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1. Arterioectatic Spinal Angiopathy of Childhood: Clinical, Imaging, Laboratory, Histologic, and Genetic Description of a Novel CNS Vascular Pathology

Author

Abruzzo, T, van den Berg, R, Vadivelu, S, Hetts, SW, Dishop, M, Cornejo, P, Narayanan, V, Ramsey, KE, Coopwood, C, Herik, EG Medici-van den, Roosendaal, SD, Lawton, M, and Bernes, S

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Physical Injury - Accidents and Adverse Effects, Neurodegenerative, Rare Diseases, Traumatic Head and Spine Injury, Spinal Cord Injury, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Angiography, Child, Humans, Magnetic Resonance Imaging, Retrospective Studies, Spinal Cord, Spinal Cord Diseases, Nuclear Medicine & Medical Imaging, Clinical sciences, Physical chemistry
Abstract

Pediatric patients with myelopathy expressing intradural spinal vascular ectasia without arteriovenous shunting were studied at four tertiary referral neuropediatric centers. Patients were identified by retrospective review of institutional records and excluded if spinal vascular pathology could be classified into a previously described category of spinal vascular malformation. Four patients meeting the study criteria were enrolled in the study. Clinical, magnetic resonance imaging, catheter-directed angiography, laboratory, histological and genetic data were analyzed to characterize the disease process and elucidate underlying pathomechanisms. Our study revealed a highly lethal, progressive multi-segmental myelopathy associated with a unique form of non-inflammatory spinal angiopathy featuring diffuse enlargement and tortuosity of spinal cord arteries, spinal cord hyperemia, and spinal cord edema (Arterioectatic Spinal Angiopathy of Childhood). The condition was shown to mimic venous congestive myelopathy associated with pediatric spinal cord arteriovenous shunts on MRI but to have distinct pathognomonic findings on catheter-directed angiography. Clinicopathological, genetic, and neuroimaging features, which are described in detail, closely overlap with those of mitochondrial disease.

Published
2022

3. Specific heat studies of pure Nb3Sn single crystals at low temperature

Author

Escudero, R., Morales, F., and Bernes, S.

Subjects
Condensed Matter - Superconductivity
Abstract

Specific heat measurements performed on high purity vapor-grown Nb$_3$Sn crystals show clear features related to both the martensitic and superconducting transitions. Our measurements indicate that the martensitic anomaly does not display hysteresis, meaning that the martensitic transition could be a weak first or a second order thermodynamic transition. Careful measurements of the two transition temperatures display an inverse correlation between both temperatures. At low temperature specific heat measurements show the existence of a single superconducting energy gap feature., Comment: Accepted in Journal of Physics: Condensed Matter

Published
2009
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10. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Author

