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103 results on '"Schmitt-Mechelke, T."'

2. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Author

Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, Jr, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., and Vitobello, A.

Published
2019
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3. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., Houlden, H., Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., and Houlden, H.

Abstract

Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access), Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

5. LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations

Author

Stellingwerff, M.D., Figuccia, S., Bellacchio, E., Alvarez, K., Castiglioni, C., Topaloglu, P., Stutterd, C.A., Erasmus, C.E., Sanchez-Valle, A., Lebon, S., Hughes, S., Schmitt-Mechelke, T., Vasco, G., Chow, G., Rahikkala, E., Dallabona, C., Okuma, C., Aiello, C., Goffrini, P., Abbink, T.E., Bertini, E.S., Knaap, M.S. van der, Stellingwerff, M.D., Figuccia, S., Bellacchio, E., Alvarez, K., Castiglioni, C., Topaloglu, P., Stutterd, C.A., Erasmus, C.E., Sanchez-Valle, A., Lebon, S., Hughes, S., Schmitt-Mechelke, T., Vasco, G., Chow, G., Rahikkala, E., Dallabona, C., Okuma, C., Aiello, C., Goffrini, P., Abbink, T.E., Bertini, E.S., and Knaap, M.S. van der

Abstract

Contains fulltext : 234042.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNA(Asp) binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Published
2021

6. LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

Author

Stellingwerff, MD, Figuccia, S, Bellacchio, E, Alvarez, K, Castiglioni, C, Topaloglu, P, Stutterd, CA, Erasmus, CE, Sanchez-Valle, A, Lebon, S, Hughes, S, Schmitt-Mechelke, T, Vasco, G, Chow, G, Rahikkala, E, Dallabona, C, Okuma, C, Aiello, C, Goffrini, P, Abbink, TEM, Bertini, ES, Van der Knaap, MS, Stellingwerff, MD, Figuccia, S, Bellacchio, E, Alvarez, K, Castiglioni, C, Topaloglu, P, Stutterd, CA, Erasmus, CE, Sanchez-Valle, A, Lebon, S, Hughes, S, Schmitt-Mechelke, T, Vasco, G, Chow, G, Rahikkala, E, Dallabona, C, Okuma, C, Aiello, C, Goffrini, P, Abbink, TEM, Bertini, ES, and Van der Knaap, MS

Abstract

OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Published
2021

7. LBSL case series and DARS2 variant analysis in early severe forms with unexpected presentations

Author

Stellingwerff, M. D. (Menno D.), Figuccia, S. (Sonia), Bellacchio, E. (Emanuele), Alvarez, K. (Karin), Castiglioni, C. (Claudia), Topaloglu, P. (Pinar), Stutterd, C. A. (Chloe A.), Erasmus, C. E. (Corrie E.), Sanchez‐Valle, A. (Amarilis), Lebon, S. (Sebastien), Hughes, S. (Sarah), Schmitt-Mechelke, T. (Thomas), Vasco, G. (Gessica), Chow, G. (Gabriel), Rahikkala, E. (Elisa), Dallabona, C. (Cristina), Okuma, C. (Cecilia), Aiello, C. (Chiara), Goffrini, P. (Paola), Abbink, T. E. (Truus E.M.), Bertini, E. S. (Enrico S.), Van der Knaap, M. S. (Marjo S.), Stellingwerff, M. D. (Menno D.), Figuccia, S. (Sonia), Bellacchio, E. (Emanuele), Alvarez, K. (Karin), Castiglioni, C. (Claudia), Topaloglu, P. (Pinar), Stutterd, C. A. (Chloe A.), Erasmus, C. E. (Corrie E.), Sanchez‐Valle, A. (Amarilis), Lebon, S. (Sebastien), Hughes, S. (Sarah), Schmitt-Mechelke, T. (Thomas), Vasco, G. (Gessica), Chow, G. (Gabriel), Rahikkala, E. (Elisa), Dallabona, C. (Cristina), Okuma, C. (Cecilia), Aiello, C. (Chiara), Goffrini, P. (Paola), Abbink, T. E. (Truus E.M.), Bertini, E. S. (Enrico S.), and Van der Knaap, M. S. (Marjo S.)

Abstract

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants’ impact on mtAspRS structure and mitochondrial function. Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-59-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Published
2021

9. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Author

Genetica, Genetica Klinische Genetica, Child Health, Brain, ZL Kinder Ner en Nec Medisch, Genetica Sectie Genoomdiagnostiek, Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., Vitobello, A., Genetica, Genetica Klinische Genetica, Child Health, Brain, ZL Kinder Ner en Nec Medisch, Genetica Sectie Genoomdiagnostiek, Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., and Vitobello, A.

Published
2019

10. Health related quality of life and manual ability 5 years after neonatal ischemic stroke

Author

Caspar-Teuscher, Miriam, primary, Studer, Martina, additional, Regényi, Maria, additional, Steinlin, Maja, additional, Grunt, Sebastian, additional, Bigi, Sandra, additional, Mori, Andrea Capone, additional, Datta, Alexandre, additional, Fluss, Joel, additional, Hackenberg, Annette, additional, Keller, Elmar, additional, Maier, Oliver, additional, Mercati, Danielle, additional, Marcoz, Jean-Pierre, additional, Poloni, Claudia, additional, Ramelli, Gian-Paolo, additional, Schmid, R., additional, and Schmitt-Mechelke, T., additional

Published
2019
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12. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Author

Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), Møller, R.S. (Rikke), Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), and Møller, R.S. (Rikke)

Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme

Published
2017
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13. CLINICAL HETEROGENEITY AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN CHILDREN WITH SCN2A-RELATED DISORDERS

Author

Ceulemans, B., Lederer, D., Dorn, T., Helbig, K. L., Hardies, K., Stamberger, H., de Jonghe, P., Weckhuysen, S., Lemke, J. R., Helbig, I, Kluger, G., Moller, R. S., Johannesen, K. M., Wolf, M., Masnada, S., Rubboli, G., Gardella, E., Milh, M., Villard, L., Mignot, C., Lardennois, C., Bourel-Ponchel, Emilie, Nava, C., Lesca, G., Gerard, M., Perrin, L., Doummar, D., Auvin, S., Miranda, M. J., Brilstra, E., Knoers, N., Doecker, M., Bast, T., Loddenkemper, T., Wong-Kisiel, L., Baumeister, F. M., Fazeli, W., Striano, P., Kurlemann, G., Klepper, J., Thoene, J. G., Arndt, D. H., Schmitt-Mechelke, T., Maier, O., Muhle, H., Wical, B., Finetti, C., Brueckner, R., Pietz, J., Golla, G., Jillella, D., Afenjar, A., Linnet, K. M., Charles, P., Oiglane-Slik, E., Mantovani, J. F., Deprez, M., Scalais, E., Lagae, L., Nikanorova, M., Hjalgrim, H., Depienne, C., Scheidecker, S., Kremer, V, Doray, B., Alembik, y., University of British Columbia (UBC), Pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) - Hôpital de la Timone, Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-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), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Insulaire du Vivant et de l'Environnement (LIVE), Université de la Nouvelle-Calédonie (UNC), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Child Neurology, Development and Rehabilitation [Hospital of Eastern Switzerland], Children's Hospital of Eastern Switzerland St.Gallen, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], IMEC (IMEC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Statens seruminstitut, and Les Hôpitaux Universitaires de Strasbourg (HUS)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

14. Specific MRI abnormalities reveal severe perrault syndrome due to CLPP defects

Author

Theunissen, T.E.J. (Tom E.J.), Szklarczyk, R. (Radek), Gerards, M. (Mike), Hellebrekers, D.M.E.I. (Debby), Mulder-Den Hartog, E.N.M. (Elvira N.M.), Vanoevelen, J. (Jo), Kamps, R. (Rick), De Koning, B. (Bart), Lane Rutledge, S., Schmitt-Mechelke, T. (Thomas), Berkel, C.G.M. (Carola) van, Knaap, M.S. (Marjo) van der, Coo, I.F.M. (René) de, Smeets, H.J.M. (Hubert), Theunissen, T.E.J. (Tom E.J.), Szklarczyk, R. (Radek), Gerards, M. (Mike), Hellebrekers, D.M.E.I. (Debby), Mulder-Den Hartog, E.N.M. (Elvira N.M.), Vanoevelen, J. (Jo), Kamps, R. (Rick), De Koning, B. (Bart), Lane Rutledge, S., Schmitt-Mechelke, T. (Thomas), Berkel, C.G.M. (Carola) van, Knaap, M.S. (Marjo) van der, Coo, I.F.M. (René) de, and Smeets, H.J.M. (Hubert)

