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2. Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease)

Author

Oliveira, JRM, Spiteri, E, Sobrido, MJ, Hopfer, S, Klepper, J, Voit, T, Gilbert, J, Wszolek, ZK, Calne, DB, Stoessl, AJ, Hutton, M, Manyam, BV, Boller, F, Baquero, M, and Geschwind, DH

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Rare Diseases, Neurodegenerative, Genetics, Neurological, Basal Ganglia Diseases, Calcinosis, Chromosomes, Human, Pair 14, Female, Genes, Dominant, Genetic Heterogeneity, Humans, Lod Score, Male, Neurologic Examination, Pedigree, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Familial idiopathic basal ganglia calcification (IBGC, Fahr disease) is an inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications, parkinsonism, and neuropsychiatric symptoms. The authors examined six families for linkage to the previously identified genetic locus (IBGC1) located on chromosome 14q. The authors found evidence against linkage to IBGC1 in five of the six families supporting previous preliminary studies demonstrating genetic heterogeneity in familial IBGC.

Published
2004

4. Effect of anticonvulsive treatment on neuropsychological performance in children with BECTS

Author

Baumeister, F.A.M., Baethmann, M., Schreiber-Gollwitzer, B., Bentele, K., Blank, C., Held, J., Blank, H.M., Liebrich, K., Bode, H., Braun, J., Bosch, F., Wagner, R., Brandl, U., Wetzel, K., Brockmann, K., Schlockwerder, C., Dahlem, P., Baudler, I., Ernst, J.P., Mayer, H., Feldmann, E., Pattber-Wolff, A., Fiedler, A., Sonnleitner, S., Gerigk, M., Heß, S., Feiereis, T., Hikel, C., Hoffmann, H.G., Rickeshenrich, A., Kieslich, M., Dewitz, R., Baz Bartels, M., Klepper, J., Kleuker, S., Kluger, G., Kirsch, A., Koch, H., Meerpohl, U., Koch, W., Korinthenberg, R., Stehle-Renner, B., Krois, I., Wegener, A., Kühne, H., Weiß, C., Kurlemann, G., Elkemann, U., Mandl, M., Friedl, A., Mause, U., Müller, M., Navratil, P., Iken, U., Opp, J., Walter, J., Penzien, J., Prietsch, V., Siegrist, B., Quattländer, A., Rating, D., Reuner, G., Schara, U., Shamdeen, M.G., Struchholz, H., Sprinz, A., Wendker-Magrabi, H., Stephani, U., Muhle, H., Carlsson, G., Straßburg, H.M., Ottensmeier, H., Töpke, B., Tatsek, K., Trollmann, R., Poida-Herzing, E., Tuschen-Hofstätter, E., Menschig, M., Waltz, S., Pickartz, A., Weber, G., Gehnen, T., Wien, F.U., Antemann, J., Wolff, M., Serra, E., Polster, T., Freitag, H., Sönmez, Ö, Rheinhardt, K., Traus, M., Schröder, A., Hoovey, S., Navratil, C., Tacke, Moritz, Gerstl, Lucia, Heinen, Florian, Heukaeufer, Isabel, Bonfert, Michaela, Bast, Thomas, Cornell, Sonia, Neubauer, Bernd Axel, and Borggraefe, Ingo

Published
2016
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7. Percutaneous Gastrostomy for Ketogenic Diet Therapy in Glut1DS

Author

Klepper J

Subjects
Embryology, medicine.medical_specialty, Percutaneous gastrostomy, business.industry, medicine.medical_treatment, medicine, Cell Biology, Anatomy, business, Developmental Biology, Surgery, Ketogenic diet
Abstract

