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142 results on '"Torti, E."'

3. Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

Author

Happ, HC, Sadleir, LG, Zemel, M, de Valles-Ibáñez, G, Hildebrand, MS, McConkie-Rosell, A, McDonald, M, May, H, Sands, T, Aggarwal, V, Elder, C, Feyma, T, Bayat, A, Møller, RS, Fenger, CD, Klint Nielsen, JE, Datta, AN, Gorman, KM, King, MD, Linhares, ND, Burton, BK, Paras, A, Ellard, S, Rankin, J, Shukla, A, Majethia, P, Olson, RJ, Muthusamy, K, Schimmenti, LA, Starnes, K, Sedláčková, L, Štěrbová, K, Vlčková, M, Laššuthová, P, Jahodová, A, Porter, BE, Couque, N, Colin, E, Prouteau, C, Collet, C, Smol, T, Caumes, R, Vansenne, F, Bisulli, F, Licchetta, L, Person, R, Torti, E, McWalter, K, Webster, R, Gerard, EE, Lesca, G, Szepetowski, P, Scheffer, IE, Mefford, HC, Carvill, GL, Happ, HC, Sadleir, LG, Zemel, M, de Valles-Ibáñez, G, Hildebrand, MS, McConkie-Rosell, A, McDonald, M, May, H, Sands, T, Aggarwal, V, Elder, C, Feyma, T, Bayat, A, Møller, RS, Fenger, CD, Klint Nielsen, JE, Datta, AN, Gorman, KM, King, MD, Linhares, ND, Burton, BK, Paras, A, Ellard, S, Rankin, J, Shukla, A, Majethia, P, Olson, RJ, Muthusamy, K, Schimmenti, LA, Starnes, K, Sedláčková, L, Štěrbová, K, Vlčková, M, Laššuthová, P, Jahodová, A, Porter, BE, Couque, N, Colin, E, Prouteau, C, Collet, C, Smol, T, Caumes, R, Vansenne, F, Bisulli, F, Licchetta, L, Person, R, Torti, E, McWalter, K, Webster, R, Gerard, EE, Lesca, G, Szepetowski, P, Scheffer, IE, Mefford, HC, and Carvill, GL

Abstract

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenot

Published
2023

4. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.

Abstract

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

5. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

Author

Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., Maroofian, R., Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., and Maroofian, R.

Abstract

01 januari 2023, Item does not contain fulltext, PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Published
2023

7. Multimodal retinal imaging as biomarker for cardiovascular disease in patients with diabetes mellitus

Author

Vujosevic, S., Fantaguzzi, F., Salongcay, R., Cushley, L., Brambilla, M., Torti, E., and Peto, T.

Subjects
SDG 17 - Partnerships for the Goals, SDG 3 - Good Health and Well-being
Abstract

DESIGNBi-center, retrospective, observational case-series.PURPOSETo evaluate association between macrovascular systemic comorbidities and multimodal retinal imaging in patients with diabetes mellitus (DM) with different stages of diabetic retinopathy (DR).METHODS516 eyes of 259 DM patients with systemic history and imaging were enrolled in two centers (Milano and Belfast). Ultrawidefield color fundus photos (CFP) were obtained with OPTOS California and OCT/OCT-Angiography (OCT-A) imaging with Heidelberg Spectralis. The presence of predominantly peripheral lesions (PPL) was confirmed by two independent graders as >50% of CFP lesions. OCT-A imaging (3 × 3 mm) was used to determine perimeter, area and circularity index of the foveal avascular zone (FAZ) and vessel density (VD); perfusion density (PD); fractal dimension (FD) on superficial (SCP), intermediate (ICP) and deep (DCP) plexuses; flow voids (FV) in the choriocapillaris (CC).RESULTS81.5% of patients had DM type 2, with mean age of 67.1 ± 13.7 years. Out of 516 eyes, 108 eyes (20.9%) did not have DR, and 6 eyes were not gradable. The remaining 402 eyes were: 10.3% (53) mild non-proliferative DR (NPDR), 38.2% (197) moderate NPDR, 11.8% (61) severe NPDR, 17.6% (91) proliferative DR (PDR). PPL was present in 35.5%, associated with longer DM duration and worse DR severity (p CONCLUSIONSOCT-A metrics show an association with the cerebrovascular and cardiovascular complications of DM, providing potentially useful biomarkers for estimating systemic vascular risk in DM patients.

Published
2022

8. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

Author

Cordovado, A., Schaettin, M., Jeanne, M., Panasenkava, V., Denomme-Pichon, A. -S., Keren, B., Mignot, C., Doco-Fenzy, M., Rodan, L., Ramsey, K., Narayanan, V., Jones, J. R., Prijoles, E. J., Mitchell, W. G., Ozmore, J. R., Juliette, K., Torti, E., Normand, E. A., Granger, L., Petersen, A. K., Au, M. G., Matheny, J. P., Phornphutkul, C., Chambers, M. -K., Fernandez-Ramos, J. -A., Lopez-Laso, E., Kruer, M. C., Bakhtiari, S., Zollino, Marcella, Morleo, M., Marangi, Giuseppe, Mei, D., Pisano, T., Guerrini, R., Louie, R. J., Childers, A., Everman, D. B., Isidor, B., Audebert-Bellanger, S., Odent, S., Bonneau, D., Gilbert-Dussardier, B., Redon, R., Bezieau, S., Laumonnier, F., Stoeckli, E. T., Toutain, A., Vuillaume, M. -L., Zollino M. (ORCID:0000-0003-4871-9519), Marangi G. (ORCID:0000-0002-6898-8882), Cordovado, A., Schaettin, M., Jeanne, M., Panasenkava, V., Denomme-Pichon, A. -S., Keren, B., Mignot, C., Doco-Fenzy, M., Rodan, L., Ramsey, K., Narayanan, V., Jones, J. R., Prijoles, E. J., Mitchell, W. G., Ozmore, J. R., Juliette, K., Torti, E., Normand, E. A., Granger, L., Petersen, A. K., Au, M. G., Matheny, J. P., Phornphutkul, C., Chambers, M. -K., Fernandez-Ramos, J. -A., Lopez-Laso, E., Kruer, M. C., Bakhtiari, S., Zollino, Marcella, Morleo, M., Marangi, Giuseppe, Mei, D., Pisano, T., Guerrini, R., Louie, R. J., Childers, A., Everman, D. B., Isidor, B., Audebert-Bellanger, S., Odent, S., Bonneau, D., Gilbert-Dussardier, B., Redon, R., Bezieau, S., Laumonnier, F., Stoeckli, E. T., Toutain, A., Vuillaume, M. -L., Zollino M. (ORCID:0000-0003-4871-9519), and Marangi G. (ORCID:0000-0002-6898-8882)

Abstract

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Published
2022

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

Author

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

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

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

Published
2019

11. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., Eichler, E.E., Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., and Eichler, E.E.

Abstract

Contains fulltext : 245103.pdf (Publisher’s version ) (Open Access), BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare va

Published
2021

12. Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification

Author

Schottlaender, LV, Abeti, R, Jaunmuktane, Z, Macmillan, C, Chelban, V, O'Callaghan, B, McKinley, J, Maroofian, R, Efthymiou, S, Athanasiou-Fragkouli, A, Forbes, R, Soutar, MPM, Livingston, JH, Kalmar, B, Swayne, O, Hotton, G, SYNAPS Study Group, Pittman, A, Mendes de Oliveira, JR, de Grandis, M, Richard-Loendt, A, Launchbury, F, Althonayan, J, McDonnell, G, Carr, A, Khan, S, Beetz, C, Bisgin, A, Tug Bozdogan, S, Begtrup, A, Torti, E, Greensmith, L, Giunti, P, Morrison, PJ, Brandner, S, Aurrand-Lions, M, and Houlden, H

Abstract

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.