Abstract

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

Published
2016
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15. Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

Author

Theunissen, T E J, Szklarczyk, R, Gerards, M, Hellebrekers, DMEI, den Hartog, NM (Elvira), Vanoevelen, J, Kamps, R, de Koning, B, Rutledge, S L, Schmitt-Mechelke, T, van Berkel, CGM, van der Knaap, MS, Coo, IFM, Smeets, HJM, Theunissen, T E J, Szklarczyk, R, Gerards, M, Hellebrekers, DMEI, den Hartog, NM (Elvira), Vanoevelen, J, Kamps, R, de Koning, B, Rutledge, S L, Schmitt-Mechelke, T, van Berkel, CGM, van der Knaap, MS, Coo, IFM, and Smeets, HJM

Published
2016

17. Attention-deficit/hyperactivity disorder in childhood epilepsy: a neuropsychological and functional imaging study

Author

Bechtel, N., Kobel, M., Penner, I., Specht, K., Klarhöfer , M., Scheffler, K., Opwis, K., Schmitt-Mechelke, T., Capone, A., and Weber, P.

Subjects
mental disorders, behavioral disciplines and activities
Abstract

Purpose: Children with epilepsy have a significant risk for attention-deficit/hyperactivity disorder (ADHD), which is often accompanied by deficits in working memory performance. However, it is not yet clear whether there are specific differences in the underlying mechanisms of working memory capability between children with epilepsy-related ADHD and those with developmental ADHD. There is evidence that methylphenidate can improve the behavioral difficulties in children with developmental ADHD. Whether this medication has the same effect on ADHD symptoms in patients with epilepsy is not yet well understood. The aim of the present study is, therefore, to evaluate whether boys with epilepsy-related ADHD and developmental ADHD share a common behavioral, pharmacoresponsive, and neurofunctional pathophysiology. Methods: Seventeen boys with diagnosed combined epilepsy/ADHD, 15 boys with developmental ADHD, and 15 healthy controls (aged 8–14 years) performed on working memory tasks (N-back) while brain activation was recorded using functional magnetic resonance imaging. Each patient was tested twice: once after the intake of methylphenidate and once without in a counterbalanced order. Key Findings: On a behavioral level, we show that boys with epilepsy-related ADHD as well as those with developmental ADHD performed similarly poorly on tasks with high cognitive load when compared to healthy controls, and that intake of methylphenidate improved performance almost to normal levels in both ADHD groups. On the functional level, both patient groups showed similar reductions of activation in all relevant parts of the functional network of working memory when compared to controls. Of interest, intake of methylphenidate did not significantly alter this activity pattern. Significance: Our data show strong similarities between epilepsy-related and developmental ADHD on the behavioral, pharmacoresponsive, and neural level, favoring the view that ADHD with and without epilepsy shares a common underlying neurobehavioral pathophysiology.

Published
2012

18. Quality of Life 5 Years after Neonatal Arterial Ischemic Stroke: Is there an Association with Hand Motor Performance?

Author

Teuscher, M., primary, Grunt, S., additional, Studer, M., additional, Boltshauser, E., additional, Capone Mori, A., additional, Datta, A., additional, Fluss, J., additional, Mercati, D., additional, Keller, E., additional, Maier, O., additional, Poloni, C., additional, Ramelli, G., additional, Schmitt-Mechelke, T., additional, and Steinlin, M., additional

Published
2015
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21. Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

Author

Neilson, D.E. Adams, M.D. Orr, C.M.D. Schelling, D.K. Eiben, R.M. Kerr, D.S. Anderson, J. Bassuk, A.G. Bye, A.M. Childs, A.-M. Clarke, A. Crow, Y.J. Di Rocco, M. Dohna-Schwake, C. Dueckers, G. Fasano, A.E. Gika, A.D. Gionnis, D. Gorman, M.P. Grattan-Smith, P.J. Hackenberg, A. Kuster, A. Lentschig, M.G. Lopez-Laso, E. Marco, E.J. Mastroyianni, S. Perrier, J. Schmitt-Mechelke, T. Servidei, S. Skardoutsou, A. Uldall, P. van der Knaap, M.S. Goglin, K.C. Tefft, D.L. Aubin, C. de Jager, P. Hafler, D. Warman, M.L.