Glut1 Deficiency Syndrome (Glut1DS) results from impaired glucose transport into brain and presents with seizures, movement abnormalities, and developmental deficits. The only effective treatment is a high-fat, carbohydrate-restricted ketogenic diet providing ketones as an alternative fuel to the brain. The potential of ketogenic diets has recently been discussed in your journal [1]. Here we report a 24 year old woman with very mild cognitive impairment, a mild movement disorder and epilepsy. Glut1DS was confirmed at the age of six years by hypoglycorrhachia and a heterozygous pathogenic de novo missense mutation in the SLC2A1 gene (Thr137Ile). On a classical 3:1 ketogenic diet treatment she was seizure-free with significant improved endurance, cognitive and motor performance if blood ketones (3-hydroxy-butyrate) were above 2.0mmol/l. She experienced near continuous absence seizures and also dyskinetic movements if her ketones were below this threshold. However, despite achieving puberty at the age of 14 years, she had difficulties meeting her nutritional requirements because of persistent vomiting. All efforts to improve the tolerability of the ketogenic diet, as well as modifications of the diet, were unsuccessful. Her bone density and BMI continued to decrease and she developed more seizures and abnormal movements despite many nutritional manoeuvres. At a BMI of 15.2 a Percutaneous Gastrostomy (PEG) was suggested. It took three years before she came to terms with this option and following insertion of a gastrostomy her BMI improved to 18 within four months and with no evidence of biochemical derangements as a consequence of her rapid weight gain. Two years following this she remains on a classical 2:1 ketogenic diet with ketones consistently above her threshold of 2.0mmol/l, normal biochemistry, an improving bone density and a stable BMI of 18.6. She feels that it was a good decision, improving her quality of life by taking some of the stress out of meals, providing an alternative route for the delivery of fluids, food and medication, tailored to her ongoing needs. She has experienced less in the way of ictal events or dyskinesias since this time. A PEG is an established option in patients with feeding difficulties and severe cognitive impairment. It is, however, a difficult decision to suggest to a young, mildy impaired woman with high overall quality of life. Our patient, her caretakers, and the treating physicians felt very uneasy with this procedure. However, we felt that it was important to report that this measure improved the quality of life in our patient. We propose that in Glut1DS patients dependent on a ketogenic diet and a level of ketosis that otherwise that cannot be obtained, the option of a PEG should be offered early.

Published
2021
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12. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Author

Klepper, J. Akman, C. Armeno, M. Auvin, S. Cervenka, M. Cross, H.J. De Giorgis, V. Della Marina, A. Engelstad, K. Heussinger, N. Kossoff, E.H. Leen, W.G. Leiendecker, B. Monani, U.R. Oguni, H. Neal, E. Pascual, J.M. Pearson, T.S. Pons, R. Scheffer, I.E. Veggiotti, P. Willemsen, M. Zuberi, S.M. De Vivo, D.C.

Abstract

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle. © 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Published
2020

14. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Author

Klepper, J., Akman, C.I., Armeno, Marisa, Auvin, S., Cervenka, Mackenzie, Cross, Helen J., Willemsen, M.A., Zuberi, S.M., Vivo, D.C. De, Klepper, J., Akman, C.I., Armeno, Marisa, Auvin, S., Cervenka, Mackenzie, Cross, Helen J., Willemsen, M.A., Zuberi, S.M., and Vivo, D.C. De

Abstract

Contains fulltext : 233745.pdf (Publisher’s version ) (Open Access)

Published
2020

15. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

Author

Klepper, J, Akman, C, Armeno, M, Auvin, S, Cervenka, M, Cross, HJ, De Giorgis, V, Della Marina, A, Engelstad, K, Heussinger, N, Kossoff, EH, Leen, WG, Leiendecker, B, Monani, UR, Oguni, H, Neal, E, Pascual, JM, Pearson, TS, Pons, R, Scheffer, IE, Veggiotti, P, Willemsen, M, Zuberi, SM, De Vivo, DC, Klepper, J, Akman, C, Armeno, M, Auvin, S, Cervenka, M, Cross, HJ, De Giorgis, V, Della Marina, A, Engelstad, K, Heussinger, N, Kossoff, EH, Leen, WG, Leiendecker, B, Monani, UR, Oguni, H, Neal, E, Pascual, JM, Pearson, TS, Pons, R, Scheffer, IE, Veggiotti, P, Willemsen, M, Zuberi, SM, and De Vivo, DC

Abstract

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Im

Published
2020

16. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

Author

Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, HC, Lambrechts, DA, Liu, YM, Nathan, JK, Nordli, DR, Jr, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, Elles, Veggiotti, P, Wheless, JW, Wirrell, EC, Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, HC, Lambrechts, DA, Liu, YM, Nathan, JK, Nordli, DR, Jr, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, Elles, Veggiotti, P, Wheless, JW, and Wirrell, EC

Published
2020

20. Optimal clinical management of children receiving ketogenic parenteral nutrition: a clinical practice guide

Author

van der Louw, E., Aldaz, V., Harvey, J. (J.), Roan, M., van den Hurk, D., Cross, JH, Auvin, S., Forbes, E., van de Bor, B., Olieman, J.F. (Joanne), Simchowitz, V., Storme, T., Klepper, J., Dressler, A., van der Louw, E., Aldaz, V., Harvey, J. (J.), Roan, M., van den Hurk, D., Cross, JH, Auvin, S., Forbes, E., van de Bor, B., Olieman, J.F. (Joanne), Simchowitz, V., Storme, T., Klepper, J., and Dressler, A.

Abstract

AIM To give evidence-based recommendations on the application of ketogenic diet parenteral nutrition (KD-PN) in emergency situations. METHOD An international group of experts (n=14) researched the literature and distributed a survey among 150 expert centers. International accepted guidelines (European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition and the American Society for Parenteral and Enteral Nutrition) and handbooks for parenteral nutrition were considered general standards of care. RESULTS In the literature, we identified 35 reports of patients treated by KD-PN. International guidelines and handbooks provided some conflicting information. Twenty-four expert teams from nine countries responded to the survey, reflecting the limited clinical experience. INTERPRETATION This paper highlights 23 consensus-based recommendations for safe and effective KD-PN (e.g. diet initiation, calculation, application, monitoring, and evaluation) based on the best evidence available and expert opinions.

Published
2019
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22. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group

Author

Kossoff, E.H., Zupec-Kania, B.A., Auvin, S., Ballaban-Gil, K.R., Christina Bergqvist, A.G., Blackford, R., Buchhalter, J.R., Caraballo, R.H., Cross, JH, Dahlin, M.G., Donner, E.J., Guzel, O., Jehle, R.S., Klepper, J., Kang, H.C., Lambrechts, D.A., Liu, Y. (YongMei), Nathan, J.K., Nordli, D.R., Jr., Pfeifer, H.H., Rho, J.M., Scheffer, I.E., Sharma, S., Stafstrom, C.E., Thiele, EA, Turner, Z., Vaccarezza, M.M., Louw, E.J.T.M. (Elles) van der, Veggiotti, P., Wheless, J.W., Wirrell, E.C., Kossoff, E.H., Zupec-Kania, B.A., Auvin, S., Ballaban-Gil, K.R., Christina Bergqvist, A.G., Blackford, R., Buchhalter, J.R., Caraballo, R.H., Cross, JH, Dahlin, M.G., Donner, E.J., Guzel, O., Jehle, R.S., Klepper, J., Kang, H.C., Lambrechts, D.A., Liu, Y. (YongMei), Nathan, J.K., Nordli, D.R., Jr., Pfeifer, H.H., Rho, J.M., Scheffer, I.E., Sharma, S., Stafstrom, C.E., Thiele, EA, Turner, Z., Vaccarezza, M.M., Louw, E.J.T.M. (Elles) van der, Veggiotti, P., Wheless, J.W., and Wirrell, E.C.

Abstract

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Published
2018
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23. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.

Author

Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, H-C, Lambrechts, DA, Liu, YMC, Nathan, JK, Nordli, DR, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, EJTM, Veggiotti, P, Wheless, JW, Wirrell, EC, Charlie Foundation, Matthew's Friends, Practice Committee of the Child Neurology Society, Kossoff, EH, Zupec-Kania, BA, Auvin, S, Ballaban-Gil, KR, Christina Bergqvist, AG, Blackford, R, Buchhalter, JR, Caraballo, RH, Cross, JH, Dahlin, MG, Donner, EJ, Guzel, O, Jehle, RS, Klepper, J, Kang, H-C, Lambrechts, DA, Liu, YMC, Nathan, JK, Nordli, DR, Pfeifer, HH, Rho, JM, Scheffer, IE, Sharma, S, Stafstrom, CE, Thiele, EA, Turner, Z, Vaccarezza, MM, van der Louw, EJTM, Veggiotti, P, Wheless, JW, Wirrell, EC, Charlie Foundation, Matthew's Friends, and Practice Committee of the Child Neurology Society

Abstract

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

Published
2018

27. 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

28. Upstream SLC2A1 translation initiation causes GLUT1 deficiency syndrome

Author

Willemsen, M.A.A.P., Vissers, L.E.L.M., Verbeek, M.M., Bon, B.W.M. van, Geuer, S., Gilissen, C.F., Klepper, J., Kwint, M.P., Leen, W.G., Pennings, M., Wevers, R.A., Veltman, J.A., Kamsteeg, E.J., Willemsen, M.A.A.P., Vissers, L.E.L.M., Verbeek, M.M., Bon, B.W.M. van, Geuer, S., Gilissen, C.F., Klepper, J., Kwint, M.P., Leen, W.G., Pennings, M., Wevers, R.A., Veltman, J.A., and Kamsteeg, E.J.

Abstract

Contains fulltext : 174080.pdf (publisher's version ) (Closed access), Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder with a complex phenotypic spectrum but simple biomarkers in cerebrospinal fluid. The disorder is caused by impaired glucose transport into the brain resulting from variants in SCL2A1. In 10% of GLUT1DS patients, a genetic diagnosis can not be made. Using whole-genome sequencing, we identified a de novo 5'-UTR variant in SLC2A1, generating a novel translation initiation codon, severely compromising SLC2A1 function. This finding expands our understanding of the disease mechanisms underlying GLUT1DS and encourages further in-depth analysis of SLC2A1 non-coding regions in patients without variants in the coding region.

Published
2017

29. 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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30. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.

Abstract

Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Published
2016

31. Effect of anticonvulsive treatment on neuropsychological performance in children with BECTS

Author

Tacke, Moritz, primary, Gerstl, Lucia, additional, Heinen, Florian, additional, Heukaeufer, Isabel, additional, Bonfert, Michaela, additional, Bast, Thomas, additional, Cornell, Sonia, additional, Neubauer, Bernd Axel, additional, Borggraefe, Ingo, additional, Baumeister, F.A.M., additional, Baethmann, M., additional, Schreiber-Gollwitzer, B., additional, Bentele, K., additional, Blank, C., additional, Held, J., additional, Blank, H.M., additional, Liebrich, K., additional, Bode, H., additional, Braun, J., additional, Bosch, F., additional, Wagner, R., additional, Brandl, U., additional, Wetzel, K., additional, Brockmann, K., additional, Schlockwerder, C., additional, Dahlem, P., additional, Baudler, I., additional, Ernst, J.P., additional, Mayer, H., additional, Feldmann, E., additional, Pattber-Wolff, A., additional, Fiedler, A., additional, Sonnleitner, S., additional, Gerigk, M., additional, Heß, S., additional, Feiereis, T., additional, Hikel, C., additional, Hoffmann, H.G., additional, Rickeshenrich, A., additional, Kieslich, M., additional, Dewitz, R., additional, Baz Bartels, M., additional, Klepper, J., additional, Kleuker, S., additional, Kluger, G., additional, Kirsch, A., additional, Koch, H., additional, Meerpohl, U., additional, Koch, W., additional, Korinthenberg, R., additional, Stehle-Renner, B., additional, Krois, I., additional, Wegener, A., additional, Kühne, H., additional, Weiß, C., additional, Kurlemann, G., additional, Elkemann, U., additional, Mandl, M., additional, Friedl, A., additional, Mause, U., additional, Müller, M., additional, Navratil, P., additional, Iken, U., additional, Opp, J., additional, Walter, J., additional, Penzien, J., additional, Prietsch, V., additional, Siegrist, B., additional, Quattländer, A., additional, Rating, D., additional, Reuner, G., additional, Schara, U., additional, Shamdeen, M.G., additional, Struchholz, H., additional, Sprinz, A., additional, Wendker-Magrabi, H., additional, Stephani, U., additional, Muhle, H., additional, Carlsson, G., additional, Straßburg, H.M., additional, Ottensmeier, H., additional, Töpke, B., additional, Tatsek, K., additional, Trollmann, R., additional, Poida-Herzing, E., additional, Tuschen-Hofstätter, E., additional, Menschig, M., additional, Waltz, S., additional, Pickartz, A., additional, Weber, G., additional, Gehnen, T., additional, Wien, F.U., additional, Antemann, J., additional, Wolff, M., additional, Serra, E., additional, Polster, T., additional, Freitag, H., additional, Sönmez, Ö, additional, Rheinhardt, K., additional, Traus, M., additional, Schröder, A., additional, Hoovey, S., additional, and Navratil, C., additional

Published
2016
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36. OP64 – 2760: Oligoclonal bands predict multiple sclerosis in children with isolated optic neuritis

Author

Heussinger, N., primary, Kontopantelis, E., additional, Gburek-Augustat, J., additional, Jenke, J., additional, Vollrath, G., additional, Korinthenberg, R., additional, Hofstetter, P., additional, Meyer, S., additional, Brecht, I., additional, Kornek, B., additional, Herkenrath, P., additional, Schimmel, M., additional, Wenner, K., additional, Häußler, M., additional, Lutz, S., additional, Karenfort, M., additional, Blaschek, A., additional, Smitka, M., additional, Karch, S., additional, Piepkorn, M., additional, Rostasy, K., additional, Lücke, T., additional, Weber, P., additional, Trollmann, R., additional, Klepper, J., additional, Hofmann, R., additional, Weißert, R., additional, Merkenschlager, A., additional, and Buttmann, M., additional

