiromerisiou, Georgia, additional

Published
2017
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26. Identification of UBAP1mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Author

Bourinaris, Thomas, Smedley, Damian, Cipriani, Valentina, Sheikh, Isabella, Athanasiou-Fragkouli, Alkyoni, Chinnery, Patrick, Morris, Huw, Real, Raquel, Harrison, Victoria, Reid, Evan, Wood, Nicholas, Vandrovcova, Jana, Houlden, Henry, and Tucci, Arianna

Abstract

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1needs to be established.

Published
2020
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27. 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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28. Spastic paraplegia preceding PSEN1 -related familial Alzheimer's disease.

Author

Chelban V, Breza M, Szaruga M, Vandrovcova J, Murphy D, Lee CJ, Alikhwan S, Bourinaris T, Vavougios G, Ilyas M, Halim SA, Al-Harrasi A, Kartanou C, Ronald C, Blumcke I, Alexoudi A, Gatzonis S, Stefanis L, Karadima G, Wood NW, Chávez-Gutiérrez L, Hardy J, Houlden H, and Koutsis G

Abstract

Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 ( PSEN1 ) related familial Alzheimer's disease (AD)., Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ-secretase., Results: We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ-secretase reconstitution, it destabilizes γ-secretase-amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid-ring arteries, and severe CAA., Discussion: We show that pure SP can precede dementia onset in PSEN1- related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP-related genes, particularly when associated with a family history of cognitive decline., Competing Interests: The authors declare no competing conflict of interest. M. Breza has received a research grant from European Academy of Neurology (EAN) and travel grants from Genesis Pharma, Teva‐ Specifar, Pfizer, Sanofi‐Genzyme. G. Koutsis has received research grants from Genesis Pharma and Teva; and consultation fees, advisory boards, and honoraria from Sanofi‐Genzyme, Genesis Pharma, Teva, Novartis, Roche, Merck, Pfizer, Specifar, and Integris Pharma. G. Karadima has received research grants from Pfizer and advisory board remuneration from Roche., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Published
2021
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29. Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project.

Author

Bourinaris T, Smedley D, Cipriani V, Sheikh I, Athanasiou-Fragkouli A, Chinnery P, Morris H, Real R, Harrison V, Reid E, Wood N, Vandrovcova J, Houlden H, and Tucci A

Subjects
Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Mutation, Phenotype, Spastic Paraplegia, Hereditary pathology, Carrier Proteins genetics, Spastic Paraplegia, Hereditary genetics
Abstract

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Published
2020
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