Abstract

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE. © 2009 The American Society of Human Genetics.

Published
2009

22. Quality of life after paediatric ischaemic stroke.

Author

Kornfeld, Salome, Studer, Martina, Winkelbeiner, Stephanie, Regényi, Mária, Boltshauser, Eugen, Steinlin, Maja, Mori, A Capone, Datta, A, Fluss, J, Hackenberg, A, Keller, E, Maier, O, Marcoz, J‐P, Poloni, C, Ramelli, G‐P, Schmid, R, and Schmitt‐Mechelke, T

Subjects
QUALITY of life, STROKE, CEREBROVASCULAR disease in children, PEDIATRIC neurology, MOTOR ability, COGNITIVE analysis
Abstract

Aim: Paediatric arterial ischaemic stroke can lead to reduced quality of life (QoL). It is important to identify predictors of QoL to support recovery. We examined long-term QoL after arterial ischaemic stroke concerning different variables.Method: Children registered in the Swiss Neuropediatric Stroke Registry and suffering from arterial ischaemic stroke between 2000 and 2008 were included. Two years post-stroke, assessments included intelligence quotient tests for cognitive impairment and modified Rankin Scale (mRS) for neurological impairment; 5 years post-stroke, the Kidscreen-27 was used for QoL, DSM-IV criteria screening was used for attention deficits, and the ABILHAND-Kids was used for manual motor skills. Age at stroke, sex, socioeconomic status, lesion characteristics, neuropsychological and motor outcome, and mRS were correlated with QoL measures.Results: Seventy children were examined (49 males, 21 females; mean age 7y 2wks). Age at stroke, sex, socioeconomic status, and lesion characteristics did not influence QoL; IQ below average and attention deficits partially influenced QoL. The highest predictive value for QoL was found for manual motor impairment (p=0.002) and mRS scores (p=0.013). Combined motor, cognitive, and attention impairment negatively affected QoL (p=0.001).Interpretation: Neurological and cognitive impairments after paediatric arterial ischaemic stroke negatively influence QoL. Children with motor and neurological problems, as well as those with combined motor, cognitive, and attention problems, are at higher risk for low QoL. [ABSTRACT FROM AUTHOR]

Published
2017
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23. P11. Quality of Life after pediatric ischemic stroke: Five year follow-up of swiss children

Author

Kornfeld, S., primary, Winkelbeiner, S., additional, Studer, M., additional, Boltshauser, E., additional, Capone Mori, A., additional, Datta, A., additional, Fluss, J., additional, Mercati, D., additional, Hackenberg, A., additional, Keller, E., additional, Maier, O., additional, Marcoz, J.P., additional, Ramelli, G.P., additional, Poloni, C., additional, Schmid, R., additional, Schmitt-Mechelke, T., additional, Wehrli, E, additional, Heinks, T., additional, and Steinlin, M., additional

Published
2014
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25. Factors affecting cognitive outcome in early pediatric stroke

Author

Studer, M., primary, Boltshauser, E., additional, Capone Mori, A., additional, Datta, A., additional, Fluss, J., additional, Mercati, D., additional, Hackenberg, A., additional, Keller, E., additional, Maier, O., additional, Marcoz, J.-P., additional, Ramelli, G.-P., additional, Poloni, C., additional, Schmid, R., additional, Schmitt-Mechelke, T., additional, Wehrli, E., additional, Heinks, T., additional, and Steinlin, M., additional

Published
2014
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26. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2