Published
2020

13. De novo missense mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Lehalle, D., Vabres, P., Bierhals, T., Cho, M. T., Cogne, B., Avila, M., Carmignac, V., Duplomb-Jego, L., De Bont, E., Duffourd, Y., Duijkers, F., Elpeleg, O., Fattal-Valevski, A., Genevieve, D., Guimier, A., Harris, D., Hempel, M., Isidor, B., Jouan, T., Kuentz, P., Lichtenbelt, K., Ramey, V. Loik, Pasquier, L., St-Onge, J., Sorlin, A., Thevenon, J., Torti, E., Van Gassen, K., Van Haelst, M., van Koningsbruggen, S., Riviere, J., Thauvin, C., Betschinger, J., Faivre, L., Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development

Published
2019

14. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V. Dixon, C.L. Guo, H. Bello, O.D. Vandrovcova, J. Efthymiou, S. Maroofian, R. Heimer, G. Burglen, L. Valence, S. Torti, E. Hacke, M. Rankin, J. Tariq, H. Colin, E. Procaccio, V. Striano, P. Mankad, K. Lieb, A. Chen, S. Pisani, L. Bettencourt, C. Männikkö, R. Manole, A. Brusco, A. Grosso, E. Ferrero, G.B. Armstrong-Moron, J. Gueden, S. Bar-Yosef, O. Tzadok, M. Monaghan, K.G. Santiago-Sim, T. Person, R.E. Cho, M.T. Willaert, R. Yoo, Y. Chae, J.-H. Quan, Y. Wu, H. Wang, T. Bernier, R.A. Xia, K. Blesson, A. Jain, M. Motazacker, M.M. Jaeger, B. Schneider, A.L. Boysen, K. Muir, A.M. Myers, C.T. Gavrilova, R.H. Gunderson, L. Schultz-Rogers, L. Klee, E.W. Dyment, D. Osmond, M. Parellada, M. Llorente, C. Gonzalez-Peñas, J. Carracedo, A. Van Haeringen, A. Ruivenkamp, C. Nava, C. Heron, D. Nardello, R. Iacomino, M. Minetti, C. Skabar, A. Fabretto, A. Hanna, M.G. Bugiardini, E. Hostettler, I. O’Callaghan, B. Khan, A. Cortese, A. O’Connor, E. Yau, W.Y. Bourinaris, T. Kaiyrzhanov, R. Chelban, V. Madej, M. Diana, M.C. Vari, M.S. Pedemonte, M. Bruno, C. Balagura, G. Scala, M. Fiorillo, C. Nobili, L. Malintan, N.T. Zanetti, M.N. Krishnakumar, S.S. Lignani, G. Jepson, J.E.C. Broda, P. Baldassari, S. Rossi, P. Fruscione, F. Madia, F. Traverso, M. De-Marco, P. Pérez-Dueñas, B. Munell, F. Kriouile, Y. El-Khorassani, M. Karashova, B. Avdjieva, D. Kathom, H. Tincheva, R. Van-Maldergem, L. Nachbauer, W. Boesch, S. Gagliano, A. Amadori, E. Goraya, J.S. Sultan, T. Kirmani, S. Ibrahim, S. Jan, F. Mine, J. Banu, S. Veggiotti, P. Zuccotti, G.V. Ferrari, M.D. Van Den Maagdenberg, A.M.J. Verrotti, A. Marseglia, G.L. Savasta, S. Soler, M.A. Scuderi, C. Borgione, E. Chimenz, R. Gitto, E. Dipasquale, V. Sallemi, A. Fusco, M. Cuppari, C. Cutrupi, M.C. Ruggieri, M. Cama, A. Capra, V. Mencacci, N.E. Boles, R. Gupta, N. Kabra, M. Papacostas, S. Zamba-Papanicolaou, E. Dardiotis, E. Maqbool, S. Rana, N. Atawneh, O. Lim, S.Y. Shaikh, F. Koutsis, G. Breza, M. Coviello, D.A. Dauvilliers, Y.A. AlKhawaja, I. AlKhawaja, M. Al-Mutairi, F. Stojkovic, T. Ferrucci, V. Zollo, M. Alkuraya, F.S. Kinali, M. Sherifa, H. Benrhouma, H. Turki, I.B.Y. Tazir, M. Obeid, M. Bakhtadze, S. Saadi, N.W. Zaki, M.S. Triki, C.C. Benfenati, F. Gustincich, S. Kara, M. Belcastro, V. Specchio, N. Capovilla, G. Karimiani, E.G. Salih, A.M. Okubadejo, N.U. Ojo, O.O. Oshinaike, O.O. Oguntunde, O. Wahab, K. Bello, A.H. Abubakar, S. Obiabo, Y. Nwazor, E. Ekenze, O. Williams, U. Iyagba, A. Taiwo, L. Komolafe, M. Senkevich, K. Shashkin, C. Zharkynbekova, N. Koneyev, K. Manizha, G. Isrofilov, M. Guliyeva, U. Salayev, K. Khachatryan, S. Rossi, S. Silvestri, G. Haridy, N. Ramenghi, L.A. Xiromerisiou, G. David, E. Aguennouz, M. Fidani, L. Spanaki, C. Tucci, A. Raspall-Chaure, M. Chez, M. Tsai, A. Fassi, E. Shinawi, M. Constantino, J.N. De Zorzi, R. Fortuna, S. Kok, F. Keren, B. Bonneau, D. Choi, M. Benzeev, B. Zara, F. Mefford, H.C. Scheffer, I.E. Clayton-Smith, J. Macaya, A. Rothman, J.E. Eichler, E.E. Kullmann, D.M. Houlden, H. SYNAPS Study Group

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Published
2019

17. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, Tucci, A, Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, and Tucci, A

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

18. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

Author

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

Abstract

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

Published
2019

23. Relationship between circulating syndecan-1 levels (CD138s) and serum free light chains in monoclonal gammopathies

Author

Cigliana, G., Torti, E., Gulli, F., De Santis, E., Dell'Abate, Maria Teresa, Colacicco, Luigi, Pisani, F., Conti, L., Basile, U., Dell'Abate M. T., Colacicco L. (ORCID:0000-0002-0039-3727), Cigliana, G., Torti, E., Gulli, F., De Santis, E., Dell'Abate, Maria Teresa, Colacicco, Luigi, Pisani, F., Conti, L., Basile, U., Dell'Abate M. T., and Colacicco L. (ORCID:0000-0002-0039-3727)

Abstract

Background: Monoclonal gammopathies encompass a wide range of diseases characterized by the monoclonal expansion of a B-cell clone. Despite emerging therapeutic strategies, chances of survival of patients who are affected are still scarce, which implies that new tools are necessary not only for the diagnosis but also for the follow-up of patients affected by such diseases. In this context, the use of free light chains (FLCs) has been incorporated into many guidelines. Likewise, tumor microenvironment is consistently gaining importance as role player in tumor pathogenesis. Specifically, Syndecan-1 (CD138), a heparan-sulfate proteoglycan is attracting interests as it is highly expressed and shed by myeloma plasma-cells. The aim of our study was to analyze CD138 levels in the serum of patients affected by multiple myeloma or light chain only disease, and to compare the values obtained with free light chain (FLC) kappa, lambda and FLC ratio in both groups of patients. Methods: 84 patients affected by Multiple Myeloma and Light Chain Myeloma were recruited for this study. Serum CD138 was assessed by ELISA (Diaclone Research, France) and FLC values were quantified by nephelometry (Freelite TM Human Kappa and Lambda Free Kits, The Binding Site, UK). Data was analyzed by GraphPad Prism software and Statgraph. Results: We observed higher CD138 mean values in myeloma patients compared to the light chain only myeloma group. A positive linear regression of CD138 and FLC was observed in the light chain only cohort as opposed to myeloma patients which show an inverse trend. Conclusions: The study highlighted an existing relationship between FLCs and CD138 and wishes to seek also a correlation in order to rapidly and efficiently perform diagnosis and different diagnostic schemes.