Lorena, Travaglini, Francesco, Brancati, Jennifer, Silhavy, Miriam, Iannicelli, Elizabeth, Nickerson, Nadia, Elkhartoufi, Eric, Scott, Emily, Spencer, Stacey, Gabriel, Sophie, Thomas, Bruria, Ben Zeev, Enrico, Bertini, Eugen, Boltshauser, Malika, Chaouch, Maria, Roberta Cilio, Mirjam, M. de Jong, Hulya, Kayserili, Gonul, Ogur, Andrea, Poretti, Sabrina, Signorini, Graziella, Uziel, Maha, S. Zaki, Ali Pacha, L, Zankl, A, Leventer, R, Grattan Smith, P, Janecke, A, Koch, J, Freilinger, M, D'Hooghe, M, Sznajer, Y, Vilain, C, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Dakovic, I, Loncarevic, D, Mejaski Bosnjak, V, Petkovic, D, Abdel Salam GM, Abdel Aleem, A, Marti, I, Pinard, Jm, Quijano Roy, S, Sigaudy, S, de Lonlay, P, Romano, S, Verloes, A, Touraine, R, Koenig, M, Dollfus, H, Flori, E, Fradin, M, Lagier Tourenne, C, Messer, J, Collignon, P, Penzien, Jm, Bussmann, C, Merkenschlager, A, Philippi, H, Kurlemann, G, Grundmann, K, Dacou Voutetakis, C, Kitsiou Tzeli, S, Pons, R, Jerney, J, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, Sr, Girisha, Km, Doshi, H, Udani, V, Kaul, M, Stuart, B, Magee, A, Spiegel, R, Shalev, S, Mandel, H, Lev, D, Michelson, M, Idit, M, Ben Zeev, B, Gershoni Baruch, R, Ficcadenti, A, Fischetto, R, Gentile, M, Della Monica, M, Pezzani, M, Graziano, C, Seri, M, Benedicenti, F, Stanzial, F, Borgatti, R, Romaniello, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Pinelli, L, Boccone, L, Barone, R, Sorge, G, Briatore, E, Bigoni, S, Ferlini, A, Donati, Ma, Biancheri, R, Caridi, G, Divizia, Mt, Faravelli, F, Ghiggeri, G, Mirabelli, M, Pessagno, A, Rossi, A, Uliana, V, Amorini, M, Briguglio, M, Briuglia, S, Salpietro, Cd, Tortorella, G, Adami, A, Bonati, Mt, Castorina, P, D'Arrigo, S, Lalatta, F, Marra, G, Moroni, I, Pantaleoni, C, Riva, D, Scelsa, B, Spaccini, L, Del Giudice, E, Ludwig, K, Permunian, A, Suppiej, A, Macaluso, C, Pichiecchio, A, Battini, R, Di Giacomo, M, Priolo, M, Timpani, P, Pagani, G, Di Sabato ML, Emma, F, Leuzzi, V, Mancini, F, Majore, S, Micalizzi, A, Parisi, P, Romani, M, Stringini, G, Zanni, G, Ulgheri, L, Pollazzon, M, Renieri, Alessandra, Belligni, E, Grosso, E, Pieri, I, Silengo, M, Devescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al Tawari AA, Bastaki, L, Mégarbané, A, Sabolic Avramovska, V, Said, E, Stromme, P, Koul, R, Rajab, A, Azam, M, Barbot, C, Salih, Ma, Tabarki, B, Jocic Jakubi, B, Martorell Sampol, L, Rodriguez, B, Pascual Castroviejo, I, Gener, B, Puschmann, A, Starck, L, Capone, A, Lemke, J, Fluss, J, Niedrist, D, Hennekam, Rc, Wolf, N, Gouider Khouja, N, Kraoua, I, Ceylaner, S, Teber, S, Akgul, M, Anlar, B, Comu, S, Kayserili, H, Yüksel, A, Akcakus, M, Caglayan, Ao, Aldemir, O, Al Gazali, L, Sztriha, L, Nicholl, D, Woods, Cg, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Hemingway, C, Lees, M, Wakeling, E, Blair, E, Bernes, S, Sanchez, H, Clark, Ae, Demarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh, Ca, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, Karaca, E, Swoboda, Kj, Viskochil, D, Dobyns, Wb, Colin, Johnson, Tania, Attié Bitach, Joseph, G. Gleeson, Enza, Maria Valente, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, Paediatrics, OMÜ, University of Zurich, Valente, Enza Maria, Fluss, Joel Victor, Travaglini, L, Brancati, F, Silhavy, J, Iannicelli, M, Nickerson, E, Elkhartoufi, N, Scott, E, Spencer, E, Gabriel, S, Thomas, S, Ben Zeev, B, Bertini, E, Boltshauser, E, Chaouch, M, Cilio, Mr, de Jong, Mm, Kayserili, H, Ogur, G, Poretti, A, Signorini, S, Uziel, G, Zaki, M, Johnson, C, Atti? Bitach, T, Gleeson, Jg, Valente, Em, International JSRD Study, Group, and DEL GIUDICE, Ennio

Subjects
Male, Ciliata -- Anatomy, Proband, 10039 Institute of Medical Genetics, Meckel syndrome, RPGRIP1L, Syndromes, INPP5E, MODIFIER, Phosphoric Monoester Hydrolases/genetics, Ciliopathies, Polycystic Kidney Diseases/diagnosis/genetics, CILIUM, 0302 clinical medicine, Gene Frequency, Cerebellum, Prenatal Diagnosis, RETINAL DEGENERATION, Prevalence, MECKEL, ciliopathies, Joubert syndrome and related disorders, Eye Abnormalities, Child, Genetics (clinical), Encephalocele, Joubert syndrome, Genetics, Polycystic Kidney Diseases, 0303 health sciences, ddc:618, Cerebellar Diseases/diagnosis/genetics, Kidney Diseases, Cystic, Pedigree, 3. Good health, Phenotype, Child, Preschool, Medical genetics, Female, Retinitis Pigmentosa, FORM, Ciliary Motility Disorders, Heterozygote, medicine.medical_specialty, 2716 Genetics (clinical), Adolescent, Molecular Sequence Data, Encephalocele/diagnosis/genetics, AHI1, 610 Medicine & health, Biology, Retina, Article, Ciliopathies, INPP5E, Joubert syndrome and related disorders, Meckel syndrome, NO, Ciliary Motility Disorders/diagnosis/genetics, 03 medical and health sciences, 1311 Genetics, Cerebellar Diseases, REVEALS, medicine, Humans, Abnormalities, Multiple, Amino Acid Sequence, Kidney Diseases, Cystic/diagnosis/genetics, abnormalities, multiple, adolescent, amino acid sequence, cerebellar diseases, cerebellum, child, preschool, ciliary motility disorders, encephalocele, eye abnormalities, female, heterozygote, humans, infant, kidney diseases, cystic, male, molecular sequence data, pedigree, phosphoric monoester hydrolases, polycystic kidney diseases, prenatal diagnosis, prevalence, retina, gene frequency, mutation, phenotype, 030304 developmental biology, Eye Abnormalities/diagnosis/genetics, COACH SYNDROME, Retina/abnormalities, Genetic heterogeneity, Respiration disorders -- Therapy, Infant, medicine.disease, Phosphoric Monoester Hydrolases, INPP5E mutation, 10036 Medical Clinic, Mutation, 030217 neurology & neurosurgery
Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS foetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus., peer-reviewed

Published
2013

11. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome

Author

Cantagrel, V, Silhavy, Jl, Bielas, S, Swistun, D, Marsh, Se, Bertrand, J, Audollent, S, Attié Bitach, T, Holden, Kr, Dobyns, Wb, Traver, D, Al Gazali, L, Ali, Br, Lindner, Th, Caspary, T, Otto, Ea, Hildebrandt, F, Glass, Ia, Logan, Cv, Johnson, Ca, Bennett, C, Brancati, F, Grattan Smith, P, Leventer, J, Van Coster, R, Dias, K, Moco, C, Moreira, Ae Kim, C, Akiss, A, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Marti, I, Quijano Roy, S, de Lonlay, P, Verloes A, A., Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Magee, A, Stuart, B, Lev, D, Michelson, M, Ben Zeev, B, Fischetto, R, Gentile, M, Battaglia, Giordano, L, Boccone, L, Ruggieri, M, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Lapi, E, Genuardi, M, Caridi, G, Faravelli, F, Ghiggeri, G, Briuglia, Silvana, Tortorella, Gaetano, Rigoli, Luciana Concetta, SALPIETRO DAMIANO, Carmelo, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Laverda, Am, Permunian, A, Bova, S, Fazz, Ei, Sabrina, S, Battini, R, Bertini, E, Dallapiccola, B, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Ahmad Aqueel, A, Jong, Mm, Koul, R, Rajab, A, Sztriha, L, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Eugen Boltshauser, E, Hulya, H, Comu, S, Akcakus, M, Sahin, Y, Phadke, Sr, Melick, N, Mikati, M, Nicholl, D, Hurst, J, Hennekam, Rcm, Bernes, S, Sanchez, H, Clark, Ae, Wynshaw Boris, A, Donahue, C, Sherr, Eh, Barkovich, Aj, Hahn, D., Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh CA, Soul, Jmckanna, T, Joanne Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Amy Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Cruse, Rp, Lotzete, Swoboda, Kj, Viskochil, Dh, Valente, Em, Woods, Cg, and Gleeson, Jg

Subjects
Cerebellum, Ataxia, TMEM67, Molecular Sequence Data, Biology, Joubert Syndrome, Joubert syndrome, Article, cilia gene ARL13B, mutation, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, INPP5E, medicine, Genetics, Animals, Humans, Genetics(clinical), Abnormalities, Multiple, Genetic Predisposition to Disease, Cilia, Genetics (clinical), Conserved Sequence, Zebrafish, 030304 developmental biology, Neurons, 0303 health sciences, Brain Diseases, ADP-Ribosylation Factors, Cilium, Chromosome Mapping, Computational Biology, Syndrome, Mutation, medicine.disease, Cell biology, medicine.anatomical_structure, RPGRIP1L, medicine.symptom, Abnormalities, Multiple, 030217 neurology & neurosurgery
Abstract

Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the “molar tooth sign” on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Published
2008

12. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Author

Brancati, F., Barrano, G., Silhavy, J. L., Marsh, S. E., Travaglini, L., Bielas, S. L., Amorini, M., Zablocka, D., Kayserili, H., Al-Gazali, L., Bertini, E., Boltshauser, E., D'Hooghe, M., Fazzi, Eleonora, Fenerci, E. Y., Hennekam, R. C. M., Kiss, A., Lees, M. M., Marco, E., Phadke, S. R., Rigoli, L., Romano, S., Salpietro, C. D., Sherr, E. H., Signorini, S., Stromme, P., Stuart, B., Sztriha, L., Viskochil, D. H., Yuksel, A., Dallapiccola, B., Valente, E. M., Gleeson, J. G., Grattan-Smith, P., Leventer, R., Janecke, A., Van Coster, R., Dias, K., Moco, C., MOREIRA DA SILVA, CLAUDIA ALEXANDRA, Chong, A. K., Maegawa, G., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., De Lonlay, P., Verloes, A., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Gentile, M., Battaglia, S., Giordano, L., Boccone, L., Ruggieri, M., Bigoni, S., Ferlini, A., Donati, M. A., Procopio, E., Caridi, G., Faravelli, F., Ghiggeri, G., Briuglia, S., Tortorella, G., D'Arrigo, S., Pantaleoni, C., Riva, D., Uziel, G., Lavercla, A. M., Permunian, A., Bova, S., Battini, Roberta, Cilio, M. R., DI SABATO, Manuela, Emma, F., Leuzzi, V., Parisi, P., Simonati, A., Al-Tawari, A. A., Bastaki, L., Aqeel, A., De Jong, M. M., Koul, R., Rajab, A., Azam, M., Barbot, C., Rodriguez, B., Pascual-Castroviejo, I., Comu, S., Akcakus, M., Nicholl, D., Woods, C. G., Bennett, C., Hurst, J., Walsh, C. A., Bernes, S., Sanchez, H., Clark, A. E., Donahue, C., Hahn, J., Sanger, T. D., Gallager, T. E., Dobyns, W. B., Daugherty, C., Krishnamoorthy, K. S., Sarco, D., Mckanna, T., Milisa, J., Chung, W. K., De Vivo, D. C., Raynes, H., Schubert, R., Seward, A., Brooks, D. G., Goldstein, A., Caldwell, J., Finsecke, E., Maria, B. L., Holden, K., Cruse, R. P., Swoboda, K. J., ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatric Genetics

Subjects
Male, Pathology, DNA Mutational Analysis, Cell Cycle Proteins, medicine.disease_cause, Ciliopathies, Ocular Motility Disorders, Cohort Studies, Joubert syndrome–related disorders, CEP290, Genetics(clinical), Child, Genetics (clinical), Genetics, Mutation, Brain, Syndrome, Phenotype, Magnetic Resonance Imaging, Kidney Diseases, Molar, Neoplasm Proteins, Child, Preschool, Abnormalities, Multiple, Adolescent, Adult, Antigens, Neoplasm, Female, Humans, Abnormalities, Multiple, medicine.medical_specialty, Biology, Article, Joubert syndrome, Central nervous system disease, medicine, Antigens, Preschool, Genetic heterogeneity, medicine.disease, Cytoskeletal Proteins, Situs inversus, Neoplasm
Abstract

Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Löken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