Author

Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, Servidei, Serenella (ORCID:0000-0001-8478-2799), Neilson, De, Adams, Md, Orr, Cmd, Schelling, Dk, Eiben, Rm, Kerr, D, Anderson, J, Bassuk, Ag, Bye, Am, Childs, A, Clarke, A, Crow, Yj, Di Rocco, M, Dohna Schwake, C, Dueckers, G, Fasano, Ae, Gika, Ad, Gionnis, D, Gorman, Mp, Grattan Smith, Pj, Hackenberg, A, Kuster, A, Lentschig, Mg, Lopez Laso, E, Marco, Ej, Mastroyianni, S, Perrier, J, Schmitt Mechelke, T, Servidei, Serenella, Skardoutsou, A, Uldall, P, Van Der Knaap, M, Goglin, Kc, Tefft, Dl, Aubin, C, De Jager, P, Hafler, D, Warman, Ml, and Servidei, Serenella (ORCID:0000-0001-8478-2799)

Abstract

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

Published
2009

35. Sinus venous thrombosis in Swiss children

Author

Pavlovic, J, primary, Steinlin, M, additional, Kaufmann, F, additional, Boltshauser, E, additional, Gubser, D, additional, Haenggeli, C, additional, Keller, E, additional, Lütschg, J, additional, Marcoz, J, additional, Roulet, E, additional, Schmitt-Mechelke, T, additional, and Weissert, M, additional

Published
2006
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36. Neuropsychological Problems after Paediatric Stroke: Two Year Follow-Up of Swiss Children

Author

Pavlovic, J., primary, Kaufmann, F., additional, Boltshauser, E., additional, Capone Mori, A., additional, Gubser Mercati, D., additional, Haenggeli, C.-A., additional, Keller, E., additional, Lütschg, J., additional, Marcoz, J.-P., additional, Ramelli, G.-P., additional, Roulet Perez, E., additional, Schmitt-Mechelke, T., additional, Weissert, M., additional, and Steinlin, M., additional

Published
2006
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37. Leukoencephalopathy with ataxia, hypodontia, and hypomyelination

Author

Wolf, N. I., primary, Harting, I., additional, Boltshauser, E., additional, Wiegand, G., additional, Koch, M. J., additional, Schmitt-Mechelke, T., additional, Martin, E., additional, Zschocke, J., additional, Uhlenberg, B., additional, Hoffmann, G. F., additional, Weber, L., additional, Ebinger, F., additional, and Rating, D., additional

Published
2005
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38. The First Three Years of the Swiss Neuropaediatric Stroke Registry (SNPSR): A Population-Based Study of Incidence, Symptoms and Risk Factors

Author

Steinlin, M., primary, Pfister, I., additional, Pavlovic, J., additional, Everts, R., additional, Boltshauser, E., additional, Capone Mori, A., additional, Gubser Mercati, D., additional, Hänggeli, C.-A., additional, Keller, E., additional, Luetschg, J., additional, Marcoz, J., additional, Ramelli, G.-P., additional, Roulet Perez, E., additional, Schmitt-Mechelke, T., additional, and Weissert, M., additional

Published
2005
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41. Cerebral sinus venous thrombosis in Swiss children.

Author

Grunt S, Wingeier K, Wehrli E, Boltshauser E, Capone A, Fluss J, Gubser-Mercati D, Jeannet PY, Keller E, Marcoz JP, Schmitt-Mechelke T, Weber P, Weissert M, Steinlin M, and Swiss Neuropaediatric Stroke Registry

Abstract

AIMo describe the characteristics of paediatric cerebral sinus venous thrombosis (CSVT) in Switzerland. METHOD: data on clinical features, neuroimaging, risk factors, and treatment were collected for all children in Switzerland younger than 16 years of age who had CSVT between January 2000 and December 2008. A follow-up examination and a cognitive assessment were performed (mean follow-up period 26mo). Differences between neonates and children (patients older than 28d) were assessed and predictors of outcome were determined. RESULTS: twenty-one neonates (14 males, seven females; mean age 9d, SD 8d) and 44 children (30 males, 14 females; mean age 8y 7mo, SD 4y 5mo) were reported. The incidence of paediatric CSVT in Switzerland was 0.558 per 100000 per year. In neonates, the deep venous system was more often involved and parenchymal injuries were more common. The strongest predictor of poor outcome was neonatal age (odds ratio 17.8, 95% confidence interval 0.847-372.353). Most children showed global cognitive abilities within the normal range, but impairments in single cognitive subdomains were frequent. INTERPRETATION: paediatric CSVT is rare. Its outcome is poor in neonates. Most children have good neurological outcomes, but some patients have individual neuropsychological impairments. [ABSTRACT FROM AUTHOR]