Published
2015

30. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo Salpietro1, 2 3, 140, Christine L. Dixon4, Hui Guo5, 6 140, Oscar D. Bello Stephanie Efthymiou 1, 4, Reza Maroofian1, Gali Heimer7, Lydie Burglen 8, Stephanie Valence 9, Erin Torti 10, Moritz Hacke11, Julia Rankin12, Huma Tariq1, Estelle Colin13, Vincent Procaccio13, Pasquale Striano2, 3, Kshitij Mankad15, Andreas Lieb 4, Sharon Chen16, Laura Pisani16, Conceicao Bettencourt 17, Roope Männikkö 1, Andreea Manole1, Alfredo Brusco 18, Enrico Grosso18, Giovanni Battista Ferrero19, Judith Armstrong-Moron20, Sophie Gueden21, Omer Bar-Yosef7, Michal Tzadok7, Kristin G. Monaghan10, Teresa Santiago-Sim10, Richard E. Person10, Megan T. Cho10, Rebecca Willaert10, Yongjin Yoo22, Jong-Hee Chae23, Yingting Quan6, Huidan Wu6, Tianyun Wang5, 6, Raphael A. Bernier24, Kun Xia6, Alyssa Blesson25, Mahim Jain25, Mohammad M. Motazacker26, Bregje Jaeger27, Amy L. Schneider 28, Katja Boysen28, Alison M. Muir 29, Candace T. Myers30, Ralitza H. Gavrilova31, Lauren Gunderson31, Laura Schultz-Rogers 31, Eric W. Klee31, David Dyment32, Matthew Osmond32, 33 34, Mara Parellada35, Cloe Llorente36, Javier Gonzalez-Peñas37, Angel Carracedo38, Arie Van Haeringen40, Claudia Ruivenkamp40, Caroline Nava41, Delphine Heron41, Rosaria Nardello42, Michele Iacomino43, Carlo Minetti2, Aldo Skabar44, Antonella Fabretto44, SYNAPS Study GroupMiquel Raspall-Chaure45, Michael Chez46, Anne Tsai47, Emily Fassi48, Marwan Shinawi48, John N. Constantino49, Rita De Zorzi50, Sara Fortuna 50, Fernando Kok51, Boris Keren41, Dominique Bonneau13, Murim Choi 22, Bruria Benzeev7, Federico Zara43, Heather C. Mefford29, Ingrid E. Scheffer28, Jill Clayton-Smith53, Alfons Macaya45, James E. Rothman4, Evan E. Eichler 5, Dimitri M. Kullmann 4, Henry Houlden 1, SYNAPS Study Group Michael G. Hanna1, Enrico Bugiardini1, Isabel Hostettler1, Benjamin O’Callaghan1, Alaa Khan1, Andrea Cortese1, Emer O’Connor1, Wai Y. Yau1, Thomas Bourinaris1, Rauan Kaiyrzhanov1, Viorica Chelban1, Monika Madej1, Maria C. Diana2, Maria S. Vari2, Marina Pedemonte2, Claudio Bruno2, Ganna Balagura3, Marcello Scala3, Chiara Fiorillo3, Lino Nobili3, Nancy T. Malintan4, Maria N. Zanetti4, Shyam S. Krishnakumar4, Gabriele Lignani4, James E. C. Jepson4, Paolo Broda43, Simona Baldassari43, Pia Rossi43, Floriana Fruscione43, Francesca Madia43, Monica Traverso43, Patrizia De-Marco43, Belen Pérez-Dueñas45, Francina Munell45, Yamna Kriouile57, Mohamed El-Khorassani57, Blagovesta Karashova58, Daniela Avdjieva58, Hadil Kathom58, Radka Tincheva58, Lionel Van-Maldergem59, Wolfgang Nachbauer60, Sylvia Boesch60, Antonella Gagliano61, Elisabetta Amadori62, Jatinder S. Goraya63, Tipu Sultan64, Salman Kirmani65, Shahnaz Ibrahim66, Farida Jan66, Jun Mine67, Selina Banu68, Pierangelo Veggiotti69, Gian V. Zuccotti69, Michel D. Ferrari70, Arn M. J. Van Den Maagdenberg70, Alberto Verrotti71, Gian L. Marseglia72, Salvatore Savasta72, Miguel A. Soler73, Carmela Scuderi74, Eugenia Borgione74, Roberto Chimenz75, Eloisa Gitto75, Valeria Dipasquale75, Alessia Sallemi75, Monica Fusco75, Caterina Cuppari75, Maria C. Cutrupi75, Martino Ruggieri76, Armando Cama77, Valeria Capra77, Niccolò E. Mencacci78, Richard Boles79, Neerja Gupta80, Madhulika Kabra80, Savvas Papacostas81, Eleni Zamba-Papanicolaou81, Efthymios Dardiotis82, Shazia Maqbool83, Nuzhat Rana84, Osama Atawneh85, Shen Y. Lim86, Farooq Shaikh87, George Koutsis88, Marianthi Breza88, Domenico A. Coviello89, Yves A. Dauvilliers90, Issam AlKhawaja91, Mariam AlKhawaja92, Fuad Al-Mutairi93, Tanya Stojkovic94, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya96, Maria Kinali97, Hamed Sherifa98, Hanene Benrhouma99, Ilhem B. Y. Turki99, Meriem Tazir100, Makram Obeid101, Sophia Bakhtadze102, Nebal W. Saadi103, Maha S. Zaki104, Chahnez C. Triki105, Fabio Benfenati106, Stefano Gustincich106, Majdi Kara107, Vincenzo Belcastro108, Nicola Specchio109, Giuseppe Capovilla110, Ehsan G. Karimiani111, Ahmed M. Salih112, Njideka U. Okubadejo113, Oluwadamilola O. Ojo113, Olajumoke O. Oshinaike113, Olapeju Oguntunde113, Kolawole Wahab114, Abiodun H. Bello114, Sanni Abubakar115, Yahaya Obiabo116, Ernest Nwazor117, Oluchi Ekenze118, Uduak Williams119, Alagoma Iyagba120, Lolade Taiwo121, Morenikeji Komolafe122, Konstantin Senkevich123, Chingiz Shashkin124, Nazira Zharkynbekova125, Kairgali Koneyev126, Ganieva Manizha127, Maksud Isrofilov127, Ulviyya Guliyeva128, Kamran Salayev129, Samson Khachatryan130, Salvatore Rossi131, Gabriella Silvestri131, Nourelhoda Haridy132, Luca A. Ramenghi133, Georgia Xiromerisiou134, Emanuele David135, Mhammed Aguennouz136, Liana Fidani137, Cleanthe Spanaki138, Arianna Tucci139, University College of London [London] (UCL), Instituto Giannina Gaslini, Genoa, University of Genoa (UNIGE), University of Washington [Seattle], Institute of Neurology, Queen Square, London, King‘s College London, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), GeneDx [Gaithersburg, MD, USA], Heidelberg University Hospital [Heidelberg], Royal Devon and Exeter NHS Foundation Trust [UK], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Universita degli studi di Genova, Great Ormond Street Hospital for Children [London] (GOSH), The University of Sydney, Hofstra University [Hempstead], Università degli studi di Torino (UNITO), Hospital Sant Joan de Déu [Barcelona], Safra Children's Hospital, Seoul National University Hospital, Central South University [Changsha], Kennedy Krieger Institute [Baltimore], University of Amsterdam [Amsterdam] (UvA), University of Melbourne, Mayo Clinic [Rochester], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Ottawa [Ottawa], University of British Columbia (UBC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Leiden [Leiden], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Palermo - University of Palermo, University of Trieste, Universitat Autònoma de Barcelona (UAB), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California-University of California, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Washington University in Saint Louis (WUSTL), Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Psychiatry, Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, University of Oxford [Oxford], University of São Paulo (USP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Pédiatrie, CHUR Poitiers, Seoul National University [Seoul] (SNU), Pediatric Neurology and Neuromuscular Diseases Unit, University of Manchester [Manchester], Yale University School of Medicine, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Salvy-Córdoba, Nathalie, Università degli studi di Genova = University of Genoa (UniGe), Tel Aviv University (TAU), Università degli studi di Torino = University of Turin (UNITO), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Trieste = University of Trieste, University of California (UC)-University of California (UC), University of Oxford, Universidade de São Paulo = University of São Paulo (USP), Yale School of Medicine [New Haven, Connecticut] (YSM), Salpietro V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, Maroofian R, Heimer G, Burglen L, Valence S, Torti E, Hacke M, Rankin J, Tariq H, Colin E, Procaccio V, Striano P, Mankad K, Lieb A, Chen S, Pisani L, Bettencourt C, Männikkö R, Manole A, Brusco A, Grosso E, Ferrero GB, Armstrong-Moron J, Gueden S, Bar-Yosef O, Tzadok M, Monaghan KG, Santiago-Sim T, Person RE, Cho MT, Willaert R, Yoo Y, Chae JH, Quan Y, Wu H, Wang T, Bernier RA, Xia K, Blesson A, Jain M, Motazacker MM, Jaeger B, Schneider AL, Boysen K, Muir AM, Myers CT, Gavrilova RH, Gunderson L, Schultz-Rogers L, Klee EW, Dyment D, Osmond M, Parellada M, Llorente C, Gonzalez-Peñas J, Carracedo A, Van Haeringen A, Ruivenkamp C, Nava C, Heron D, Nardello R, Iacomino M, Minetti C, Skabar A, Fabretto A, SYNAPS Study Group, Raspall-Chaure M, Chez M, Tsai A, Fassi E, Shinawi M, Constantino JN, De Zorzi R, Fortuna S, Kok F, Keren B, Bonneau D, Choi M, Benzeev B, Zara F, Mefford HC, Scheffer IE, Clayton-Smith J, Macaya A, Rothman JE, Eichler EE, Kullmann DM, Houlden H, 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, Andrea, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, 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-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N, De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Bori, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C, Scheffer, Ingrid E, Clayton-Smith, Jill, Macaya, Alfon, Rothman, James E, Eichler, Evan E, Kullmann, Dimitri M, Houlden, Henry, Salpietro1, Vincenzo, 3, 2, Dixon4, Christine L., Guo5, Hui, 140, 6, Bello Stephanie Efthymiou 1, Oscar D., Maroofian1, Reza, Heimer7, Gali, 8, Lydie Burglen, 9, Stephanie Valence, Torti 10, Erin, Hacke11, Moritz, Rankin12, Julia, Tariq1, Huma, Colin13, Estelle, Procaccio13, Vincent, Striano2, Pasquale, Mankad15, Kshitij, 4, Andreas Lieb, Chen16, Sharon, Pisani16, Laura, Bettencourt 17, Conceicao, 1, Roope Männikkö, Manole1, Andreea, Brusco 18, Alfredo, Grosso18, Enrico, Battista Ferrero19, Giovanni, Armstrong-Moron20, Judith, Gueden21, Sophie, Bar-Yosef7, Omer, Tzadok7, Michal, Monaghan10, Kristin G., Santiago-Sim10, Teresa, Person10, Richard E., Cho10, Megan T., Willaert10, Rebecca, Yoo22, Yongjin, Chae23, Jong-Hee, Quan6, Yingting, Wu6, Huidan, Wang5, Tianyun, Bernier24, Raphael A., Xia6, Kun, Blesson25, Alyssa, Jain25, Mahim, Motazacker26, Mohammad M., Jaeger27, Bregje, Schneider 28, Amy L., Boysen28, Katja, Muir 29, Alison M., Myers30, Candace T., Gavrilova31, Ralitza H., Gunderson31, Lauren, Schultz-Rogers 31, Laura, Klee31, Eric W., Dyment32, David, Osmond32, Matthew, 34, 33, Parellada35, Mara, Llorente36, Cloe, Gonzalez-Peñas37, Javier, Carracedo38, Angel, Van Haeringen40, Arie, Ruivenkamp40, Claudia, Nava41, Caroline, Heron41, Delphine, Nardello42, Rosaria, Iacomino43, Michele, Minetti2, Carlo, Skabar44, Aldo, Fabretto44, Antonella, Study GroupMiquel Raspall-Chaure45, Synap, Chez46, Michael, Tsai47, Anne, Fassi48, Emily, Shinawi48, Marwan, Constantino49, John N., De Zorzi50, Rita, Fortuna 50, Sara, Kok51, Fernando, Keren41, Bori, Bonneau13, Dominique, Choi 22, Murim, Benzeev7, Bruria, Zara43, Federico, Mefford29, Heather C., Scheffer28, Ingrid E., Clayton-Smith53, Jill, Macaya45, Alfon, Rothman4, James E., Eichler 5, Evan E., Kullmann 4 &amp, Dimitri M., 1, Henry Houlden, Hanna1, SYNAPS Study Group Michael G., Bugiardini1, Enrico, Hostettler1, Isabel, O’Callaghan1, Benjamin, Khan1, Alaa, Cortese1, Andrea, O’Connor1, Emer, Yau1, Wai Y., Bourinaris1, Thoma, Kaiyrzhanov1, Rauan, Chelban1, Viorica, Madej1, Monika, Diana2, Maria C., Vari2, Maria S., Pedemonte2, Marina, Bruno2, Claudio, Balagura3, Ganna, Scala3, Marcello, Fiorillo3, Chiara, Nobili3, Lino, Malintan4, Nancy T., Zanetti4, Maria N., Krishnakumar4, Shyam S., Lignani4, Gabriele, Jepson4, James E. C., Broda43, Paolo, Baldassari43, Simona, Rossi43, Pia, Fruscione43, Floriana, Madia43, Francesca, Traverso43, Monica, De-Marco43, Patrizia, Pérez-Dueñas45, Belen, Munell45, Francina, Kriouile57, Yamna, El-Khorassani57, Mohamed, Karashova58, Blagovesta, Avdjieva58, Daniela, Kathom58, Hadil, Tincheva58, Radka, Van-Maldergem59, Lionel, Nachbauer60, Wolfgang, Boesch60, Sylvia, Gagliano61, Antonella, Amadori62, Elisabetta, Goraya63, Jatinder S., Sultan64, Tipu, Kirmani65, Salman, Ibrahim66, Shahnaz, Jan66, Farida, Mine67, Jun, Banu68, Selina, Veggiotti69, Pierangelo, Zuccotti69, Gian V., Ferrari70, Michel D., Van Den Maagdenberg70, Arn M. J., Verrotti71, Alberto, Marseglia72, Gian L., Savasta72, Salvatore, Soler73, Miguel A., Scuderi74, Carmela, Borgione74, Eugenia, Chimenz75, Roberto, Gitto75, Eloisa, Dipasquale75, Valeria, Sallemi75, Alessia, Fusco75, Monica, Cuppari75, Caterina, Cutrupi75, Maria C., Ruggieri76, Martino, Cama77, Armando, Capra77, Valeria, Mencacci78, Niccolò E., Boles79, Richard, Gupta80, Neerja, Kabra80, Madhulika, Papacostas81, Savva, Zamba-Papanicolaou81, Eleni, Dardiotis82, Efthymio, Maqbool83, Shazia, Rana84, Nuzhat, Atawneh85, Osama, Lim86, Shen Y., Shaikh87, Farooq, Koutsis88, George, Breza88, Marianthi, Coviello89, Domenico A., Dauvilliers90, Yves A., Alkhawaja91, Issam, Alkhawaja92, Mariam, Al-Mutairi93, Fuad, Stojkovic94, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya96, Fowzan S., Kinali97, Maria, Sherifa98, Hamed, Benrhouma99, Hanene, Turki99, Ilhem B. Y., Tazir100, Meriem, Obeid101, Makram, Bakhtadze102, Sophia, Saadi103, Nebal W., Zaki104, Maha S., Triki105, Chahnez C., Benfenati106, Fabio, Gustincich106, Stefano, Kara107, Majdi, Belcastro108, Vincenzo, Specchio109, Nicola, Capovilla110, Giuseppe, Karimiani111, Ehsan G., Salih112, Ahmed M., Okubadejo113, Njideka U., Ojo113, Oluwadamilola O., Oshinaike113, Olajumoke O., Oguntunde113, Olapeju, Wahab114, Kolawole, Bello114, Abiodun H., Abubakar115, Sanni, Obiabo116, Yahaya, Nwazor117, Ernest, Ekenze118, Oluchi, Williams119, Uduak, Iyagba120, Alagoma, Taiwo121, Lolade, Komolafe122, Morenikeji, Senkevich123, Konstantin, Shashkin124, Chingiz, Zharkynbekova125, Nazira, Koneyev126, Kairgali, Manizha127, Ganieva, Isrofilov127, Maksud, Guliyeva128, Ulviyya, Salayev129, Kamran, Khachatryan130, Samson, Rossi131, Salvatore, Silvestri131, Gabriella, Haridy132, Nourelhoda, Ramenghi133, Luca A., Xiromerisiou134, Georgia, David135, Emanuele, Aguennouz136, Mhammed, Fidani137, Liana, Spanaki138 &amp, Cleanthe, and Tucci139, Arianna