Published
2007

13. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Author

Brancati, F, Barrano, G, Silhavy, Jl, Marsh, Se, Travaglini, L, Bielas, Sl, Amorini, M, Zablocka, D, Kayserili, H, Al Gazali, L, Bertini, E, Boltshauser, E, D'Hooghe, M, Fazzi, E, Fenerci, Ey, Hennekam, Rc, Kiss, A, Lees, Mm, Marco, E, Phadke, Sr, Rigoli, L, Romano, S, Salpietro, Cd, Sherr, Eh, Signorini, S, Stromme, P, Stuart, B, Sztriha, L, Viskochil, Dh, Yuksel, A, Dallapiccola, [International JSRD Study Group], Valente, Em, Gleeson, Jg, Smith, P, Leventer, R, Janecke, A, Van Coster, R, Dias, K, Moco, C, Moreira, A, Chong, Ak, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Martu, I, Quijano Roy, S, De Lonlay, P, Verloes, A, Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdotir, J, Ludvigsson, P, Magee, A, Lev, D, Michelson, M, Ben Zev, B, Fischetto, R, Gentile, M, Battaglia, S, Giordano, L, Boccone, L, Ruggieri, Martino, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Cardidi, G, Faravelli, F, Ghiggeri, G, Briuglia, S, Tortorella, G, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Lavercla, Am, Permunian, A, Bova, S, Battini, R, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Aqeel, A, De Jong MM, Koul, R, Rajab, A, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Comu, S, Akcakus, M, Nicholl, D, Woods, Cg, Bennet, C, Hurst, J, Walsh, Ca, Bernes, S, Sanchez, H, Clark, Ae, Donahue, C, Hahn, J, Sanger, Td, Gallager, Te, Dobyns, Wb, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, and Swoboda, Kj

Published
2007

16. Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy

Author

Pegoraro, E., primary, Schimke, R. N., additional, Garcia, C., additional, Stern, H., additional, Cadaldini, M., additional, Angelini, C., additional, Barbosa, E., additional, Carroll, J., additional, Marks, W. A., additional, Neville, H. E., additional, Marks, H., additional, Appleton, S., additional, Toriello, H., additional, Wessel, H. B., additional, Donnelly, J., additional, Bernes, S. M., additional, Taber, J. W., additional, Weiss, L., additional, and Hoffman, E. P., additional

Published
1995
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22. Thiaplatinacycles Derived from Dibenzothiophene-Containing Phosphites as Auxiliary Ligands and Their Role in Homogeneous Desulfurization Reactions

Author

Picazo, G., Arevalo, A., Bernes, S., and Garcia, J. J.

Abstract

The reaction of complex [Pt(η2-C,S-C12H8)(PEt3)2], 1, with a variety of phosphites afforded compounds of the type [Pt(η2-C,S-C12H8)(PEt3)(P(OR)3)], where R = Et, iPr, and Ph (2a, 2b, 3, and 4, respectively) and [Pt(η2-C,S-C12H8)(P(OR)3)2], where R = Et (5). Compounds 2−4 were used to model a desulfurization process and were compared with 1 and other similar compounds. Under comparable conditions, the amount of desulfurization depended on the σ-donor/π-acceptor properties and the steric effects of the ligands and of the use of alumina in the reaction media. X-ray crystal structures are reported for 2b and 3.

Published
2003

23. Synthesis and Structure of cis-Palladium(II) Carbene Complexes Containing the 1,3-Diallylimidazolidin-2-ylidene Ligand:  trans → cis Rearrangement

Author

Chamizo, J. A., Morgado, J., Castro, M., and Bernes, S.

Abstract

Palladium(II) carbene complexes with a 1,3-diallylimidazolidin-2-ylidene ligand (LAllyl) were prepared and characterized by IR, NMR, and mass spectra. The trans → cis rearrangement of the trans-[PdCl2(LAllyl)2] complex was observed. The relative thermodynamic stability of these isomers was studied using DFT calculations.

Published
2002
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24. Reactivity of Substituted Thiophenes toward Tris(triethylphosphine)platinum(0), -palladium(0), and -nickel(0)

Author

Hernandez, M., Miralrio, G., Arevalo, A., Bernes, S., Garcia, J. J., Lopez, C., Maitlis, P. M., and Rio, F. del

Abstract

The reactions of [M(PEt3)3] (M = Pt (1), Pd (2), Ni (3)) with 3-chlorothiophene, 2-chlorothiophene, 3-nitrothiophene, 2-nitrothiophene, 2-methoxythiophene, 3-methoxythiophene, 2-acetylthiophene, and 3-acetylthiophene afforded thiaplatinacycles of the type [(Et3P)2M(C,S-C4H3RS)], (for M = Pt, R = Cl (4 and 5), NO2 (6 and 7), MeO (8 and 9), Ac (10 and 11); for M = Pd, R = Cl (12 and 13), NO2 (14), MeO (15 and 16), Ac (17 and 18), for M = Ni, R = Cl (19)). When 3 and 2-chlorothiophene were reacted, another compound resulting from the oxidative addition of the C−Cl bond could be isolated, with the formulation [(Et3P)2Ni(Cl)(η1-T)] (20). Additionally the reaction of 3 with 2-nitrothiophene produced a compound derived from a C−H activation reaction, [(Et3P)2Ni(H)(η1-NO2T)] (21). The thiaplatinacycles 8−11 were shown to be active intermediates in HDS reactions, under catalytic conditions, to give 81 cycles at 300 psi, 100 °C in THF, in the presence of metallic mercury. Crystal structures are reported for 4 and 7.

Published
2001

31. Ring Opening of Methylbenzothiophenes and Methyldibenzothiophenes by Tris(triethylphosphine)platinum(0)

Author

Arevalo, A., Bernes, S., Garcia, J. J., and Maitlis, P. M.

Abstract

The reaction of [Pt(PEt3)3], 1, with 3-methylbenzothiophene and 2-methylbenzothiophene afforded the thiaplatinacycles [(Et3P)2Pt(C,S-C9H8S)], 3 and 4, respectively. In the formation of both complexes (Et3P)2Pt has inserted into the C−S bond to the vinylic carbon. Complex 4 rearranges in solution to a dimeric thiaplatinacycle, 5, in which the platinum has moved from lying between the vinylic C−S bond into the aromatic C−S bond. Reaction of 1 with 4-methyldibenzothiophene gave a mixture of isomeric thiaplatinacycles [(Et3P)2Pt(C,S-C13H10S)], 6 and 7. The reaction of 1 with 4,6-dimethyldibenzothiophene containing some 1,9-dimethyldibenzothiophene led to the isolation of complex 9, [(Et3P)2Pt(C,S-C14H12S)]. This is derived from 1,9-dimethyldibenzothiophene, which is a byproduct in the preparation of 4,6-dimethyldibenzothiophene by a metalation pathway. The reaction of 1 with highly pure 4,6-dimethyldibenzothiophene gave the hydride complex, 10, in which (Et3P)2Pt has inserted into the C−H bond at the 3-position. The thiaplatinacycle cis-[(Et3P)2Pt(η2-C,S-C14H12S)], 8, was obtained by reaction of highly pure 4,6-dimethyldibenzothiophene with cis-[PtCl2(PEt3)2] and metallic sodium under hydrogen. X-ray structures of complexes 3, 5, and 9 are reported.

Published
1999

34. 163P Real-World outcomes following onasemnogene abeparvovec in patients with SMA and One SMN2 gene copy: findings from the RESTORE Registry.

Author

Servais, L., Mathews, K., Bernes, S., Lakhotia, A., Tizzano, E., Raju, D., Benguerba, K., Reyna, S., Dabbous, O., and Finkel, R.

Subjects
*SPINAL muscular atrophy, *RESPIRATORY insufficiency, *NEWBORN screening, *GESTATIONAL age, *GENE therapy
Abstract

Spinal muscular atrophy (SMA) severity generally correlates with SMN2 gene copy number. Patients with only one SMN2 copy are at risk for the most severe SMA phenotype, characterized by profound hypotonia and respiratory insufficiency at birth and a rapidly progressive and fatal course. Clinical trials of onasemnogene abeparvovec (OA), a one-time gene therapy for SMA, did not include patients with one SMN2 copy. Therefore, little is known about treatment outcomes in these patients, who may receive treatment in real-world practice. We sought to describe outcomes following OA for patients with SMA and one SMN2 copy enrolled in RESTORE, a multinational, noninterventional SMA registry. As of May 23, 2023, RESTORE enrolled three OA-treated patients with one SMN2 copy. Patients had either SMA type 0 or 1. All were treated in the USA and identified by newborn screening. One patient was bridged to OA with nusinersen from 1–3 months of age, and also received add-on therapy with risdiplam, which was initiated at 13 months of age. One patient was male, and two females, all >30 weeks gestational age at birth. All patients were alive at data cutoff. All three patients received ventilatory support: two patients before OA and the third patient after OA. Post-OA CHOP INTEND was recorded for all patients, and all achieved scores >40 or significant (≥4 points) improvements during the observation period. Greatest motor milestones achieved were: one patient stood with support; one patient sat independently and stood with support; and one patient rolled from side-to-side on three separate visits. Adverse events were recorded for one patient. None were serious or treatment-related, and event types were consistent with the established safety profile of OA. Investigation of potential gene modifier is ongoing. SMA patients with one SMN2 copy survived and achieved motor improvements after OA, indicating positive benefit:risk in these particularly vulnerable children. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Reactivity of [Ru<INF>3</INF>(CO)<INF>12</INF>] with Dibenzothiophene, Methylbenzothiophene, and Methyldibenzothiophene

Author

Chehata, A., Oviedo, A., Arevalo, A., Bernes, S., and Garcia, J. J.

Abstract

The reaction of dibenzothiophene (DBT) with [Ru3(CO)12] in heptane affords the dinuclear complex [Ru2(C12H8)(μ-CO)(CO)5], derived from a double C−S bond activation−desulfurization process. The reaction of this complex with H2 under very mild conditions leads to the release of biphenyl.

Published
2003

45. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Author

S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T

Subjects
Liver Cirrhosis, 2716 Genetics (clinical), meckelin, Ciliopathies, Joubert syndrome, Genotype, congenital hepatic fibrosis, coach syndrome, mks3, meckel syndrome, joubert syndrome, tmem67, TMEM67, Meckel syndrome, DNA Mutational Analysis, 610 Medicine & health, Biology, medicine.disease_cause, MKS3, COACH syndrome, Article, NO, 1311 Genetics, Nephronophthisis, Pregnancy, Prenatal Diagnosis, Genetics, medicine, COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67, Missense mutation, Humans, Abnormalities, Multiple, Genetics (clinical), Mutation, Cilium, Membrane Proteins, Kidney Diseases, Cystic, medicine.disease, Phenotype, 10036 Medical Clinic, Female
Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Published
2010
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46. Initial Experience With Ultra-High-Definition 3D Exoscope in Thyroid and Parathyroid Surgery.

Author

Bernes S, Lilja-Fischer J, Petersen NK, Udholm N, Reinholdt KB, Londero S, Kjærgaard T, and Rolighed L

Subjects
Humans, Surgery, Computer-Assisted methods, Surgery, Computer-Assisted instrumentation, Parathyroid Glands surgery, Parathyroid Glands diagnostic imaging, Thyroid Gland surgery, Equipment Design, Female, Male, Thyroidectomy instrumentation, Thyroidectomy methods, Parathyroidectomy instrumentation, Parathyroidectomy methods, Imaging, Three-Dimensional instrumentation, Imaging, Three-Dimensional methods
Abstract

Background: Operation with a 3D exoscope has recently been introduced in clinical practice. The exoscope consists of two cameras placed in front of the operative field. Images are shown on a large 3D screen with high resolution. The system can be used to enhance precise dissection and provides new possibilities for improved ergonomics, fluorescence, and other optical-guided modalities., Methods: Initial experience with the ultra-high-definition (4K) 3D exoscope in thyroid and parathyroid operations. The exoscope (OrbEye TM ) was mounted on a holding system (Olympus)., Results: We used the exoscope in parathyroidectomy (N = 6) and thyroidectomy (N = 6). Immediate advantages and disadvantages were discussed and recorded. The learning curve for use of the exoscope may be shorter for surgeons with training in endoscopic or robotic procedures. There may be improved ergonomics compared with normal open-neck operations. Further, the optical guided operations can be used with fluorescence and have potential for different on-lay techniques in the future. The 4 K 3D image quality is state-of-art and is highly appreciated during fine surgical dissection and eliminates the need for loupes., Conclusion: In several ways, using the ORBEYE™ in thyroid and parathyroid surgery provides the surgical team with a new and enhanced experience. This includes improved possibility for teaching, surgical ergonomics, and a 4K 3D camera with a powerful magnification system. However, it is not clear if utilization of these features would improve surgical outcomes. Furthermore, the ORBEYE™ lacks incorporation of parathyroid autofluorescence, and the current costs for the system do not facilitate general access to exoscope assisted operations., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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47. Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec.