Published
2010
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43. Association between perinatal interventional activity and 2-year outcome of Swiss extremely preterm born infants: a population-based cohort study

Author

Adams, Mark, Berger, Thomas M, Borradori Tolsa, Cristina, Bickle-Graz, Myriam, Grunt, Sebastian, Gerull, Roland, Bassler, Dirk, Natalucci, Giancarlo, Swiss Neonatal Network & Follow-Up Group, Pfister, Riccardo, Hüppi, Petra Susan, Swiss Neonatal Network & Follow-Up Group, Anderegg, M.C., Mori, A.C., Kaeppeli, D., Schulzke, S., Weber, P., Ramelli, G.P., Simonetti, B.G., Nelle, M., Wagner, B., Steinlin, M., Grunt, S., Gebauer, M., Hassink, R., Bär, W., Keller, E., Killer, C., Fuhrer, K., Pfister, R.E., Hüppi, P.S., Borradori-Tolsa, C., Tolsa, J.F., Roth-Kleiner, M., Bickle-Graz, M., Berger, T.M., Schmitt-Mechelke, T., Bauder, F., Pezzoli, V., Erkert, B., Mueller, A., Ecoffey, M., Malzacher, A., Micallef, J.P., Lang-Dullenkopf, A., Hegi, L., Rhein, M.V., Bassler, D., Arlettaz, R., Bernet, V., Latal, B., Natalucci, G., and Moenkhoff, M.

Subjects
Male, fetal medicine, medicine.medical_specialty, Pediatrics, Developmental Disabilities, Gestational Age, 610 Medicine & health, Lower risk, neonatology, quality in health care, Child, Preschool, Developmental Disabilities/epidemiology, Female, Humans, Infant, Infant Mortality, Infant, Extremely Premature, Infant, Newborn, Intensive Care Units, Neonatal/standards, Length of Stay/statistics & numerical data, Perinatal Care/standards, Retrospective Studies, Switzerland/epidemiology, 03 medical and health sciences, Population based cohort, 0302 clinical medicine, Intensive Care Units, Neonatal, 030225 pediatrics, Intensive care, medicine, 030212 general & internal medicine, Neonatology, ddc:618, business.industry, Research, Extremely preterm, Paediatrics, Retrospective cohort study, General Medicine, Fetal medicine, Length of Stay, 3. Good health, Perinatal Care, Institutional repository, Cohort, Quality in health care, business, Switzerland
Abstract

ObjectivesTo investigate if centre-specific levels of perinatal interventional activity were associated with neonatal and neurodevelopmental outcome at 2 years of age in two separately analysed cohorts of infants: cohort A born at 22–25 and cohort B born at 26–27 gestational weeks, respectively.DesignGeographically defined, retrospective cohort study.SettingAll nine level III perinatal centres (neonatal intensive care units and affiliated obstetrical services) in Switzerland.PatientsAll live-born infants in Switzerland in 2006–2013 below 28 gestational weeks, excluding infants with major congenital malformation.Outcome measuresOutcomes at 2 years corrected for prematurity were mortality, survival with any major neonatal morbidity and with severe-to-moderate neurodevelopmental impairment (NDI).ResultsCohort A associated birth in a centre with high perinatal activity with low mortality adjusted OR (aOR 0.22; 95% CI 0.16 to 0.32), while no association was observed with survival with major morbidity (aOR 0.74; 95% CI 0.46 to 1.19) and with NDI (aOR 0.97; 95% CI 0.46 to 2.02). Median age at death (8 vs 4 days) and length of stay (100 vs 73 days) were higher in high than in low activity centres. The results for cohort B mirrored those for cohort A.ConclusionsCentres with high perinatal activity in Switzerland have a significantly lower risk for mortality while having comparable outcomes among survivors. This confirms the results of other studies but in a geographically defined area applying a more restrictive approach to initiation of perinatal intensive care than previous studies. The study adds that infants up to 28 weeks benefited from a higher perinatal activity and why further research is required to better estimate the added burden on children who ultimately do not survive.