Subjects
Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ion channels in the nervous system, Cohort Studies, fluids and secretions, Loss of Function Mutation, Receptors, AMPA, AMPA receptor, lcsh:Science, Child, reproductive and urinary physiology, AMPA receptor, GluA2, neurodevelopmental disorders, autism spectrum disorder, glutamatergic synaptic transmission, GRIA2, neurodevelopmental disorders, Developmental disorders, Neurodevelopmental disorders, Brain, Magnetic Resonance Imaging, Settore MED/26 - NEUROLOGIA, GluA2, Child, Preschool, Female, Adult, Heterozygote, Adolescent, Science, autism spectrum disorder, Article, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Intellectual Disability/genetics, Neurodevelopmental Disorders/genetics, Receptors AMPA/genetics, Intellectual Disability, mental disorders, Humans, Infant, Neurodevelopmental Disorders, Receptors, AMPA, GRIA2, Preschool, Ion channel in the nervous system, Developmental disorders, Synaptic development, NG sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, glutamatergic synaptic transmission, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, NG sequencing, Synaptic development, Ion channel in the nervous system, Next-generation sequencing, lcsh:Q
Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission., Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

Published
2019

31. Acute haemolytic crisis due to concomitant presence of infection and possible altered acetaminophen catabolism in a Philipino child carrying the G6PD-Vanua Lava mutation

Author

Paola Concolino, Angelo Minucci, Cecilia Zuppi, Ettore Capoluongo, Eleonora Torti, Palma Maurizi, Bruno Giardina, Daniele De Luca, Minucci, A, De Luca, D, Torti, E, Concolino, P, Maurizi, P, Giardina, B, Zuppi, C, and Capoluongo, E

Subjects
Male, Drug, Philippines, media_common.quotation_subject, Clinical Biochemistry, Glucosephosphate Dehydrogenase, Infections, medicine.disease_cause, Hemolysis, chemistry.chemical_compound, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, hemic and lymphatic diseases, parasitic diseases, GLUTATHIONE, medicine, Humans, PARACETAMOL, Acetaminophen, media_common, Mutation, IDENTIFICATION, Catabolism, business.industry, GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY, General Medicine, Glutathione, medicine.disease, Glucosephosphate Dehydrogenase Deficiency, Biochemistry, chemistry, Child, Preschool, Concomitant, Toxicity, Immunology, business, medicine.drug, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Glucose-6-phosphate dehydrogenase (G6PD), an X-linked hereditary deficiency, is the most common of all clinically significant enzyme defects. While many drugs are responsible for haemolytic anaemia in G6PD-deficient patients, acetaminophen's imputability is still under debate, although an overdose of this drug can provoke acute haemolytic events. We report a case of a Philipino child carrying the G6PD-Vanua Lava mutation with acute haemolytic crisis related to infection in progress and acetaminophen's administration. Fever and concomitant infection, through an increment of erythrocyte glutathione depletion, sensitized the infant to the haemolytic event. In this condition, acetaminophen (or paracetamol [PCM]) was capable of inducing a haemolytic crisis in our G6PD-deficient patient although administered under standard conditions. PCM seems to have induced the haemolytic event, probably by the alteration of its catabolism due to dehydration and fever. The enzymatic G6PD instability associated to the presence of the G6PD-Vanua Lava mutation could have led to an increment of red blood cells' sensitivity to lysis; hence, it is possible that PCM toxicity may also be due to the presence of this particular mutation. Finally, we propose a new biochemical classification of this G6PD variant.