Published
2015
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37. Oligoclonal Bands Predict Multiple Sclerosis in Children with Isolated Optic Neuritis: A Retrospective Multicenter Cohort Study

Author

Heußinger, N., primary, Kontopantelis, E., additional, Gburek-Augustat, J., additional, Jenke, A., additional, Vollrath, G., additional, Korinthenberg, R., additional, Hofstetter, P., additional, Meyer, S., additional, Brecht, I., additional, Bajer-Kornek, B., additional, Herkenrath, P., additional, Schimmel, M., additional, Wenner, K., additional, Häusler, M., additional, Lutz, S., additional, Blaschek, A., additional, Smitka, M., additional, Karch, S., additional, Piepkorn, M., additional, Rostasy, K., additional, Weber, P., additional, Trollmann, R., additional, Klepper, J., additional, Häußler, M., additional, Hofmann, R., additional, Weissert, R., additional, Merkenschlager, A., additional, and Buttmann, M., additional

Published
2015
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39. Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities

Author

Baasch, A.L., Huning, I., Gilissen, C., Klepper, J., Veltman, J.A., Gillessen-Kaesbach, G., Hoischen, A., Lohmann, K., Baasch, A.L., Huning, I., Gilissen, C., Klepper, J., Veltman, J.A., Gillessen-Kaesbach, G., Hoischen, A., and Lohmann, K.

Abstract

Item does not contain fulltext, Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the alphaII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Published
2014

40. De Novo SCN2A Mutations Cause Variable Phenotypes in Children with Epilepsy

Author

Wolff, M., primary, Bast, T., additional, Loddenkemper, T., additional, Jillella, D., additional, Döcker, M., additional, Wong-Kisiel, L., additional, Möller, R., additional, Weckhuysen, S., additional, Ceulemans, B., additional, Klepper, J., additional, Baumeister, F., additional, Finetti, C., additional, Kurlemann, G., additional, Muhle, H., additional, and Kluger, G., additional

Published
2014
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41. Child Neurology: Differential diagnosis of a low CSF glucose in children and young adults

Author

Leen, W.G., Wit, C.J. de, Wevers, R.A., Engelen, B.G.M. van, Kamsteeg, E.J., Klepper, J., Verbeek, M.M., Willemsen, M.A.A.P., Leen, W.G., Wit, C.J. de, Wevers, R.A., Engelen, B.G.M. van, Kamsteeg, E.J., Klepper, J., Verbeek, M.M., and Willemsen, M.A.A.P.

Abstract

Item does not contain fulltext, Analysis of CSF is daily routine in patients with acute neurologic disorders like CNS infections. In those patients, the finding of a low CSF glucose may influence further diagnostic workup and therapeutic choices. The interpretation of a low CSF glucose in patients with a chronic neurologic disorder, however, is a less common practice. We present a practical overview on the differential diagnosis of a low CSF glucose and stress the importance of recognizing a low CSF glucose as the diagnostic marker for GLUT1 deficiency syndrome, a treatable neurometabolic disorder.

Published
2013

42. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Author

Hsu, SC, Sears, RL, Lemos, RR, Quintans, B, Huang, A, Spiteri, E, Nevarez, L, Nevarez, C, Zatz, M, Pierce, KD, Fullerton, JM, Adair, JC, Berner, JE, Bower, M, Brodaty, H, Carmona, O, Dobricic, V, Fogel, BL, Garcia-Estevez, D, Goldman, JM, Goudreau, J, Goudreau, S, Jankovic, M, Jauma, S, Jen, JC, Kirdlarp, S, Klepper, J, Kostic, V, Lang, AE, Linglart, A, Maisenbacher, MK, Manyam, BV, Mazzoni, P, Miedzybrodzka, Z, Mitarnun, W, Mitchell, PB, Mueller, J, Novakovic, I, Paucar, M, Paulson, H, Simpson, SA, Svenningsson, P, Tuite, P, Vitek, J, Wetchaphanphesat, S, Williams, C, Yang, M, Schofield, PR, Oliveira, JRMD, Sobrido, MJ, Geschwind, DH, Coppola, G, Hsu, SC, Sears, RL, Lemos, RR, Quintans, B, Huang, A, Spiteri, E, Nevarez, L, Nevarez, C, Zatz, M, Pierce, KD, Fullerton, JM, Adair, JC, Berner, JE, Bower, M, Brodaty, H, Carmona, O, Dobricic, V, Fogel, BL, Garcia-Estevez, D, Goldman, JM, Goudreau, J, Goudreau, S, Jankovic, M, Jauma, S, Jen, JC, Kirdlarp, S, Klepper, J, Kostic, V, Lang, AE, Linglart, A, Maisenbacher, MK, Manyam, BV, Mazzoni, P, Miedzybrodzka, Z, Mitarnun, W, Mitchell, PB, Mueller, J, Novakovic, I, Paucar, M, Paulson, H, Simpson, SA, Svenningsson, P, Tuite, P, Vitek, J, Wetchaphanphesat, S, Williams, C, Yang, M, Schofield, PR, Oliveira, JRMD, Sobrido, MJ, Geschwind, DH, and Coppola, G