Published
2019

44. Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008

Author

Mark Raymond Adams, Elena Proietti, Maude Aebischer, Hans Ulrich Bucher, Cristina Borradori-Tolsa, Sebastian Grunt, Beatrice Latal, Giancarlo Natalucci, Myriam Bickle-Graz, Luregn J. Schlapbach, Swiss Neonatal Network & Follow-up Group, Zeilinger, G., Capone, A., Steiner, F., Schulzke, S., Weber, P., Ramelli, GP., Nelle, M., Steinlin, M., Grunt, S., Hassink, R., Bär, W., Keller, E., Killer, Ch., Fuhrer, K., Tolsa, JF., Bickle-Graz, M., Pfister, RE., Huppi, PS., Borradori-Tolsa, C., Berger, TM., Schmitt-Mechelke, T., Pezzoli, V., Ecoffey, M., Mueller, A., Malzacher, A., Micallef, JP., Schaefer, Ch., von Rhein, M., Arlettaz Mieth, R., Bernet, V., Latal, B., Natalucci, G., University of Zurich, and Natalucci, Giancarlo

Subjects
Male, Pediatrics, Multivariate analysis, Developmental Disabilities, Infant, Premature, Diseases, Severity of Illness Index, Nervous System Diseases/epidemiology/etiology/mortality, 0302 clinical medicine, Switzerland/epidemiology, Risk Factors, 030212 general & internal medicine, Prospective Studies, Registries, 610 Medicine & health, Prospective cohort study, Outcome, education.field_of_study, ddc:618, Incidence (epidemiology), Follow up studies, lcsh:RJ1-570, 3. Good health, Child, Preschool, Infant, Extremely Premature, Developmental Disabilities/epidemiology/etiology/mortality, Female, Switzerland, Research Article, medicine.medical_specialty, Population, Development, National cohort, 03 medical and health sciences, Preterm, 030225 pediatrics, Severity of illness, medicine, Humans, 2735 Pediatrics, Perinatology and Child Health, Pediatrics, Perinatology, and Child Health, Mortality, education, Infant, Premature, Diseases/epidemiology/etiology/mortality, Psychological Tests, Disability, business.industry, Extremely preterm, Infant, Newborn, lcsh:Pediatrics, 10027 Clinic for Neonatology, Logistic Models, 10036 Medical Clinic, Pediatrics, Perinatology and Child Health, Multivariate Analysis, Nervous System Diseases, business, Follow-Up Studies
Abstract

BackgroundWhile survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling.MethodsProspective longitudinal multicentre cohort study of preterm infants born in Switzerland between 240/7and 276/7weeks gestational age during 2000–2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System.ResultsOf 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p 0/7weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p ConclusionsIn this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.

Published
2012

45. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.

Author

Scala M, Wortmann SB, Kaya N, Stellingwerff MD, Pistorio A, Glamuzina E, van Karnebeek CD, Skrypnyk C, Iwanicka-Pronicka K, Piekutowska-Abramczuk D, Ciara E, Tort F, Sheidley B, Poduri A, Jayakar P, Jayakar A, Upadia J, Walano N, Haack TB, Prokisch H, Aldhalaan H, Karimiani EG, Yildiz Y, Ceylan AC, Santiago-Sim T, Dameron A, Yang H, Toosi MB, Ashrafzadeh F, Akhondian J, Imannezhad S, Mirzadeh HS, Maqbool S, Farid A, Al-Muhaizea MA, Alshwameen MO, Aldowsari L, Alsagob M, Alyousef A, AlMass R, AlHargan A, Alwadei AH, AlRasheed MM, Colak D, Alqudairy H, Khan S, Lines MA, García Cazorla MÁ, Ribes A, Morava E, Bibi F, Haider S, Ferla MP, Taylor JC, Alsaif HS, Firdous A, Hashem M, Shashkin C, Koneev K, Kaiyrzhanov R, Efthymiou S, Genomics QS, Schmitt-Mechelke T, Ziegler A, Issa MY, Elbendary HM, Striano P, Alkuraya FS, Zaki MS, Gleeson JG, Barakat TS, Bierau J, van der Knaap MS, Maroofian R, and Houlden H