Published
2011

32. Common genetic variants of MUTYH are not associated with cutaneous malignant melanoma: application of molecular screening by means of high-resolution melting technique in a pilot case-control study

Author

Concetta Santonocito, Cecilia Zuppi, Eleonora Torti, Ettore Capoluongo, Rodolfo Capizzi, Sara Lanza-Silveri, Andrea Paradisi, Romina Penitente, Santonocito, C, Paradisi, A, Capizzi, R, Torti, E, LANZA SILVERI, S, Penitente, R, Zuppi, C, and Capoluongo, Ed

Subjects
0301 basic medicine, Oncology, Adult, Male, Risk, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Clinical Biochemistry, Context (language use), Pilot Projects, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, High Resolution Melt, Pathology and Forensic Medicine, DNA Glycosylases, 03 medical and health sciences, 0302 clinical medicine, MUTYH, Internal medicine, medicine, Humans, Neoplasm Invasiveness, Melanoma, Aged, Genetics, Molecular screening, Guanosine, business.industry, Case-control study, Genetic variants, Base excision repair, Sequence Analysis, DNA, Middle Aged, medicine.disease, 030104 developmental biology, DNA Repair Enzymes, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Case-Control Studies, Female, genetic, Settore MED/35 - MALATTIE CUTANEE E VENEREE, business
Abstract

MUTYH glycosylase recognizes the 8-oxoG:A mismatch and is able to excise the adenine base using proofreading mechanisms. Some papers have reported a strong association between cancer development or aggressiveness and MUTYH gene mutations. The aim of this study was to find a possible association between the most frequent MUTYH mutations and melanoma in the context of a case-control pilot study. One hundred ninety-five melanoma patients and 195 healthy controls were matched for sex and age. Clinical and laboratory data were collected in a specific database and all individuals were analyzed for MUTYH mutations by high-resolution melting and direct sequencing techniques. Men and women had significantly different distributions of tumor sites and phototypes. No significant associations were observed between the Y165C, G382D and V479F MUTYH mutations and risk of melanoma development or aggressiveness. Our preliminary findings therefore do not confirm a role for MUTYH gene mutations in the melanoma risk. Further studies are necessary for the assessment of MUTYH not only in melanoma but also other cancer types with the same embryonic origin, in the context of larger arrays studies of genes involved in DNA stability or integrity.

Published
2010

33. Genetic cystic fibrosis transmembrane regulator 4016insT D1152H compound heterozygosity and male infertility: an Italian case report

Author

Paola Concolino, Concetta Santonocito, Bruno Giardina, Eleonora Torti, Sandro Rocchetti, Cecilia Zuppi, Ettore Capoluongo, Rocchetti, S, Santonocito, C, Concolino, P, Torti, E, Zuppi, C, Giardina, B, and Capoluongo, E.

Subjects
Genetics, Biochemistry (medical), Clinical Biochemistry, medicine, Regulator, General Medicine, Biology, medicine.disease, Compound heterozygosity, Cystic fibrosis, Transmembrane protein, Male infertility
Published
2007

34. Association between cutaneous melanoma, Breslow thickness and vitamin D receptor BsmI polymorphism

Author

Ettore Capoluongo, A. Paradisi, M.M. Lavieri, Concetta Santonocito, Franco Ameglio, Paola Concolino, Eleonora Torti, A. Di Carlo, R. Capizzi, E. Di Stasio, Sergio Rutella, Cecilia Zuppi, Sandro Rocchetti, Stefano Gentileschi, Santonocito, C, Capizzi, R, Concolino, P, Lavieri, Mm, Paradisi, A, Gentileschi, S, Torti, E, Rutella, S, Rocchetti, S, DI CARLO, A, DI STASIO, E, Ameglio, F, Zuppi, C, and Capoluongo, E.

Subjects
Adult, Male, medicine.medical_specialty, Skin Neoplasms, TaqI, Single-nucleotide polymorphism, Dermatology, Calcitriol receptor, Gastroenterology, Breslow Thickness, chemistry.chemical_compound, Internal medicine, medicine, Vitamin D and neurology, Humans, Melanoma, Aged, biology, business.industry, Middle Aged, FokI, Genotype frequency, Endocrinology, chemistry, Italy, Case-Control Studies, biology.protein, Receptors, Calcitriol, Regression Analysis, Female, Restriction fragment length polymorphism, business, Polymorphism, Restriction Fragment Length
Abstract

Summary Background Literature data report an association between some vitamin D receptor (VDR) polymorphisms and different kinds of tumours, including malignant melanoma (MM). Only three VDR polymorphisms (FokI, TaqI and A-1012G) have been investigated in association with the presence of cutaneous MM or the development of metastases. Objectives The present paper analyses for the first time the association between BsmI polymorphism and MM prevalence together with Breslow thickness. In addition, the FokI single nucleotide polymorphism was also determined. Methods One hundred and one patients with MM and 101 healthy donors matched for age and sex were enrolled. Molecular VDR typing was performed by means of restriction fragment length polymorphism analysis. Results All cases and controls were in Hardy–Weinberg equilibrium for BsmI, FokI and A-1012G. Significant associations were found between the BsmI bb genotype frequency and MM (P = 0·02) along with Breslow thickness (P = 0·001). This same behaviour was not observed for the FokI or A-1012G polymorphisms. Multivariate logistic regression analysis confirmed these significant results after correction for age, gender, skin type and MM localization. Conclusions Although the biological meaning of the effects exerted by BsmI polymorphism is still under debate, the statistical association found in the present study suggests that further work should be done to verify this variant as a possible risk marker for MM and its aggressiveness, also considering that the real association may be due to other unknown genes linked to the BsmI b allele.

Published
2007

35. 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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36. Early Choriocapillaris Dysfunction in Fellow Eyes of Patients with Unilateral Neovascular Age-Related Macular Degeneration.

Author

Toma C, Gatti V, Servillo A, Galotta A, Leonardi M, Ferrante D, Torti E, Leporati F, and Cillà S

Abstract

Purpose: To investigate early changes in AMD by evaluating and comparing choriocapillaris (CC) flow in fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) and in healthy controls using swept-source optical coherence tomography angiography (SS-OCTA)., Methods: Patients with unilateral nAMD and no/early/intermediate AMD (no/e/iAMD) in their fellow eye and normal controls who underwent SS-OCT and OCTA where included. CC perfusion was assessed on MATLAB as percentage of flow deficits (FD%) in the central 4.5 × 4.5 mm macular region, after removing artifacts., Results: 81 eyes/patients (22 eyes with noAMD, 30 with eAMD, 29 with iAMD) with unilateral nAMD and 24 controls were analyzed. Median FD% was 8.97 (IQR 8.58-9.53) in AMD group, 8.92 (IQR 8.64-9.27) in noAMD group, 8.96 (IQR 8.46-9.38) in eAMD group, 9.05 (IQR 8.58-9.8) in iAMD group, and 8.22 (IQR 7.78-8.55) in controls. A statistically significant difference in FD% was observed between controls and AMD group (p < 0.001), as well as between each AMD subgroup and controls (noAMD vs controls p = 0.0037; eAMD vs control p = 0.0012; iAMD vs controls p = 0.0002)., Conclusion: This study suggests that CC dysfunction may occur in fellow eyes of patients with unilateral nAMD before visible AMD signs, potentially preceding RPE changes. Further longitudinal studies are needed to confirm these findings and explore the correlation with AMD development/progression.

Published
2024
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37. Microvascular changes in eyes with non-proliferative diabetic retinopathy with or without macular microaneurysms: an OCT-angiography study.

Author

Toma C, Cavallari E, Varano P, Servillo A, Gatti V, Ferrante D, Torti E, Muraca A, and De Cillà S

Abstract

Purpose: To evaluate different quantitative non-invasive retinal biomarkers of microvascular impairment and neurodegeneration in patients affected by mild and moderate non proliferative diabetic retinopathy (NPDR) with or without macular microaneurysms (MAs)., Methods: A cross-sectional case-control study. Ninety-seven eyes with NPDR, 49 with no central MAs and 48 with central MAs, underwent color fundus photography and optical coherence tomography (OCT)/OCT-angiography (OCT-A). Thickness of central macula, retinal nerve fiber layer (NFL), ganglion cell layer (GCL+) and NFL + GCL + was evaluated on OCT. FAZ metrics (ImageJ), perfusion and vessel density (PD/VD), and fractal dimension (FD) (MATLAB) were evaluated on 3 × 3 OCT-A slabs of both superficial and deep capillary plexuses (SCP/DCP). All evaluations were performed on the full image and after subdivision in 4 quadrants., Results: In the MA group, 77 MAs were detected (45.5% in the DCP). The MA group showed: increased FAZ area and perimeter in the SCP (p < 0.01) and DCP (p = 0.02), and reduced circularity index in the SCP (p = 0.03); reduced VD in the SCP (p < 0.01) and reduced PD, VD (p < 0.01) and FD (p = 0.02) in the DCP; decreased VD and FD in the SCP (p = 0.02 and p = 0.05), and in VD and FD in the DCP in the inferior quadrant (p = 0.04 and p = 0.03); a decrease in VD in the SCP in the nasal quadrant (p = 0.05). No differences have been detected in OCT parameters., Conclusions: Our results suggest that the presence of central MAs in patients with NPDR may correlate with more pronounced macular microvascular impairment, particularly during the mild and moderate stages of the disease., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Published
2024
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38. A gender-based analysis of retinal microvascular alterations in patients with diabetes mellitus using OCT angiography.

