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3. Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1.

Author

Thalwitzer, K.M., Driedger, J.H., Xian, J., Saffari, A., Zacher, P., Bölsterli, B.K., Ruggiero, S.M., Sullivan, K.R., Datta, A.N., Kellinghaus, C., Althaus, J., Wiemer-Kruel, A., Baalen, A. van, Pampel, A., Alber, M., Braakman, H.M.H., Debus, O.M., Denecke, J., Hobbiebrunken, E., Breitweg, I., Diehl, D., Eitel, H., Gburek-Augustat, J., Preisel, M., Schlump, J.U., Laufs, M., Mammadova, D., Wurst, C., Prager, C., Löhr-Nilles, C., Martin, P., Garbade, S.F., Platzer, K., Benkel-Herrenbrueck, I., Egler, K., Fazeli, W., Lemke, J.R., Runkel, E., Klein, B., Linden, T., Schröter, J., Steffeck, H., Thies, B., Deimling, F. von, Illsinger, S., Borggraefe, I., Classen, G., Wieczorek, D., Ramantani, G., Koelker, S., Hoffmann, G.F., Ries, M., Helbig, I., Syrbe, S., Thalwitzer, K.M., Driedger, J.H., Xian, J., Saffari, A., Zacher, P., Bölsterli, B.K., Ruggiero, S.M., