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1. Structural brain anomalies in Cri-du-Chat syndrome: MRI findings in 14 patients and possible genotype-phenotype correlations

Author

Villa, R., Fergnani, V.G.C., Silipigni, R., Guerneri, S., Cinnante, C., Guala, A., Danesino, C., Scola, E., Conte, G., Fumagalli, M., Gangi, S., Colombo, L., Picciolini, O., Ajmone, P.F., Accogli, A., Madia, F., Tassano, E., Scala, M., Capra, V., Srour, M., Spaccini, L., Righini, A., Greco, D., Castiglia, L., Romano, C., and Bedeschi, M.F.

Published
2020
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3. Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Author

Faraguna, M, Musto, F, Crescitelli, V, Iascone, M, Spaccini, L, Tonduti, D, Fedeli, T, Kullmann, G, Canonico, F, Cattoni, A, Dell'Acqua, F, Rizzari, C, Gasperini, S, Faraguna M. C., Musto F., Crescitelli V., Iascone M., Spaccini L., Tonduti D., Fedeli T., Kullmann G., Canonico F., Cattoni A., Dell'acqua F., Rizzari C., Gasperini S., Faraguna, M, Musto, F, Crescitelli, V, Iascone, M, Spaccini, L, Tonduti, D, Fedeli, T, Kullmann, G, Canonico, F, Cattoni, A, Dell'Acqua, F, Rizzari, C, Gasperini, S, Faraguna M. C., Musto F., Crescitelli V., Iascone M., Spaccini L., Tonduti D., Fedeli T., Kullmann G., Canonico F., Cattoni A., Dell'acqua F., Rizzari C., and Gasperini S.

Abstract

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1–2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation.

Published
2022

6. Guidelines for vascular anomalies by the Italian Society for the study of Vascular Anomalies (SISAV)

Author

Stillo, F., Mattassi, R., Diociaiuti, A., Neri, I., Baraldini, V., Dalmonte, P., Amato, B., Ametrano, O., Amico, G., Bianchini, G., Campisi, C., Cattaneo, E., Causin, F., Cavalli, R., Colletti, G., Corbeddu, M., Coppo, P., De Fiores, A., Di Giuseppe, P., El Hachem, M., Esposito, F., Fulcheri, E., Gandolfo, C., Grussu, F., Guglielmo, A., Leuzzi, M., Manunza, F., Moneghini, L., Monzani, N. A., Nicodemi, E. M., Occella, C., Orso, M., Pagella, F. G., Paolantonio, G., Pasetti, F., Rollo, M., Ruggiero, F., Santecchia, L., Spaccini, L., Taurino, M., Vaghi, M., Vercellio, G., Zama, M., Zocca, A., Aguglia, M., Castronovo, E. L., De Lorenzi, E., Fontana, E., Gusson, E., Lanza, J., Lizzio, R., Mancardi, M. M., Rosina, E., Chiti, D., Lugli, M., and Maleti, O.

Subjects
Humans, Italy, Vascular Diseases, Vascular Malformations, Cardiology and Cardiovascular Medicine
Published
2022

7. Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring

Author

Bonaventura, E., Alberti, L., Lucchi, S., Cappelletti, L., Fazzone, S., Cattaneo, E., Bellini, M., Izzo, G., Parazzini, C., Bosetti, A., Di Profio, E., Fiore, G., Ferrario, M., Mameli, C., Sangiorgio, A., Masnada, S., Zuccotti, G.V., Veggiotti, P., Spaccini, L., Iascone, M., Verduci, E., Cereda, C., and Tonduti, D.

Subjects
X-ALD, Settore MED/38 - Pediatria Generale e Specialistica, hematopoietic stem cell transplantation (HCST), Neurology, newborn screening (NBS), Aicardi-Goutières syndrome (AGS), C26:0-lysophosphatidylcholine, DBS, X-linked adrenoleukodystrophy (X-ALD), Zellweger Spectrum Disorders, Neurology (clinical)
Abstract

IntroductionX-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the ABCD1 gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD.MethodsIn June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation via focused NGS.DiscussionGenetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience.ConclusionThe primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD.EthicsThe study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Published
2022

9. L1CAM variants cause two distinct imaging phenotypes on fetal MRI.

Author

Accogli A., Goergen S., Izzo G., Mankad K., Krajden Haratz K., Parazzini C., Fahey M., Menzies L., Baptista J., Carpineta L., Tortora D., Fulcheri E., Gaetano Vellone V., Paladini D., Spaccini L., Toto V., Trayers C., Ben Sira L., Reches A., Malinger G., Salpietro V., De Marco P., Srour M., Zara F., Capra V., Rossi A., Severino M., Accogli A., Goergen S., Izzo G., Mankad K., Krajden Haratz K., Parazzini C., Fahey M., Menzies L., Baptista J., Carpineta L., Tortora D., Fulcheri E., Gaetano Vellone V., Paladini D., Spaccini L., Toto V., Trayers C., Ben Sira L., Reches A., Malinger G., Salpietro V., De Marco P., Srour M., Zara F., Capra V., Rossi A., and Severino M.

Abstract

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.Copyright © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Published
2021

10. L1CAM variants cause two distinct imaging phenotypes on fetal MRI

Author

Accogli, A, Goergen, S, Izzo, G, Mankad, K, Haratz, KK, Parazzini, C, Fahey, M, Menzies, L, Baptista, J, Carpineta, L, Tortora, D, Fulcheri, E, Vellone, VG, Paladini, D, Spaccini, L, Toto, V, Trayers, C, Ben Sira, L, Reches, A, Malinger, G, Salpietro, V, De Marco, P, Srour, M, Zara, F, Capra, V, Rossi, A, Severino, M, Accogli, A, Goergen, S, Izzo, G, Mankad, K, Haratz, KK, Parazzini, C, Fahey, M, Menzies, L, Baptista, J, Carpineta, L, Tortora, D, Fulcheri, E, Vellone, VG, Paladini, D, Spaccini, L, Toto, V, Trayers, C, Ben Sira, L, Reches, A, Malinger, G, Salpietro, V, De Marco, P, Srour, M, Zara, F, Capra, V, Rossi, A, and Severino, M

Abstract

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.

Published
2021

14. Refining the Phenotype of Recurrent Rearrangements of Chromosome 16

Author

Redaelli, S, Maitz, S, Crosti, F, Sala, E, Villa, N, Spaccini, L, Selicorni, A, Rigoldi, M, Conconi, D, Dalprà, L, Roversi, G, Bentivegna, A, Redaelli, Serena, Maitz, Silvia, Crosti, Francesca, Sala, Elena, Villa, Nicoletta, Spaccini, Luigina, Selicorni, Angelo, Rigoldi, Miriam, Conconi, Donatella, Dalprà, Leda, Roversi, Gaia, Bentivegna, Angela, Redaelli, S, Maitz, S, Crosti, F, Sala, E, Villa, N, Spaccini, L, Selicorni, A, Rigoldi, M, Conconi, D, Dalprà, L, Roversi, G, Bentivegna, A, Redaelli, Serena, Maitz, Silvia, Crosti, Francesca, Sala, Elena, Villa, Nicoletta, Spaccini, Luigina, Selicorni, Angelo, Rigoldi, Miriam, Conconi, Donatella, Dalprà, Leda, Roversi, Gaia, and Bentivegna, Angela

Abstract

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

Published
2019

15. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Author

Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), Garavelli, L. (Livia), Ivanovski, I. (Ivan), Djuric, O. (Olivera), Caraffi, S.G. (Stefano Giuseppe), Santodirocco, D. (Daniela), Pollazzon, M. (Marzia), Rosato, S. (Simonetta), Cordelli, D.M. (Duccio M.), Abdalla, E. (Ebtesam), Accorsi, P. (Patrizia), Adam, M.P. (Margaret), Ajmone, P.F. (Paola Francesca), Badura-Stronka, M. (Magdalena), Baldo, C. (Chiara), Baldi, M. (Maddalena), Bayat, A. (Allan), Bigoni, S. (Stefania), Bonvicini, F. (Federico), Breckpot, J. (Jeroen), Callewaert, L., Cocchi, G. (Guido), Cuturilo, G. (Goran), De Brasi, D. (Daniele), Devriendt, K. (Koenraad), Dinulos, M.B. (Mary Beth), Hjortshøj, T.D. (Tina Duelund), Epifanio, R. (Roberta), Faravelli, F. (Francesca), Fiumara, A. (Agata), Formisano, D. (Debora), Giordano, L. (Lucio), Grasso, M. (Marina), Grønborg, S. (Sabine), Iodice, A. (Alessandro), Iughetti, L. (Lorenzo), Kuburovic, V. (Vladimir), Kutkowska-Kazmierczak, A. (Anna), Lacombe, D. (Didier), Lo Rizzo, C. (Caterina), Luchetti, A. (Anna), Malbora, B. (Baris), Mammi, I. (Isabella), Mari, F. (Francesca), Montorsi, G. (Giulia), Moutton, S. (Sebastien), Møller, R.S. (Rikke), Muschke, P. (Petra), Nielsen, J.E.K. (Jens Erik Klint), Obersztyn, E. (Ewa), Pantaleoni, C. (Chiara), Pellicciari, A. (Alessandro), Pisanti, M.A. (Maria Antonietta), Prpic, I. (Igor), Poch-Olive, M.L. (Maria Luisa), Raviglione, F. (Federico), Renieri, A. (Alessandra), Ricci, E. (Emilia), Rivieri, F. (Francesca), Santen, G.W.E. (Gijs), Savasta, S. (Salvatore), Scarano, G. (Gioacchino), Schanze, I. (Ina), Selicorni, A. (Angelo), Silengo, M.C., Smigiel, R. (Robert), Spaccini, L. (Luigina), Sorge, G. (Giovanni), Szczaluba, K. (Krzysztof), Tarani, L. (Luigi), Tone, L.G. (Luis Gonzaga), Toutain, A. (Annick), Trimouille, A. (Aurelien), Valera, E.T. (Elvis Terci), Vergano, S.S. (Samantha Schrier), Zanotta, N. (Nicoletta), Zenker, M. (Martin), Conidi, A. (Andrea), Zollino, M., Rauch, A., Zweier, C. (Christiane), and Garavelli, L. (Livia)

Abstract

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluatio

Published
2018
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16. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Author

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, Garavelli, L, Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, and Garavelli, L

Published
2018

19. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Author

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

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

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

Published
2013

20. Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions

Author

Ferraris, A, Bernardini, L, Sabolic Avramovska, V, Zanni, G, Loddo, S, Sukarova Angelovska, E, Parisi, V, Capalbo, A, Tumini, S, Travaglini, L, Mancini, F, Duma, F, Barresi, S, Novelli, A, Mercuri, E, Tarani, L, Italian CBCD Study Group, Bertini, E, Dallapiccola, B, Collaborators: Arrigoni F, Valente E. M., Borgatti, R, Romaniello, R, Accorsi, P, Fazzi, E, Giordano, L, Pinelli, L, Biancheri, R, Mirabelli, M, Rossi, A, Briguglio, M, Tortorella, G, Chiapparini, L, D' Arrigo, S, Moroni, I, Pantaleoni, C, Spaccini, L, Uziel, G, D' Amico, A, Del Giudice, E, Pichiecchio, A, Signorini, S, Battini, R, Casarani, M, Colafati, S, Digilio, Mc, Leuzzi, V, Micalizzi, A, Romani, M, Spalice, A, Vitiello, G, Cirillo, Margherita, Simonati, A., Ferraris, A, Bernardini, L, Sabolic Avramovska, V, Zanni, G, Loddo, S, Sukarova Angelovska, E, Parisi, V, Capalbo, A, Tumini, S, Travaglini, L, Mancini, F, Duma, F, Barresi, S, Novelli, A, Mercuri, E, Tarani, L, Italian, CBCD Study Group, and DEL GIUDICE, Ennio

Subjects
Dandy-Walker malformation, Wisconsin syndrome, 3q deletion, ZIC1-ZIC4 genes, Hemizygosity, 0302 clinical medicine, Dandy–Walker syndrome, Ptosis, Genetics(clinical), Pharmacology (medical), Child, Genetics (clinical), Medicine(all), Genetics, 0303 health sciences, 030305 genetics & heredity, Zinc Fingers, General Medicine, Single Nucleotide, Penetrance, Phenotype, Child, Preschool, Pair 3, Female, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion, zic1-zic4 genes, Human, Adult, wisconsin syndrome, dandy-walker malformation, Biology, ZIC1, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Young Adult, Wisconsin, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, medicine, Humans, Polymorphism, Preschool, Genetic Association Studies, Research, medicine.disease, Blepharophimosis, Human genetics, Face, Dandy-Walker Syndrome, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Background The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM. Methods and results Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q. Conclusions Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS.

Published
2013

21. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

Author

Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D?arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., Mejaski-Bosnjak, V., Pantaleoni, C., Rigoli, L., Salpietro, C. D., Signorini, S., Stringini, G. R., Verloes, A., Zabloka, D., Dallapiccola, B., Gleeson, J. G., Valente, E. M., Zankl, A., Leventer, R., Smith, P. G., Janecke, A., D?hooghe, M., Sznajer, Y., Van Coster, R., Demerleir, L., Dias, K., Moco, C., Moreira, A., Ae Kim, C., Maegawa, G., Petkovic, D., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., Sigaudy, S., De Lonlay, P., Romano, S., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Collignon, P., Wolf, N., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Phadke, S. R., Udani, V., Stuart, B., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Benedicenti, F., Stanzial, F., Borgatti, R., Accorsi, P., Battaglia, S., Giordano, L., Pinelli, L., Boccone, L., Bigoni, S., Ferlini, A., Donati, M. A., Caridi, G., Divizia, M. T., Faravelli, F., Ghiggeri, G., Pessagno, A., Briuglia, S., Tortorella, G., Adami, A., Castorina, P., Lalatta, F., Marra, G., Riva, D., Scelsa, B., Spaccini, L., Uziel, G., Giudice, E. D., Laverda, A. M., Ludwig, K., Permunian, A., Suppiej, A., Uggetti, C., Battini, R., Giacomo, M. D., Cilio, M. R., Di Sabato, M. L., Leuzzi, V., Parisi, P., Pollazzon, M., Silengo, M., De Vescovi, R., Greco, D., Romano, C., Cazzagon, M., Simonati, A., Al-Tawari, A. A., Bastaki, L., M('e)garban('e), A., Sabolic Avramovska, V., De Jong, M. M., Stromme, P., Koul, R., Rajab, A., Azam, M., Barbot, C., Martorell Sampol, L., Rodriguez, B., Pascual-Castroviejo, I., Teber, S., Anlar, B., Comu, S., Karaca, E., Kayserili, H., Y, Brancati, F, Iannicelli, M, Travaglini, L, Mazzotta, A, Bertini, E, Boltshauser, E, D'Arrigo, S, Emma, F, Fazzi, E, Gallizzi, R, Gentile, M, Loncarevic, D, Mejaski Bosnjak, V, Pantaleoni, C, Rigoli, L, Salpietro, Cd, Signorini, S, Stringini, Gr, Verloes, A, Zabloka, D, Dallapiccola, B, Gleeson, Jg, Valente, Em, International, JSRD Study Group, DEL GIUDICE, Ennio, and Pediatric surgery

Subjects
Pathology, medicine.medical_specialty, TMEM67, DNA Mutational Analysis, Molecular Sequence Data, education, Biology, Article, Joubert syndrome, NO, MKS3, COACH, Multiple Abnormalities, Nephronophthisis, Amino Acid Sequence, Base Sequence, Humans, Liver, Magnetic Resonance Imaging, Membrane Proteins, Mutation, Phenotype, RNA Splice Sites, Syndrome, Genetics, medicine, congenital hepatic fibrosis, Abnormalities, Multiple, Meckel syndrome, COACH syndrome, Joubert syndrome and related disorders, Genetics (clinical), Aplasia, medicine.disease, MKS3/TMEM67 mutation, COACH Syndrome, Ciliopathy, RPGRIP1L, Congenital hepatic fibrosis, human activities
Abstract

MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert syndrome related disorder with liver involvement. The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

Published
2009
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22. Insights into genotype–phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein–Taybi syndrome patients

Author

Spena, S., primary, Milani, D., additional, Rusconi, D., additional, Negri, G., additional, Colapietro, P., additional, Elcioglu, N., additional, Bedeschi, F., additional, Pilotta, A., additional, Spaccini, L., additional, Ficcadenti, A., additional, Magnani, C., additional, Scarano, G., additional, Selicorni, A., additional, Larizza, L., additional, and Gervasini, C., additional

Published
2014
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23. Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy

Author

Marini, C, Darra, F, Specchio, N, Mei, D, Terracciano, A, Parmeggiani, L, Ferrari, A, Sicca, F, Mastrangelo, M, Spaccini, L, Canopoli, Ml, Cesaroni, E, Zamponi, N, Caffi, L, Ricciardelli, P, Grosso, S, Pisano, T, Canevini, Mp, Granata, T, Accorsi, P, Battaglia, Domenica Immacolata, Cusmai, R, Vigevano, F, Dalla Bernardina, B, Guerrini, R., Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Marini, C, Darra, F, Specchio, N, Mei, D, Terracciano, A, Parmeggiani, L, Ferrari, A, Sicca, F, Mastrangelo, M, Spaccini, L, Canopoli, Ml, Cesaroni, E, Zamponi, N, Caffi, L, Ricciardelli, P, Grosso, S, Pisano, T, Canevini, Mp, Granata, T, Accorsi, P, Battaglia, Domenica Immacolata, Cusmai, R, Vigevano, F, Dalla Bernardina, B, Guerrini, R., and Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021)

Abstract

Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients.