Author

Vujosevic S, Limoli C, Piccoli G, Costanzo E, Marenzi E, Torti E, Giannini D, Polito MS, Luzi L, Nucci P, and Parravano M

Subjects
Humans, Female, Male, Cross-Sectional Studies, Middle Aged, Retrospective Studies, Aged, Sex Factors, Fluorescein Angiography methods, Adult, Microvessels diagnostic imaging, Microvessels physiopathology, Sex Characteristics, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 diagnostic imaging, Tomography, Optical Coherence methods, Diabetic Retinopathy diagnostic imaging, Diabetic Retinopathy physiopathology, Retinal Vessels diagnostic imaging, Retinal Vessels pathology
Abstract

Purpose: To assess the difference in microvascular changes between males and females with diabetes mellitus (DM) without diabetic retinopathy (NoDR) and with mild-to-moderate non-proliferative diabetic retinopathy (NPDR) using Optical Coherence Tomography Angiography (OCT-A)., Design: Retrospective cross-sectional study., Methods: 267 DM patients, 133 females (49.81 %), 111 with NoDR (41.57 %) and 156 NPDR (58.43 %) were included. Foveal-centered 3 × 3 mm OCT-A images corresponding to the superficial (SCP), intermediate (ICP) and deep capillary plexus (DCP), and full retinal (RET) slab were used for analysis. For each slab, FAZ area, perimeter, and circularity index (CI) were determined, following manual delineation of the FAZ; perfusion (PD) and vessel density (VD), fractal dimension (FD), vessel length density (VLD), geometric perfusion deficits (GPD) were also computed. Flow voids (FV) were determined in the choriocapillaris plexus; and perfused capillary density (PCD) in the RET slab., Results: Females showed larger FAZ CI in SCP and greater FAZ area and perimeter than males in NPDR group. Males had higher central macular thickness than females in NPDR group. All density metrics at the level of ICP and DCP were affected in the NPDR group with no gender differences. Of note, the same significant findings were found in type 1 DM patients, and not in type 2 DM patients., Conclusions: Our OCT-A findings suggest significant microvascular changes in females with NPDR compared to males, but no such differences in patients without DR. Therefore, gender-related vascular alterations might be present in early stages of DR with potential role., Competing Interests: Declaration of competing interest Stela Vujosevic: Consultant to Abbvie, Apellis, Bayer, Novartis, Hoffman La Roche, Zeiss; Paolo Nucci: Thea, Hoya, Essilor Luxottica e Fondazione One-sight, Sifi, Bausch& Lomb, Alfa Intes, Alcon, Doc, Santen, Eyerising. Mariacristina Parravano reports personal fees from Abbvie, Novartis, Bayer, La-Roche, Zeiss outside the submitted work. Celeste Limoli, Gabriele Piccoli, Eliana Costanzo, Elisa Marenzi, Emanuele Torti, Daniela Giannini, Maria Sole Polito and Livio Luzi have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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39. Severity of Disorganization of Retinal Layers and Visual Function Impairment in Diabetic Retinopathy.

Author

Vujosevic S, Alovisi C, Piccoli G, Brambilla M, Torti E, Marenzi E, Leporati F, Luzi L, and Nucci P

Subjects
Humans, Retrospective Studies, Male, Female, Middle Aged, Case-Control Studies, Retina physiopathology, Retina diagnostic imaging, Fundus Oculi, Aged, Severity of Illness Index, Visual Field Tests, Diabetic Retinopathy physiopathology, Diabetic Retinopathy diagnosis, Diabetic Retinopathy complications, Visual Acuity, Tomography, Optical Coherence methods, Fluorescein Angiography methods, Visual Fields physiology
Abstract

Purpose: To evaluate best-corrected visual acuity (BCVA), retina sensitivity (RS), and fixation impairment by microperimetry (MP) due to the presence and severity of disorganization of retinal inner and outer layers (DRIL/DROL) and ischemia in OCT/OCT angiography (OCTA) in diabetic retinopathy (DR)., Design: Retrospective case-control study., Subjects: Seventy-six eyes (65 patients) with DR were analyzed. Major exclusion criteria were: center-involving diabetic macular edema (DME), significant media opacity, nondiabetic macular pathology, and active proliferative DR. Patients with DRIL and DROL within central 3 mm were enrolled as cases. Patients with DR and no retina disorganization were considered as controls., Methods: A detailed grading of MP and OCT/OCTA images using Image J software, and specific Image Manipulation Program was applied to colocalize the presence of retina disorganization and RS. Best-corrected visual acuity and RS were correlated with the disorganization of retina layers' characteristics and grading (grade 1-DRIL; grade 2-DROL; grade 3-DROL plus, with involvement of the ellipsoid zone). The same procedure of colocalization was applied to the vascular layers on OCTA using MATLAB., Main Outcome Measures: Correlation between BCVA and MP parameters with disorganization of retina layers grading and OCTA parameters., Results: Best-corrected visual acuity, mean RS within 1 mm and central 3 mm (overall RS [oRS]), perfusion density, vessel density, and geometric perfusion deficit in intermediate and deep capillary plexuses were lower in cases versus controls (P < 0.001). Mean RS within 1 mm (21.4 decibels [dB] ± 2.4 vs. 13.8 dB ± 5.4, P = 0.002), oRS (22.0 dB ± 2.1 vs. 14.4 dB ± 4.6, P < 0.001), and BCVA (76.1 ± 7.4 vs. 61.2 ± 20.4 ETDRS letters; P = 0.02), had a significant decrease from grade 1 to grade 3 retina disorganization. Choriocapillaris flow voids (CC-FVs) increased from grade 1 to grade 3 (DROL plus) (P = 0.004). Overall retina sensitivity and CC-FV were identified as significant predictors of retina disorganization grade with an adjusted coefficient of determination, R 2  = 0.45. Cases had more dense scotomas (P = 0.03) than controls with a positive correlation between the worsening of fixation stability and the severity of DRIL/DROL (P = 0.04)., Conclusions: Microperimetry and BCVA documented a reduction in visual function in patients with DR and disorganization of retina layers at different grades, with greater functional impairment when outer retina layers and photoreceptors are involved. The severity of retina disorganization and the presence of ischemia could serve as a potential biomarker of functional impairment., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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40. Clinical Features Related to OCT Angiography Artifacts in Patients with Diabetic Macular Edema.

Author

Tamer Kaderli S, Piccoli G, Limoli C, Ginelli S, Caboni S, Brotto L, Torti E, O'Toole L, Nucci P, and Vujosevic S

Subjects
Humans, Retrospective Studies, Male, Cross-Sectional Studies, Female, Aged, Middle Aged, Macular Edema diagnosis, Macular Edema etiology, Macular Edema diagnostic imaging, Tomography, Optical Coherence methods, Diabetic Retinopathy diagnosis, Artifacts, Fluorescein Angiography methods, Visual Acuity, Retinal Vessels diagnostic imaging, Retinal Vessels pathology, Fundus Oculi
Abstract

Purpose: To investigate the frequency and type of artifacts on OCT angiography (OCTA) images and the relationship with clinical features in eyes with diabetic macular edema (DME)., Design: Retrospective, cross-sectional comparative study., Subjects: One hundred ninety-two eyes of 140 patients with DME were included., Methods: Medical records, OCT and OCTA images (Spectralis), and ultrawidefield color fundus photographs (Optos plc) were evaluated., Main Outcome Measures: The frequency of artifact types (segmentation, motion, projection artifact, and low signal) was determined. The relationships between artifact types and clinical features such as best-corrected visual acuity (BCVA), mean central retinal thickness (CRT), foveal avascular zone (FAZ) area, perimeter, circularity index, perfusion density (PD), vessel density (VD), fractal dimension (FD) in the superficial capillary plexus, intermediate capillary plexus (ICP), and deep capillary plexus (DCP), flow voids (FVs) in the choriocapillaris, presence of hard exudate (HE), and cataract were determined., Results: The mean age was 71.6 ± 11.4 years, and 86 (61.4%) out of 140 were men. Artifacts were present in 63 (32.8%) of 192 eyes. Twenty-nine (15.1%) eyes had segmentation artifacts, 12 (6.3%) had motion artifacts, 11 (5.7%) had projection artifacts, and 18 (9.4%) had low signal. Best-corrected visual acuity, PD, VD, and FD in ICP and DCP were significantly lower; and CRT, FAZ area and perimeter in ICP and DCP, and presence of cystoid macular edema, HE, and cataract were higher in eyes with artifacts versus eyes without artifacts (P < 0.05 for each). Multivariate linear regression analysis showed a significant association between segmentation artifacts and decreased BCVA (odds ratio [OR], 5.277; P = 0.02), increased CRT (OR, 1.015; P < 0.001), increased area of FAZ in DCP (OR, 6.625; P = 0.02), and increased perimeter of FAZ in DCP (OR, 1.775; P < 0.04); there was also a significant association between projection artifacts and presence of HE (OR, 2.017; P = 0.02) and between motion artifacts and presence of cataract (OR, 4.102; P = 0.01)., Conclusions: OCT angiography artifacts were present in one third of DME eyes, with segmentation artifacts being the most frequent type. Determining OCTA artifacts is crucial to ensure accurate clinical evaluation. These data could help in developing more standardized clinical protocols for image acquisition and interpretation used in clinical practice and research., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Published
2024
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41. De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.

Author

Mullegama SV, Kiernan KA, Torti E, Pavlovsky E, Tilton N, Sekula A, Gao H, Alaimo JT, Engleman K, Rush ET, Blocker K, Dipple KM, Fettig VM, Hare H, Glass I, Grange DK, Griffin M, Phornphutkul C, Massingham L, Mehta L, Miller DE, Thies J, Merritt JL 2nd, Muller E 2nd, Osmond M, Sawyer SL, Slaugh R, Hickey RE, Wolf B, Choudhary S, Simonović M, Zhang Y, Palculict TB, Telegrafi A, Carere DA, Wentzensen IM, Morrow MM, Monaghan KG, Juusola J, and Yang J

Published
2024
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42. Macula vs periphery in diabetic retinopathy: OCT-angiography and ultrawide field fluorescein angiography imaging of retinal non perfusion.

Author

Vujosevic S, Fantaguzzi F, Silva PS, Salongcay R, Brambilla M, Torti E, Nucci P, and Peto T

Subjects
Humans, Female, Male, Middle Aged, Aged, Adult, Visual Acuity physiology, Fluorescein Angiography methods, Diabetic Retinopathy physiopathology, Diabetic Retinopathy diagnosis, Diabetic Retinopathy diagnostic imaging, Tomography, Optical Coherence methods, Retinal Vessels diagnostic imaging, Retinal Vessels pathology, Retinal Vessels physiopathology, Macula Lutea diagnostic imaging, Macula Lutea blood supply
Abstract

Objectives: To investigate the association between peripheral non-perfusion index (NPI) on ultrawide-field fluorescein angiography (UWF-FA) and quantitative OCT-Angiography (OCT-A) metrics in the macula., Methods: In total, 48 eyes with UWF-colour fundus photos (CFP), UWF-FA (California, Optos) and OCT-A (Spectralis, Heidelberg) were included. OCT-A (3 × 3 mm) was used to determine foveal avascular zone (FAZ) parameters and vessel density (VD), perfusion density (PD), fractal dimension (FD) on superficial capillary plexus (SCP). NPI's extent and distribution was determined on UWF-FA within fovea centred concentric rings corresponding to posterior pole (<10 mm), mid-periphery (10-15 mm), and far-periphery (>15 mm) and within the total retinal area, the central macular field (6×6 mm), ETDRS fields and within each extended ETDRS field (P3-P7)., Results: Macular PD was correlated to NPI in total area of retina (Spearman ρ = 0.69, p < 0.05), posterior pole (ρ = 0.48, p < 0.05), mid-periphery (ρ = 0.65, p < 0.05), far-periphery (ρ = 0.59, p < 0.05), P3-P7 (ρ = 0,55 at least, p < 0.05 for each), central macula (ρ = 0.47, p < 0.05), total area in ETDRS (ρ = 0.55, p < 0.05). Macular VD and FD were correlated to NPI of total area of the retina (ρ = 0.60 and 0.61, p < 0.05), the mid-periphery (ρ = 0.56, p < 0.05) and far-periphery (ρ = 0.60 and ρ = 0.61, p < 0.05), and in P3-P7 (p < 0.05). FAZ perimeter was significantly corelated to NPI at posterior pole and central macular area (ρ = 0.37 and 0.36, p < 0.05), and FAZ area to NPI in central macular area (ρ = 0.36, p < 0.05)., Conclusions: Perfusion macular metrics on OCT-A correlated with UWF-FA's non-perfusion (NP), particularly in the retina's mid and far periphery, suggesting that OCT-A might be a useful non-invasive method to estimate peripheral retinal NP., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Published
2024
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43. Acceleration of Hyperspectral Skin Cancer Image Classification through Parallel Machine-Learning Methods.

Author

Petracchi B, Torti E, Marenzi E, and Leporati F

Subjects
Humans, Machine Learning, Hyperspectral Imaging, Acceleration, Support Vector Machine, Algorithms, Skin Neoplasms
Abstract

Hyperspectral imaging (HSI) has become a very compelling technique in different scientific areas; indeed, many researchers use it in the fields of remote sensing, agriculture, forensics, and medicine. In the latter, HSI plays a crucial role as a diagnostic support and for surgery guidance. However, the computational effort in elaborating hyperspectral data is not trivial. Furthermore, the demand for detecting diseases in a short time is undeniable. In this paper, we take up this challenge by parallelizing three machine-learning methods among those that are the most intensively used: Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGB) algorithms using the Compute Unified Device Architecture (CUDA) to accelerate the classification of hyperspectral skin cancer images. They all showed a good performance in HS image classification, in particular when the size of the dataset is limited, as demonstrated in the literature. We illustrate the parallelization techniques adopted for each approach, highlighting the suitability of Graphical Processing Units (GPUs) to this aim. Experimental results show that parallel SVM and XGB algorithms significantly improve the classification times in comparison with their serial counterparts.

Published
2024
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44. Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.

Author

Küry S, Stanton JE, van Woerden G, Hsieh TC, Rosenfelt C, Scott-Boyer MP, Most V, Wang T, Papendorf JJ, de Konink C, Deb W, Vignard V, Studencka-Turski M, Besnard T, Hajdukowicz AM, Thiel F, Möller S, Florenceau L, Cuinat S, Marsac S, Wentzensen I, Tuttle A, Forster C, Striesow J, Golnik R, Ortiz D, Jenkins L, Rosenfeld JA, Ziegler A, Houdayer C, Bonneau D, Torti E, Begtrup A, Monaghan KG, Mullegama SV, Volker-Touw CMLN, van Gassen KLI, Oegema R, de Pagter M, Steindl K, Rauch A, Ivanovski I, McDonald K, Boothe E, Dauber A, Baker J, Fabie NAV, Bernier RA, Turner TN, Srivastava S, Dies KA, Swanson L, Costin C, Jobling RK, Pappas J, Rabin R, Niyazov D, Tsai AC, Kovak K, Beck DB, Malicdan M, Adams DR, Wolfe L, Ganetzky RD, Muraresku C, Babikyan D, Sedláček Z, Hančárová M, Timberlake AT, Al Saif H, Nestler B, King K, Hajianpour MJ, Costain G, Prendergast D, Li C, Geneviève D, Vitobello A, Sorlin A, Philippe C, Harel T, Toker O, Sabir A, Lim D, Hamilton M, Bryson L, Cleary E, Weber S, Hoffman TL, Cueto-González AM, Tizzano EF, Gómez-Andrés D, Codina-Solà M, Ververi A, Pavlidou E, Lambropoulos A, Garganis K, Rio M, Levy J, Jurgensmeyer S, McRae AM, Lessard MK, D'Agostino MD, De Bie I, Wegler M, Jamra RA, Kamphausen SB, Bothe V, Busch LM, Völker U, Hammer E, Wende K, Cogné B, Isidor B, Meiler J, Bosc-Rosati A, Marcoux J, Bousquet MP, Poschmann J, Laumonnier F, Hildebrand PW, Eichler EE, McWalter K, Krawitz PM, Droit A, Elgersma Y, Grabrucker AM, Bolduc FV, Bézieau S, Ebstein F, and Krüger E

Abstract

Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.

Published
2024
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45. Ambient assisted living for frail people through human activity recognition: state-of-the-art, challenges and future directions.

Author

Guerra BMV, Torti E, Marenzi E, Schmid M, Ramat S, Leporati F, and Danese G

Abstract

Ambient Assisted Living is a concept that focuses on using technology to support and enhance the quality of life and well-being of frail or elderly individuals in both indoor and outdoor environments. It aims at empowering individuals to maintain their independence and autonomy while ensuring their safety and providing assistance when needed. Human Activity Recognition is widely regarded as the most popular methodology within the field of Ambient Assisted Living. Human Activity Recognition involves automatically detecting and classifying the activities performed by individuals using sensor-based systems. Researchers have employed various methodologies, utilizing wearable and/or non-wearable sensors, and employing algorithms ranging from simple threshold-based techniques to more advanced deep learning approaches. In this review, literature from the past decade is critically examined, specifically exploring the technological aspects of Human Activity Recognition in Ambient Assisted Living. An exhaustive analysis of the methodologies adopted, highlighting their strengths and weaknesses is provided. Finally, challenges encountered in the field of Human Activity Recognition for Ambient Assisted Living are thoroughly discussed. These challenges encompass issues related to data collection, model training, real-time performance, generalizability, and user acceptance. Miniaturization, unobtrusiveness, energy harvesting and communication efficiency will be the crucial factors for new wearable solutions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Guerra, Torti, Marenzi, Schmid, Ramat, Leporati and Danese.)