Subjects
Humans, Inosine, Inosine Triphosphate, Mutation, Prognosis, Inosine Triphosphatase, Epilepsy, Generalized, Microcephaly pathology, Pyrophosphatases genetics
Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Published
2022
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47. Feasibility and usefulness of rapid 2-channel-EEG-monitoring (point-of-care EEG) for acute CNS disorders in the paediatric emergency department: an observational study.

Author

Simma L, Bauder F, and Schmitt-Mechelke T

Subjects
Child, Child, Preschool, Electroencephalography, Emergency Service, Hospital, Feasibility Studies, Humans, Infant, Point-of-Care Systems, Status Epilepticus diagnosis
Abstract

Introduction: The aim of this study was to determine the feasibility and clinical utility of point-of-care electroencephalogram (pocEEG) in the paediatric emergency department (ED) for children presenting with acute non-traumatic central nervous system (CNS) disorders., Methods: Retrospective observational study of prospectively collected data in paediatric patients (0-16 years) with acute non-traumatic CNS-disorders presenting between April 2014 and February 2017 to a single paediatric ED in Switzerland.The 2-channel EEG was applied to all patients presenting with acute seizures or impaired consciousness to the ED. For a pocEEG, scalp surface electrodes are applied in five locations, thus allowing registration of fronto-temporal bilateral cortical activity. Neurology consultants assisted with interpretation of readings. EEG findings and clinical characteristics were collected. Feasibility and usefulness were rated via Likert scale., Results: 36 patients with acute seizures or altered mental status were analysed. Age range was 9 months to 15 years, median age of 34 months. 21 of 36 (58%) patients arrived out of hours. Application of electrodes was rated as 'easy' in 28 (77.8%) patients and rated as 'difficult' in 8 (22.2%). The utility of the EEG was rated by physicians as 'very useful/diagnostic' in 13 cases (36%), 'useful' in 21 cases (58%), 'not useful' in two cases (8%). None were rated 'negative.', Conclusion: Uptake of pocEEG introduction has been very encouraging. Provider ratings were overwhelmingly positive. Recognition of non-convulsive status epilepticus was improved and pocEEG facilitated more targeted interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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48. Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families.

Author

Spenger J, Maier EM, Wechselberger K, Bauder F, Kocher M, Sperl W, Preisel M, Schiergens KA, Konstantopoulou V, Röschinger W, Häberle J, Schmitt-Mechelke T, Wortmann SB, and Fingerhut R

Abstract

Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1.

Published
2021
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49. LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

Author

Stellingwerff MD, Figuccia S, Bellacchio E, Alvarez K, Castiglioni C, Topaloglu P, Stutterd CA, Erasmus CE, Sanchez-Valle A, Lebon S, Hughes S, Schmitt-Mechelke T, Vasco G, Chow G, Rahikkala E, Dallabona C, Okuma C, Aiello C, Goffrini P, Abbink TEM, Bertini ES, and Van der Knaap MS

Abstract

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2 , encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes., Methods: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function., Results: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNA Asp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function., Conclusions: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2021
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50. The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Author

Papuc SM, Abela L, Steindl K, Begemann A, Simmons TL, Schmitt B, Zweier M, Oneda B, Socher E, Crowther LM, Wohlrab G, Gogoll L, Poms M, Seiler M, Papik M, Baldinger R, Baumer A, Asadollahi R, Kroell-Seger J, Schmid R, Iff T, Schmitt-Mechelke T, Otten K, Hackenberg A, Addor MC, Klein A, Azzarello-Burri S, Sticht H, Joset P, Plecko B, and Rauch A

Subjects
Adolescent, Adult, Child, Child, Preschool, Epilepsy diagnosis, Exome, Female, Genes, Recessive, Humans, Infant, Male, DNA Copy Number Variations, Epilepsy genetics, Mutation Rate, Exome Sequencing methods
Abstract

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.

Published
2019
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