Abstract

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

Published
2013

44. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

Author

Leen, W.G., Klepper, J., Verbeek, M.M., Leferink, M., Hofste, T., Engelen, B.G.M. van, Wevers, R.A., Arthur, T., Bahi-Buisson, N., Ballhausen, D., Bekhof, J., Bogaert, P. van, Carrilho, I., Chabrol, B., Champion, M.P., Coldwell, J., Clayton, P., Donner, E., Evangeliou, A., Ebinger, F., Farrell, K., Forsyth, R.J., Goede, C.G. de, Gross, S., Grunewald, S., Holthausen, H., Jayawant, S., Lachlan, K., Laugel, V., Leppig, K., Lim, M.J., Mancini, G., Marina, A.D., Martorell, L., McMenamin, J., Meuwissen, M.E., Mundy, H., Nilsson, N.O., Panzer, A., Poll-The, B.T., Rauscher, C., Rouselle, C.M., Sandvig, I., Scheffner, T., Sheridan, E., Simpson, N., Sykora, P., Tomlinson, R., Trounce, J., Webb, D., Weschke, B., Scheffer, H., Willemsen, M.A.A.P., Leen, W.G., Klepper, J., Verbeek, M.M., Leferink, M., Hofste, T., Engelen, B.G.M. van, Wevers, R.A., Arthur, T., Bahi-Buisson, N., Ballhausen, D., Bekhof, J., Bogaert, P. van, Carrilho, I., Chabrol, B., Champion, M.P., Coldwell, J., Clayton, P., Donner, E., Evangeliou, A., Ebinger, F., Farrell, K., Forsyth, R.J., Goede, C.G. de, Gross, S., Grunewald, S., Holthausen, H., Jayawant, S., Lachlan, K., Laugel, V., Leppig, K., Lim, M.J., Mancini, G., Marina, A.D., Martorell, L., McMenamin, J., Meuwissen, M.E., Mundy, H., Nilsson, N.O., Panzer, A., Poll-The, B.T., Rauscher, C., Rouselle, C.M., Sandvig, I., Scheffner, T., Sheridan, E., Simpson, N., Sykora, P., Tomlinson, R., Trounce, J., Webb, D., Weschke, B., Scheffer, H., and Willemsen, M.A.A.P.

Abstract

1 maart 2010, Contains fulltext : 88466.pdf (publisher's version ) (Closed access), Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. T