Published
2023
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46. LONGITUDINAL MICROVASCULAR AND NEURONAL RETINAL EVALUATION IN PATIENTS WITH DIABETES MELLITUS TYPES 1 AND 2 AND GOOD GLYCEMIC CONTROL.

Author

Vujosevic S, Toma C, Villani E, Nucci P, Brambilla M, Torti E, Leporati F, and De Cillà S

Subjects
Humans, Longitudinal Studies, Prospective Studies, Glycemic Control, Retinal Vessels diagnostic imaging, Tomography, Optical Coherence methods, Fluorescein Angiography methods, Diabetic Retinopathy diagnosis, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 diagnosis
Abstract

Purpose: To evaluate microvascular and neuronal changes over 3 years in patients with Type 1/2 diabetes mellitus (DM1/DM2), good metabolic control, and no signs of diabetic retinopathy., Methods: In this prospective, longitudinal study, 20 DM1, 48 DM2, and 24 controls underwent macular optical coherence tomography and optical coherence tomography angiography at baseline and after 3 years. Following parameters were considered: thickness of the central macula, retinal nerve fiber layer, ganglion cell (GCL+/GCL++) complex; perfusion and vessel density and fractal dimension at the superficial and deep capillary plexuses; choriocapillaris flow deficits; and foveal avascular zone metrics. MATLAB and ImageJ were used for optical coherence tomography angiography scans analyses., Results: The mean HbA1c was 7.4 ± 0.8% in DM1 and 7.2 ± 0.8% in DM2 at baseline, with no change at 3 years. No eye developed diabetic retinopathy. In longitudinal analyses, perfusion density at superficial capillary plexuses ( P = 0.03) and foveal avascular zone area and perimeter ( P < 0.0001) significantly increased in DM2 compared with other groups. No longitudinal changes occurred in optical coherence tomography parameters. In comparisons within groups, DM2 had a significant thinning of GCL++ in the outer ring, decreased perfusion density at deep capillary plexuses and choriocapillaris flow deficits, and increase in foveal avascular zone perimeter and area in deep capillary plexuses; DM1 had an increase in foveal avascular zone perimeter in deep capillary plexuses ( P < 0.001 for all comparisons)., Conclusion: Longitudinal data showed significant microvascular retinal changes in DM2. No changes were detected in neuronal parameters and in DM1. Longer and larger studies are needed to confirm these preliminary data.

Published
2023
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47. Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome.

Author

Ramond F, Dalgliesh C, Grimmel M, Wechsberg O, Vetro A, Guerrini R, FitzPatrick D, Poole RL, Lebrun M, Bayat A, Grasshoff U, Bertrand M, Witt D, Turnpenny PD, Faundes V, Santa María L, Mendoza Fuentes C, Mabe P, Hussain SA, Mullegama SV, Torti E, Oehl-Jaschkowitz B, Salmon LB, Orenstein N, Shahar NR, Hagari O, Bazak L, Hoffjan S, Prada CE, Haack T, and Elliott DJ

Subjects
Humans, Alternative Splicing, RNA-Binding Proteins genetics, HEK293 Cells, Protein Isoforms genetics, Serine-Arginine Splicing Factors genetics, Serine-Arginine Splicing Factors metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Autism Spectrum Disorder, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
Abstract

Purpose: Transformer2 proteins (Tra2α and Tra2β) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder., Methods: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2β-1 and Tra2β-3 isoforms from patient-derived cells were performed. Tra2β1-GFP, Tra2β3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells., Results: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2β-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2β-1 isoform, whereas they increased the expression of the Tra2β-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2β-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2β-1., Conclusion: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2β protein., Competing Interests: Conflict of Interest S.V.M. and E.T. are employees of GeneDx, LLC. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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48. Perceptive SARS-CoV-2 End-To-End Ultrasound Video Classification through X3D and Key-Frames Selection.

Author

Gazzoni M, La Salvia M, Torti E, Secco G, Perlini S, and Leporati F

Abstract

The SARS-CoV-2 pandemic challenged health systems worldwide, thus advocating for practical, quick and highly trustworthy diagnostic instruments to help medical personnel. It features a long incubation period and a high contagion rate, causing bilateral multi-focal interstitial pneumonia, generally growing into acute respiratory distress syndrome (ARDS), causing hundreds of thousands of casualties worldwide. Guidelines for first-line diagnosis of pneumonia suggest Chest X-rays (CXR) for patients exhibiting symptoms. Potential alternatives include Computed Tomography (CT) scans and Lung UltraSound (LUS). Deep learning (DL) has been helpful in diagnosis using CT scans, LUS, and CXR, whereby the former commonly yields more precise results. CXR and CT scans present several drawbacks, including high costs. Radiation-free LUS imaging requires high expertise, and physicians thus underutilise it. LUS demonstrated a strong correlation with CT scans and reliability in pneumonia detection, even in the early stages. Here, we present an LUS video-classification approach based on contemporary DL strategies in close collaboration with Fondazione IRCCS Policlinico San Matteo's Emergency Department (ED) of Pavia. This research addressed SARS-CoV-2 patterns detection, ranked according to three severity scales by operating a trustworthy dataset comprising ultrasounds from linear and convex probes in 5400 clips from 450 hospitalised subjects. The main contributions of this study are related to the adoption of a standardised severity ranking scale to evaluate pneumonia. This evaluation relies on video summarisation through key-frame selection algorithms. Then, we designed and developed a video-classification architecture which emerged as the most promising. In contrast, the literature primarily concentrates on frame-pattern recognition. By using advanced techniques such as transfer learning and data augmentation, we were able to achieve an F1-Score of over 89% across all classes.

Published
2023
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49. Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5 .

Author

Happ HC, Sadleir LG, Zemel M, de Valles-Ibáñez G, Hildebrand MS, McConkie-Rosell A, McDonald M, May H, Sands T, Aggarwal V, Elder C, Feyma T, Bayat A, Møller RS, Fenger CD, Klint Nielsen JE, Datta AN, Gorman KM, King MD, Linhares ND, Burton BK, Paras A, Ellard S, Rankin J, Shukla A, Majethia P, Olson RJ, Muthusamy K, Schimmenti LA, Starnes K, Sedláčková L, Štěrbová K, Vlčková M, Laššuthová P, Jahodová A, Porter BE, Couque N, Colin E, Prouteau C, Collet C, Smol T, Caumes R, Vansenne F, Bisulli F, Licchetta L, Person R, Torti E, McWalter K, Webster R, Gerard EE, Lesca G, Szepetowski P, Scheffer IE, Mefford HC, and Carvill GL

Subjects
Child, Humans, Infant, Newborn, Mutation, Phenotype, Seizures genetics, Epilepsy genetics, Epilepsy, Generalized genetics, Ether-A-Go-Go Potassium Channels genetics
Abstract

Background and Objectives: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants., Methods: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details., Results: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death., Discussion: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy., (© 2022 American Academy of Neurology.)

Published
2023
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50. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer EE, Pusch M, Picollo A, Forwood C, Nguyen MH, Suckow V, Gibbons J, Hoff A, Sigfrid L, Megarbane A, Nizon M, Cogné B, Beneteau C, Alkuraya FS, Chedrawi A, Hashem MO, Stamberger H, Weckhuysen S, Vanlander A, Ceulemans B, Rajagopalan S, Nunn K, Arpin S, Raynaud M, Motter CS, Ward-Melver C, Janssens K, Meuwissen M, Beysen D, Dikow N, Grimmel M, Haack TB, Clement E, McTague A, Hunt D, Townshend S, Ward M, Richards LJ, Simons C, Costain G, Dupuis L, Mendoza-Londono R, Dudding-Byth T, Boyle J, Saunders C, Fleming E, El Chehadeh S, Spitz MA, Piton A, Gerard B, Abi Warde MT, Rea G, McKenna C, Douzgou S, Banka S, Akman C, Bain JM, Sands TT, Wilson GN, Silvertooth EJ, Miller L, Lederer D, Sachdev R, Macintosh R, Monestier O, Karadurmus D, Collins F, Carter M, Rohena L, Willemsen MH, Ockeloen CW, Pfundt R, Kroft SD, Field M, Laranjeira FER, Fortuna AM, Soares AR, Michaud V, Naudion S, Golla S, Weaver DD, Bird LM, Friedman J, Clowes V, Joss S, Pölsler L, Campeau PM, Blazo M, Bijlsma EK, Rosenfeld JA, Beetz C, Powis Z, McWalter K, Brandt T, Torti E, Mathot M, Mohammad SS, Armstrong R, and Kalscheuer VM

Subjects
Male, Female, Humans, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels genetics, Neurodevelopmental Disorders genetics
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., (© 2022. The Author(s).)

Published
2023
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