Author

Retson L, Tiwari N, Vaughn J, Bernes S, Adelson PD, Mansfield K, Libertini S, Kuzmiski B, Alecu I, Gabriel R, and Mangum R

Subjects
Humans, Male, Infant, Muscular Atrophy, Spinal therapy, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal etiology, Biological Products therapeutic use, Dependovirus genetics, Spinal Cord Neoplasms therapy, Spinal Cord Neoplasms etiology, Recombinant Fusion Proteins, Genetic Therapy methods, Genetic Vectors administration & dosage, Genetic Vectors genetics
Abstract

Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14 months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients., Competing Interests: Declaration of interests L.R., N.T., J.V., S.B., P.D.A., R.G., and R.M. have no funding or conflicts of interest to disclose. K.M., B.K., S.L., and I.A. are employees of Novartis and own stock or other holdings., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2023
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48. Arterioectatic Spinal Angiopathy of Childhood: Clinical, Imaging, Laboratory, Histologic, and Genetic Description of a Novel CNS Vascular Pathology.

Author

Abruzzo T, van den Berg R, Vadivelu S, Hetts SW, Dishop M, Cornejo P, Narayanan V, Ramsey KE, Coopwood C, Medici-van den Herik EG, Roosendaal SD, Lawton M, and Bernes S

Subjects
Angiography, Child, Humans, Magnetic Resonance Imaging, Retrospective Studies, Spinal Cord pathology, Spinal Cord Diseases diagnostic imaging, Spinal Cord Diseases genetics, Spinal Cord Diseases pathology
Abstract

Pediatric patients with myelopathy expressing intradural spinal vascular ectasia without arteriovenous shunting were studied at four tertiary referral neuropediatric centers. Patients were identified by retrospective review of institutional records and excluded if spinal vascular pathology could be classified into a previously described category of spinal vascular malformation. Four patients meeting the study criteria were enrolled in the study. Clinical, magnetic resonance imaging, catheter-directed angiography, laboratory, histological and genetic data were analyzed to characterize the disease process and elucidate underlying pathomechanisms. Our study revealed a highly lethal, progressive multi-segmental myelopathy associated with a unique form of non-inflammatory spinal angiopathy featuring diffuse enlargement and tortuosity of spinal cord arteries, spinal cord hyperemia, and spinal cord edema (Arterioectatic Spinal Angiopathy of Childhood). The condition was shown to mimic venous congestive myelopathy associated with pediatric spinal cord arteriovenous shunts on MRI but to have distinct pathognomonic findings on catheter-directed angiography. Clinicopathological, genetic, and neuroimaging features, which are described in detail, closely overlap with those of mitochondrial disease., (© 2022 by American Journal of Neuroradiology.)

Published
2022
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49. GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment.

Author

Markovitz R, Ghosh R, Kuo ME, Hong W, Lim J, Bernes S, Manberg S, Crosby K, Tanpaiboon P, Bharucha-Goebel D, Bonnemann C, Mohila CA, Mizerik E, Woodbury S, Bi W, Lotze T, Antonellis A, Xiao R, and Potocki L

Subjects
Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease physiopathology, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal physiopathology, Mutation, Missense genetics, Phenotype, Spinal Muscular Atrophies of Childhood diagnostic imaging, Spinal Muscular Atrophies of Childhood physiopathology, Genetic Predisposition to Disease, Glycine-tRNA Ligase genetics, Spinal Muscular Atrophies of Childhood genetics, Survival of Motor Neuron 1 Protein genetics
Abstract

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss-of-function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot-Marie-Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS-associated disease and support that severe early-onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment., (© 2020 Wiley Periodicals, Inc.)

Published
2020
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50. Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect.

Author

Wang J, Kim E, Dai H, Stefans V, Vogel H, Al Jasmi F, Schrier Vergano SA, Castro D, Bernes S, Bhambhani V, Long C, El-Hattab AW, and Wong LJ

Subjects
Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Prognosis, Young Adult, DNA, Mitochondrial genetics, Mitochondria genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases pathology, Muscular Diseases genetics, Muscular Diseases pathology, Mutation, Thymidine Kinase genetics
Abstract

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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