Published
2010

45. Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder

Author

Leen, W.G. (Wilhelmina), Klepper, J. (Joerg), Verbeek, M.M. (Marcel), Leferink, M. (Maike), Hofste, T. (Tom), Engelen, B.G.M. (Baziel) van, Wevers, R.A. (Ron), Arthur, T. (Todd), Bahi-Buisson, N. (Nadia), Ballhausen, D. (Diana), Bekhof, J. (Jolita), Bogaert, P. (Patrick) van, Carrilho, I. (Inês), Chabrol, B. (Brigitte), Champion, M.P. (Michael), Coldwell, J. (James), Clayton, P. (Peter), Donner, E. (Elizabeth), Evangeliou, A. (Athanasios), Ebinger, F. (Friedrich), Farrell, K. (Kevin), Forsyth, R.J. (Rob), Goede, C.G.E.L. (Christian) de, Gross, S. (Stephanie), Grünewald, S. (Sonja), Holthausen, H. (Hans), Jayawant, S. (Sandeep), Lachlan, K. (Katherine), Laugel, V. (Vincent), Leppig, K. (Kathy), Lim, M.J. (Ming), Mancini, G.M.S. (Grazia), Marina, A.D., Martorell, L. (Loreto), McMenamin, J. (Joe), Meuwissen, M.E.C. (Marije), Mundy, H. (Helen), Nilsson, N.O. (Nils), Panzer, A. (Axel), Poll-The, B.T., Rauscher, C. (Christian), Rouselle, C.M.R. (Christophe), Sandvig, I. (Inger), Scheffner, T. (Thomas), Sheridan, E. (Eamonn), Simpson, N. (Neil), Sykora, P. (Parol), Tomlinson, R. (Richard), Trounce, J. (John), Webb, D.W.M. (David), Weschke, B. (Bernhard), Scheffer, H. (Hans), Willemsen, M.A. (Michél), Leen, W.G. (Wilhelmina), Klepper, J. (Joerg), Verbeek, M.M. (Marcel), Leferink, M. (Maike), Hofste, T. (Tom), Engelen, B.G.M. (Baziel) van, Wevers, R.A. (Ron), Arthur, T. (Todd), Bahi-Buisson, N. (Nadia), Ballhausen, D. (Diana), Bekhof, J. (Jolita), Bogaert, P. (Patrick) van, Carrilho, I. (Inês), Chabrol, B. (Brigitte), Champion, M.P. (Michael), Coldwell, J. (James), Clayton, P. (Peter), Donner, E. (Elizabeth), Evangeliou, A. (Athanasios), Ebinger, F. (Friedrich), Farrell, K. (Kevin), Forsyth, R.J. (Rob), Goede, C.G.E.L. (Christian) de, Gross, S. (Stephanie), Grünewald, S. (Sonja), Holthausen, H. (Hans), Jayawant, S. (Sandeep), Lachlan, K. (Katherine), Laugel, V. (Vincent), Leppig, K. (Kathy), Lim, M.J. (Ming), Mancini, G.M.S. (Grazia), Marina, A.D., Martorell, L. (Loreto), McMenamin, J. (Joe), Meuwissen, M.E.C. (Marije), Mundy, H. (Helen), Nilsson, N.O. (Nils), Panzer, A. (Axel), Poll-The, B.T., Rauscher, C. (Christian), Rouselle, C.M.R. (Christophe), Sandvig, I. (Inger), Scheffner, T. (Thomas), Sheridan, E. (Eamonn), Simpson, N. (Neil), Sykora, P. (Parol), Tomlinson, R. (Richard), Trounce, J. (John), Webb, D.W.M. (David), Weschke, B. (Bernhard), Scheffer, H. (Hans), and Willemsen, M.A. (Michél)

Abstract

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutation

Published
2010
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46. Autosomal recessive inheritance of GLUT1 deficiency syndrome.

Author

Klepper, J., Scheffer, H., Elsaid, M.F., Kamsteeg, E.J., Leferink, M., Ben-Omran, T., Klepper, J., Scheffer, H., Elsaid, M.F., Kamsteeg, E.J., Leferink, M., and Ben-Omran, T.

Abstract

1 oktober 2009, Item does not contain fulltext, GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Molecular analysis of the SLC2A1 gene identified a novel homozygous c1402C>T (p. Arg468Trp) mutation in exon 10 in the index patient and her asymptomatic younger sister. The mutation was absent in 120 control alleles of healthy individuals as well as in 400 alleles of other GLUT1DS patients. Arg468 represents a highly conserved, functionally important amino acid residue in the GLUT1 carboxy-terminus essential for substrate recognition and transport. Both unaffected parents were heterozygous for the mutation. A younger brother and two family members were healthy and carried the GLUT1 wild type. A ketogenic diet effectively controlled seizures in the index patient. We conclude that GLUT1DS can be transmitted as an autosomal recessive disease and provide new insights into genetic counselling for this treatable disorder.