Published
2012

24. Prenatal/neonatal pathology findings in two cases of Cornelia de Lange syndrome harbouring novel mutations of NIPBL

Author

Lalatta, F, Russo, S, Gentilin, B, Spaccini, L, Boschetto, C, Cavalleri, F, Masciadri, M, Gervasini, C, Bentivegna, A, Castronovo, P, Larizza, L, Larizza, L., BENTIVEGNA, ANGELA, Lalatta, F, Russo, S, Gentilin, B, Spaccini, L, Boschetto, C, Cavalleri, F, Masciadri, M, Gervasini, C, Bentivegna, A, Castronovo, P, Larizza, L, Larizza, L., and BENTIVEGNA, ANGELA

Abstract

Purpose: This study reviews prenatal findings in two cases with a suspected diagnosis of Cornelia de Lange Syndrome, a multisystem disorder characterized by somatic defects and mental retardation, that were later confirmed by postmortem examination and molecular testing. Although the correlation between the Cornelia de Lange Syndrome genotype and phenotype is still unclear, preliminary data indicate several severe phenotypic features that are likely to be detected prenatally in NIPBL-mutated patients. Methods: We report on two prenatal/ neonatal cases with unusual pathologic findings indicating Cornelia de Lange Syndrome. The first, with suspected Cornelia de Lange Syndrome after a set of typical dysmorphisms was noted by prenatal ultrasound, was confirmed by a physical examination after termination of the pregnancy. The second was diagnosed neonatally on the basis of typical clinical signs. Medical complications led to death within the first month of life. Results: Molecular analysis of NIPBL, the gene that codes for delangin (a component of the cohesin complex), performed postnatally detected two de novo mutations: a missense change (P2056L) in a highly conserved residue and a nonsense alteration (S2490 replaced by a stop codon). Conclusion: We suggest that early diagnosis of Cornelia de Lange Syndrome would be made much easier by the assemblage of a set of prenatal diagnostic features and criteria in Cornelia de Lange Syndrome cases that have been confirmed by direct physical and molecular examinations. We also suggest that Cornelia de Lange Syndrome genotype–phenotype correlations need to be extended to prenatal cases

Published
2007

29. EP20.05: Thoracoamniotic shunting for fetal hydrothorax: fetal and maternal complications and long‐term outcomes at a single centre.

Author

Lanna, M., Lubrano, C., Consonni, D., Faiola, S., Casati, D., Lista, G., Farolfi, A., Spaccini, L., Scelsa, B., and Cetin, I.

Abstract

Identification of perinatal and long-term outcomes in a consecutive series of fetal hydrothorax (FHT) treated with thoracoamniotic shunt (TAS). Methods Retrospective analysis of cases observed in our Unit from 2000 to 2021: variables analysed were gestational age (GA) at diagnosis and procedure, resolution of hydrops, death and complications. Results On 93 cases included, 77% were complicated by hydrops, the remaining only by polyhydramnios and bilateral FHT, with an average GA at diagnosis of 27 weeks (range 16-34). [Extracted from the article]

Published
2022
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32. Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Author

Martha Caterina Faraguna, Francesca Musto, Viola Crescitelli, Maria Iascone, Luigina Spaccini, Davide Tonduti, Tiziana Fedeli, Gaia Kullmann, Francesco Canonico, Alessandro Cattoni, Fabiola Dell’Acqua, Carmelo Rizzari, Serena Gasperini, Faraguna, M, Musto, F, Crescitelli, V, Iascone, M, Spaccini, L, Tonduti, D, Fedeli, T, Kullmann, G, Canonico, F, Cattoni, A, Dell'Acqua, F, Rizzari, C, and Gasperini, S

Subjects
Lymphohistiocytosis, Male, Leukoencephalopathy, Lysosomal storage disease, Mucopolysaccharidosis-plus, Secondary hemophagocytic lymphohistiocytosis, Child, Child, Preschool, Humans, Quality of Life, Steroids, Syndrome, Lymphohistiocytosis, Hemophagocytic, Mucopolysaccharidoses, Hemophagocytic, Settore MED/39 - Neuropsichiatria Infantile, Secondary hemophagocytic lymphohistiocytosi, Genetics, Mucopolysaccharidosis-plu, Preschool, Genetics (clinical)
Abstract

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1–2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation.

Published
2022
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33. Refining the Phenotype of Recurrent Rearrangements of Chromosome 16

Author

Leda Dalprà, Luigina Spaccini, Francesca Crosti, Silvia Maitz, Gaia Roversi, Miriam Rigoldi, Nicoletta Villa, Elena Sala, Angela Bentivegna, Serena Redaelli, Angelo Selicorni, Donatella Conconi, Redaelli, S, Maitz, S, Crosti, F, Sala, E, Villa, N, Spaccini, L, Selicorni, A, Rigoldi, M, Conconi, D, Dalprà, L, Roversi, G, and Bentivegna, A

Subjects
0301 basic medicine, Male, 16p13.11 deletions and duplications, Microarray, Developmental Disabilities, developmental disability, Genome, speech disorder, lcsh:Chemistry, 0302 clinical medicine, Segmental Duplications, Genomic, Copy-number variation, Child, Homologous Recombination, lcsh:QH301-705.5, Spectroscopy, Segmental duplication, Genetics, Comparative Genomic Hybridization, 16p13.11 deletions and duplication, General Medicine, chromosome 16, Phenotype, Computer Science Applications, Child, Preschool, Female, Chromosome Deletion, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, DNA Copy Number Variations, Karyotype, CNV, Biology, Catalysis, Article, Inorganic Chemistry, 16p11.2 deletions and duplications, 03 medical and health sciences, Young Adult, Chromosome 16, Humans, Abnormalities, Multiple, Physical and Theoretical Chemistry, Molecular Biology, Chromosome Aberrations, Genetic heterogeneity, Organic Chemistry, Infant, Newborn, Infant, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, array-CGH, two-hit model, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16, Comparative genomic hybridization
Abstract

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients, one at 16p12.2 was found in four patients, two close SROs at 16p11.2 were found in twelve patients, finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

Published
2019

34. Snyder-Robinson syndrome: A novel nonsense mutation in spermine synthase and expansion of the phenotype

Author

Giovanna Weber, Joy Norris, Massimo Mastrangelo, Angelo Selicorni, Angela Peron, Luigina Spaccini, Tim Wood, Stefania Maria Bova, Charles E. Schwartz, Peron, A, Spaccini, L, Norris, J, Bova, Sm, Selicorni, A, Weber, Giovanna, Wood, T, Schwartz, Ce, and Mastrangelo, M.

Subjects
Male, medicine.medical_specialty, Pediatrics, Spermine Synthase, Osteoporosis, Nonsense mutation, Epilepsy, Internal medicine, Intellectual disability, Genetics, medicine, Humans, Kyphoscoliosis, Genetics (clinical), biology, business.industry, Infant, medicine.disease, Focal motor seizures, Phenotype, Pedigree, Endocrinology, Codon, Nonsense, Spermine synthase, Mental Retardation, X-Linked, biology.protein, business
Abstract

Snyder–Robinson syndrome is a rare form of X-linked intellectual disability caused by mutations in the spermine synthase (SMS) gene, and characterized by intellectual disability, thin habitus with diminished muscle mass, osteoporosis, kyphoscoliosis, facial dysmorphism (asymmetry, full lower lip), long great toes, and nasal or dysarthric speech. Physical signs seem to evolve from childhood to adulthood. We describe the first Italian patient with Snyder–Robinson syndrome and a novel nonsense mutation in SMS (c.200G>A; p.G67X). Apart from the typical features of the syndrome, the index patient presented with an ectopic right kidney and epilepsy from the first year of age that was characterized by focal motor seizures and negative myoclonus. The clinical and molecular evaluation of this family and the review of the literature expand the phenotype of Snyder–Robinson syndrome to include myoclonic or myoclonic-like seizures (starting even in the first years of life) and renal abnormalities in affected males. © 2013 Wiley Periodicals, Inc.

Published
2013
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35. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Author

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

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

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

Published
2010
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36. Genetic testing in benign familial epilepsies of the first year of life: Clinical and diagnostic significance

Author

Maurizio Viri, Nicola Specchio, Angela Robbiano, Marilena Vecchi, Federico Vigevano, Viviana Cardilli, Anna Maria Laverda, Francesca Vanadia, Pasquale Striano, Amedeo Bianchi, Lucio Giordano, Nicola Vanni, Gemma Incorpora, Francesca Beccaria, Massimo Mastrangelo, Mauro Budetta, Francesca Darra, Guya Occhi, Roberto Gaggero, Lorella Caffi, Lucia Fusco, Bernardo Dalla Bernardina, Carlo Minetti, Roberta Paravidino, Renzo Guerrini, Luigina Spaccini, Pierangelo Veggiotti, Elena Gennaro, Domenico A. Coviello, Maurizio Taglialatela, Federico Zara, Giuseppe Capovilla, Zara, F, Specchio, N, Striano, P, Robbiano, A, Gennaro, E, Paravidino, R, Vanni, N, Beccaria, F, Capovilla, G, Bianchi, A, Caffi, L, Cardilli, V, Darra, F, Bernardina, Bd, Fusco, L, Gaggero, R, Giordano, L, Guerrini, R, Incorpora, G, Mastrangelo, M, Spaccini, L, Laverda, Am, Vecchi, M, Vanadia, F, Veggiotti, P, Viri, M, Occhi, G, Budetta, M, Taglialatela, Maurizio, Coviello, Da, Vigevano, F, and Minetti, C.

Subjects
Adult, Male, Adolescent, Nerve Tissue Proteins, Biology, medicine.disease_cause, Bioinformatics, KCNQ3 Potassium Channel, Cohort Studies, Epilepsy, Young Adult, Predictive Value of Tests, medicine, Humans, KCNQ2 Potassium Channel, Benign familial neonatal seizures, Genetic Testing, Benign epilepsy, Age of Onset, Child, Genetic testing, Aged, Genetics, Aged, 80 and over, KCNQ2, Mutation, KCNQ3, NAV1.2 Voltage-Gated Sodium Channel, medicine.diagnostic_test, Genetic heterogeneity, Infant, Membrane Proteins, Paroxysmal dyskinesia, Middle Aged, medicine.disease, Epilepsy, Benign Neonatal, Channelopathies, PRRT2, Neurology, Child, Preschool, Multigene Family, Female, Neurology (clinical), Age of onset
Abstract

Summary Purpose To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). Methods Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. Key Findings A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. Significance Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.

Published
2013

37. Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR)

Author

Massimo Mastrangelo, Barbara Mostacci, Carlotta Stipa, Paolo Tinuper, Luigina Spaccini, Davide Mei, Francesca Bisulli, Elena Antelmi, Renzo Guerrini, Antelmi E., Mastrangelo M., Bisulli F., Spaccini L., Stipa C., Mostacci B., Mei D., Guerrini R., and Tinuper P.

Subjects
medicine.medical_specialty, Neurology, protocadherin 19, Electroencephalography, Audiology, Epilepsy, Seizures, Intellectual Disability, Medicine, Humans, Ictal, EEG, Psychiatry, Neuroradiology, ictal fear, medicine.diagnostic_test, business.industry, Neuropsychology, Genetic disorder, General Medicine, medicine.disease, Cognitive regression, epilepsy and mental retardation, Stroke, Mutation, Female, Neurology (clinical), business
Abstract

Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [ Published with video sequences]

Published
2012

38. Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females

Author

Sebastiano A. Musumeci, Freddie H. Sharkey, Roberto Giorda, Orsetta Zuffardi, Isabella Fiocchi, Bruno Leheup, Luigina Spaccini, M. Clara Bonaglia, Graeme C.M. Black, Massimo Mastrangelo, Elena Fontana, Jill Clayton-Smith, Susan Marelli, Francesca Novara, Daniela Di Benedetto, Marco Seri, Sally Ann Lynch, Emanuela Avola, Claudio Zucca, Paolo Tinuper, Girolamo Aurelio Vitello, Rita Grasso, Marco Fichera, Philippe Jonveaux, Pinella Failla, Silvana Beri, Claudia Torniero, Lucia Castiglia, Bernardo Dalla Bernardina, Pamela Magini, Jill E. Urquhart, Francesca Bisulli, Corrado Romano, Santina Reitano, Giorda R., Bonaglia M.C., Beri S., Fichera M., Novara F., Magini P., Urquhart J., Sharkey F.H., Zucca C., Grasso R., Marelli S., Castiglia L., Di Benedetto D., Musumeci S.A., Vitello G.A., Failla P., Reitano S., Avola E., Bisulli F., Tinuper P., Mastrangelo M., Fiocchi I., Spaccini L., Torniero C., Fontana E., Lynch S.A., Clayton-Smith J., Black G., Jonveaux P., Leheup B., Seri M., Romano C., dalla Bernardina B., and Zuffardi O.

Subjects
Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Audiology, Electroencephalography, Biology, mental retardation, 03 medical and health sciences, 0302 clinical medicine, Report, Gene Duplication, Intellectual Disability, dup(X)(p11.22-p11.23), EEG anomalies, Gene duplication, Genetics, medicine, Humans, Genetics(clinical), Language Development Disorders, Genetics (clinical), X chromosome, 030304 developmental biology, Segmental duplication, Chromosomes, Human, X, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, medicine.disease, Pedigree, Developmental disorder, Speech delay, dup, Female, medicine.symptom, Erratum, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

Published
2009

39. Prenatal/neonatal pathology findings in two cases of Cornelia de Lange syndrome harbouring novel mutations of NIPBL

Author

Silvia Russo, Angela Bentivegna, Barbara Gentilin, Lidia Larizza, Chiara Boschetto, Luigina Spaccini, Paola Castronovo, Florinda Cavalleri, Maura Masciadri, Faustina Lalatta, Cristina Gervasini, Lalatta, F, Russo, S, Gentilin, B, Spaccini, L, Boschetto, C, Cavalleri, F, Masciadri, M, Gervasini, C, Bentivegna, A, Castronovo, P, and Larizza, L

Subjects
Adult, Cornelia de Lange, rare disease, prenatal diagnosis, fetal dysmorphisms, NIPBL mutations, Pediatrics, medicine.medical_specialty, Cornelia de Lange Syndrome, Cohesin complex, MED/03 - GENETICA MEDICA, Cell Cycle Proteins, Physical examination, Prenatal diagnosis, Biology, Ultrasonography, Prenatal, Genotype-phenotype distinction, Pregnancy, De Lange Syndrome, medicine, Humans, Point Mutation, Missense mutation, Genetics (clinical), Genetics, medicine.diagnostic_test, Proteins, NIPBL, medicine.disease, Pedigree, Fetal Diseases, Female
Abstract

Purpose: This study reviews prenatal findings in two cases with a suspected diagnosis of Cornelia de Lange Syndrome, a multisystem disorder characterized by somatic defects and mental retardation, that were later confirmed by postmortem examination and molecular testing. Although the correlation between the Cornelia de Lange Syndrome genotype and phenotype is still unclear, preliminary data indicate several severe phenotypic features that are likely to be detected prenatally in NIPBL-mutated patients. Methods: We report on two prenatal/neonatal cases with unusual pathologic findings indicating Cornelia de Lange Syndrome. The first, with suspected Cornelia de Lange Syndrome after a set of typical dysmorphisms was noted by prenatal ultrasound, was confirmed by a physical examination after termination of the pregnancy. The second was diagnosed neonatally on the basis of typical clinical signs. Medical complications led to death within the first month of life. Results: Molecular analysis of NIPBL, the gene that codes for delangin (a component of the cohesin complex), performed postnatally detected two de novo mutations: a missense change (P2056L) in a highly conserved residue and a nonsense alteration (S2490 replaced by a stop codon). Conclusion: We suggest that early diagnosis of Cornelia de Lange Syndrome would be made much easier by the assemblage of a set of prenatal diagnostic features and criteria in Cornelia de Lange Syndrome cases that have been confirmed by direct physical and molecular examinations. We also suggest that Cornelia de Lange Syndrome genotype–phenotype correlations need to be extended to prenatal cases.

Published
2007

40. Novel Genetic Variant in HUWE1 : Prenatal and Postnatal Neuroimaging Phenotype.

Author

Tortora M, Cattaneo E, Spaccini L, Iascone M, Scelsa B, Micalizzi A, Novelli A, Lanna M, Righini A, Veggiotti P, and Doneda C

Abstract

Objectives: To provide a comprehensive description of neuroradiologic findings in a patient with a probable pathogenic variant of HUWE1 , particularly in relation to pontine and cerebellar hypoplasia., Methods: We first report prenatal and postnatal neuroradiologic phenotype of a female patient carrying a HUWE1 likely pathogenic variant and discuss its function., Results: An ultrasound shows borderline ventriculomegaly, rotated cerebellar vermis, and dysgenetic corpus callosum. An MR study identify a short, thin corpus callosum, falcine sinus persistence, reduced cerebellar vermis size, wide inferior IV ventricle, and reduced pontine bulging., Discussion: HUWE1 is a gene encoding an E3 ubitiquine ligase protein involved in nervous system development, function, and disease. The mechanisms by which HUWE1 gene affects nervous system are still largely unclear, but a growing body of literature described disease-causing variants in this gene. This report may help prenatal diagnostic experts in consider also this entity, especially when dealing with pontine and cerebellar hypoplasia findings., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2024
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41. Amnioreduction for Polyhydramnios in a Consecutive Series at a Single Center: Indications, Risks and Perinatal Outcomes.

Author

Laoreti A, Sala V, Casati D, Faiola S, Spaccini L, Cetin I, and Lanna MM

Abstract

Pregnancies complicated by severe polyhydramnios are associated with a high rate of underlying fetal anomaly. Amnioreduction may be offered to alleviate maternal symptoms. This is a retrospective study of amnioreductions performed on singleton and twin gestations complicated by symptomatic polyhydramnios between 2010 and 2023 at our tertiary referral center. The indications, procedural techniques and pregnancy and neonatal outcomes were retrieved from an archive database and reviewed with the use of the maternal and child medical record chart, the hospital electronic clinical discharge report and telephone recalls. Our study comprised 86 pregnancies, 65 singletons and 21 twin pregnancies. Fetal anomalies were identified in 79% of cases, mainly gastrointestinal obstructive anomalies; 9.3% of cases were idiopathic. The median gestational age at first amnioreduction was 32.5 weeks, and peri-procedural complications were rare (1 case of placental abruption and 2 cases of preterm delivery). The median gestational age at delivery was 36.5 weeks, with a median prolongation of the pregnancy from the time of first drain until birth of 30 days. Preterm labor < 37 weeks occurred in 48.8% of procedures, with 26.7% of patients delivering before 34 weeks and pPROM < 36 weeks recorded in 23.2% of cases. In conclusion, amnioreduction offered to alleviate maternal symptoms is a reasonably safe procedure with a low complication rate. These pregnancies necessitate management in a tertiary referral center because of their need for a multidisciplinary approach both prenatally and postnatally.

Published
2024
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42. Corrigendum: Newborn screening for X-linked adrenoleukodystrophy in Italy: diagnostic algorithm and disease monitoring.

Author

Bonaventura E, Alberti L, Lucchi S, Cappelletti L, Fazzone S, Cattaneo E, Bellini M, Izzo G, Parazzini C, Bosetti A, Di Profio E, Fiore G, Ferrario M, Mameli C, Sangiorgio A, Masnada S, Zuccotti GV, Veggiotti P, Spaccini L, Iascone M, Verduci E, Cereda C, and Tonduti D

Abstract

[This corrects the article DOI: 10.3389/fneur.2022.1072256.]., (Copyright © 2024 Bonaventura, Alberti, Lucchi, Cappelletti, Fazzone, Cattaneo, Bellini, Izzo, Parazzini, Bosetti, Di Profio, Fiore, Ferrario, Mameli, Sangiorgio, Masnada, Zuccotti, Veggiotti, Spaccini, Iascone, Verduci, Cereda, Tonduti and XALD-NBS Study Group.)

Published
2024
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43. Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study.

Author

Cavirani B, Spagnoli C, Caraffi SG, Cavalli A, Cesaroni CA, Cutillo G, De Giorgis V, Frattini D, Marchetti GB, Masnada S, Peron A, Rizzi S, Varesio C, Spaccini L, Vignoli A, Canevini MP, Veggiotti P, Garavelli L, and Fusco C

Subjects
Humans, Child, Preschool, DNA Copy Number Variations, Retrospective Studies, Seizures genetics, Epilepsy genetics, Epilepsy diagnosis, Epilepsy, Generalized
Abstract

The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children's Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

Published
2024
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44. Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study.

Author

Rosina E, Pezzani L, Apuril E, Pezzoli L, Marchetti D, Bellini M, Lucca C, Meossi C, Massimello M, Mariani M, Scatigno A, Cattaneo E, Colombo L, Maitz S, Cereda A, Milani D, Spaccini L, Bedeschi MF, Selicorni A, and Iascone M

Subjects
Humans, Child, Prospective Studies, Exome Sequencing, Genome-Wide Association Study, Italy, Outpatients, DNA Copy Number Variations
Abstract

Background: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'., Methods: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests., Results: First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases., Conclusion: Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Published
2024
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45. TSEN54 Gene-Related Pontocerebellar-Hypoplasia and Role of Prenatal MR Imaging: Besides the Common Posterior Fossa Cystic Malformations.

Author

Tortora M, Spaccini L, Lanna M, Zambon M, Izzo G, Parazzini C, and Righini A

Subjects
Pregnancy, Female, Humans, Cerebellum diagnostic imaging, Cerebellum abnormalities, Magnetic Resonance Imaging, Endoribonucleases genetics, Cerebellar Diseases, Olivopontocerebellar Atrophies diagnosis, Olivopontocerebellar Atrophies genetics, Nervous System Malformations diagnosis
Abstract

Pontocerebellar-hypoplasia (PCH) related to TSEN54-gene mutation, a rare autosomal recessive disorder, can be associated with three different phenotypes: PCH2A, PCH4 and PCH5. Prenatal imaging features are very scant, in particular for PCH4 and PCH5. The aim of this letter is to illustrate key role of prenatal MR imaging in better evaluation of the cerebellar vermis-hemispheres and pons, which may lead to the differential diagnosis between three PCH TSEN54-related phenotypes already at mid-gestation based on the pattern of the degree of involvement of the vermis and the cerebellar cortex respectively., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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46. FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy.

Author

Masnada S, Previtali R, Erba P, Beretta E, Camporesi A, Chiapparini L, Doneda C, Iascone M, Sartorio MUA, Spaccini L, Veggiotti P, Osio M, Tonduti D, and Moroni I

Subjects
Humans, Ataxia diagnosis, Ataxia genetics, Diagnosis, Differential, Mutation, Phenotype, Cerebellar Ataxia diagnosis, Peripheral Nervous System Diseases diagnosis, Peripheral Nervous System Diseases genetics, Ferredoxin-NADP Reductase genetics
Abstract

Background and Aims: Mutations in FDXR gene, involved in mitochondrial pathway, cause a rare recessive neurological disorder with variable severity of phenotypes. The most common presentation includes optic and/or auditory neuropathy, variably associated to developmental delay or regression, global hypotonia, pyramidal, cerebellar signs, and seizures. The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%). To date, 44 patients with FDXR mutations have been reported. We describe here on two new patients, siblings, who presented with a quite different phenotype compared to previously described patients., Methods: Clinical, neurophysiological, and genetic features of two siblings and a systematic literature review focused on the clinical spectrum of the disease are described., Results: Both patients presented with an acute-sub-acute onset of peripheral neuropathy and only in later stages of the disease developed the typical features of FDXR-associated disease., Interpretation: The peculiar clinical presentation at onset and the evolution of the disease in our patients and in some cases revised from the literature shed lights on a new possible phenotype of FDXR-associated disease: a peripheral neuropathy which can mimic an acute inflammatory disease., (© 2023. Fondazione Società Italiana di Neurologia.)

Published
2023
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47. The crucial role of titin in fetal development: recurrent miscarriages and bone, heart and muscle anomalies characterise the severe end of titinopathies spectrum.

Author

Di Feo MF, Lillback V, Jokela M, McEntagart M, Homfray T, Giorgio E, Casalis Cavalchini GC, Brusco A, Iascone M, Spaccini L, D'Oria P, Savarese M, and Udd B

Subjects
Female, Humans, Pregnancy, Retrospective Studies, Abortion, Habitual genetics, Connectin genetics, Muscle, Skeletal abnormalities, Myocardium
Abstract

Background: Titin truncating variants (TTNtvs) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity, they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. Often karyotype or chromosomal microarray analyses are the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum., Methods: We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv., Results: We identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes., Conclusion: We suggest TTN to be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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48. Case report: Early-onset parkinsonism among the neurological features in children with PHACTR1 variants.

Author

Previtali R, Leidi A, Basso M, Izzo G, Stignani C, Spaccini L, Iascone M, Veggiotti P, and Bova SM

Abstract

PACHTR1 is expressed in cardiovascular and neurological tissues. In the brain, it has a role in pre- and post-natal maturation. Previously reported PHACTR1 -mutated patients showed early-onset epilepsy and intellectual disability. We describe two unreported cases with de novo pathogenic variants in PHACTR1 and their clinical pictures, compared with those of cases already reported in the literature. In line with previous reports, the two patients presented early-onset developmental and epileptic encephalopathy. In addition, one patient developed a speech disorder and a progressive movement disorder characterized by hypertonus, hypo-bradykinesia, hypomimia, ataxic gait, and retropulsion. She was treated with levodopa without any clinical improvement. Pathogenic variants in PHACTR1 may result in a cardiological or neurological phenotype. Severe developmental delay, intellectual disability, and early-onset developmental and epileptic encephalopathy are the main features of PHACTR1 -mutated patients with neurological involvement. Movement and speech disorders have never previously been described and could be new features of the neurological phenotype., 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., (Copyright © 2023 Previtali, Leidi, Basso, Izzo, Stignani, Spaccini, Iascone, Veggiotti and Bova.)

Published
2023
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49. Rock around DYRK1A: Ethnic diversity, clinical challenges.

Author

Moroni A, Pezzani L, Alfei E, Scatigno A, Cereda A, Marzaroli M, Guuva C, Gabbiadini S, Pezzoli L, Marchetti D, Spaccini L, and Iascone M

Subjects
Humans, Syndrome, Phenotype, Intellectual Disability genetics, Microcephaly genetics, Language Development Disorders
Abstract

DYRK1A-related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable., (© 2023 Wiley Periodicals LLC.)

Published
2023
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50. Menkes disease complicated by concurrent ACY1 deficiency: A case report.

Author

Mauri A, Saielli LA, Alfei E, Iascone M, Marchetti D, Cattaneo E, Di Lauro A, Antonelli L, Alberti L, Bonaventura E, Veggiotti P, Spaccini L, and Cereda C

Abstract

Introduction: Menkes disease is an X-linked recessive condition caused by mutations in the ATP7A gene, which leads to severe copper deficiency. Aminoacylase-1 deficiency is a rare inborn error of metabolism caused by homozygous or compound heterozygous variant in the ACY1 gene, characterized by increased urinary excretion of specific N-acetyl amino acids. Case presentation: We report an infant with neurological findings such as seizures, neurodevelopmental delay and hypotonia. Metabolic screening showed low serum copper and ceruloplasmin, and increased urinary excretion of several N-acetylated amino acids. Whole-exome sequencing analysis (WES) revealed the novel de novo variant c.3642&#95;3649dup (p.Ala1217Aspfs*2) in the ATP7A gene, leading to a diagnosis of Menkes disease, and the simultaneous presence of the homozygous ACY1 variant c.1057C>T (p.Arg353Cys) causative of Aminoacylase-1 deficiency. Conclusion: Our patient had two rare conditions with different treatment courses but overlapping clinical features. The identified novel ATP7A mutation associated with Menkes disease expands the ATP7A gene spectrum., 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., (Copyright © 2023 Mauri, Saielli, Alfei, Iascone, Marchetti, Cattaneo, Di Lauro, Antonelli, Alberti, Bonaventura, Veggiotti, Spaccini and Cereda.)

Published
2023
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