Published
2009

49. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Author

Rice, G., Patrick, T., Parmar, R, Taylor, C.F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S.A., Bacino, C.A., Borroso, B., Baxter, P., Benko, W.S., Bergmann, C., Bertini, E., Biancheri, R., Blair, E., Blau, N., Bonthron, D.T., Briggs, T., Brueton, L., Brunner, H.G., Burke, C.J., Carr, I., Carvalho, D.R., Chandler, K.E., Christen, H.J., Corry, P.C., Cowan, F.M., Cox, H., D'Arrigo, S., Dean, J., Laet, C.E. de, Praeter, C.M. de, Dery, C., Ferrie, C.D., Flintoff, K., Frints, S.G., Garcia-Cazorla, A., Gener, B., Goizet, C., Goutieres, F., Green, A.J., Guet, A., Hamel, B.C.J., Hayward, B.E., Heiberg, A., Hennekam, R.C.M., Husson, M., Jackson, A.P., Jayatunga, R., Jiang, Y.H., Kant, S., Kao, A., King, M., Kingston, H., Klepper, J., Knaap, M.S. van der, Kornberg, A.J., Kotzot, D., Kratzer, W., Lacombe, D., Lagae, L., Landrieu, P.G., Lanzi, G., Leitch, A., Lim, M.J., Livingston, J.H., Lourenco, C.M., Lyall, E.G.H., Lynch, S.A., Lyons, M.J., Marom, D., McClure, J.P., McWilliam, R., Melancon, S.B., Mewasingh, L.D., Moutard, M.L., Nischal, K.K., Ostergaard, J.R., Prendiville, J., Rasmussen, M., Rogers, R.C., Roland, D., Rosser, E.M., Rostasy, K., Roubertie, A., Sanchis, A, Schiffmann, R., Scholl-Burgi, S., Seal, S., Shalev, S.A., Corcoles, C.S., Sinha, G.P., Soler, D., Spiegel, R., Stephenson, J.B., Tacke, U., Tan, T.Y., Willemsen, M.A.A.P., Rice, G., Patrick, T., Parmar, R, Taylor, C.F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S.A., Bacino, C.A., Borroso, B., Baxter, P., Benko, W.S., Bergmann, C., Bertini, E., Biancheri, R., Blair, E., Blau, N., Bonthron, D.T., Briggs, T., Brueton, L., Brunner, H.G., Burke, C.J., Carr, I., Carvalho, D.R., Chandler, K.E., Christen, H.J., Corry, P.C., Cowan, F.M., Cox, H., D'Arrigo, S., Dean, J., Laet, C.E. de, Praeter, C.M. de, Dery, C., Ferrie, C.D., Flintoff, K., Frints, S.G., Garcia-Cazorla, A., Gener, B., Goizet, C., Goutieres, F., Green, A.J., Guet, A., Hamel, B.C.J., Hayward, B.E., Heiberg, A., Hennekam, R.C.M., Husson, M., Jackson, A.P., Jayatunga, R., Jiang, Y.H., Kant, S., Kao, A., King, M., Kingston, H., Klepper, J., Knaap, M.S. van der, Kornberg, A.J., Kotzot, D., Kratzer, W., Lacombe, D., Lagae, L., Landrieu, P.G., Lanzi, G., Leitch, A., Lim, M.J., Livingston, J.H., Lourenco, C.M., Lyall, E.G.H., Lynch, S.A., Lyons, M.J., Marom, D., McClure, J.P., McWilliam, R., Melancon, S.B., Mewasingh, L.D., Moutard, M.L., Nischal, K.K., Ostergaard, J.R., Prendiville, J., Rasmussen, M., Rogers, R.C., Roland, D., Rosser, E.M., Rostasy, K., Roubertie, A., Sanchis, A, Schiffmann, R., Scholl-Burgi, S., Seal, S., Shalev, S.A., Corcoles, C.S., Sinha, G.P., Soler, D., Spiegel, R., Stephenson, J.B., Tacke, U., Tan, T.Y., and Willemsen, M.A.A.P.

Abstract

Contains fulltext : 52556.pdf (publisher's version ) (Closed access)

Published
2007

50. GLUT1 deficiency with delayed myelination responding to ketogenic diet.

Author

Klepper, J., Engelbrecht, V., Scheffer, H., Knaap, M.S. van der, Fiedler, A., Klepper, J., Engelbrecht, V., Scheffer, H., Knaap, M.S. van der, and Fiedler, A.

Abstract

Item does not contain fulltext, Monitoring effects of a ketogenic diet in GLUT1 deficiency syndrome without seizures is difficult. Neuroimaging is considered uninformative. We report the case of a boy with neurodevelopmental delay, severe ataxia, an E54X-mutation in the SLC2A1 gene (previously GLUT1), and neuroimaging abnormalities indicative of delayed myelination. Six months on a ketogenic diet resulted in an improved high subcortical white matter signal on T2-weighted images and a reduced N-acetylaspartate/creatine ratio. We conclude that delayed subcortical myelination may occur in GLUT1 deficiency syndrome as a nonspecific finding reflecting developmental delay. In patients without seizures, cranial magnetic resonance imaging and magnetic resonance spectroscopy may prove useful tools to monitor the response to a ketogenic diet.

Published
2007

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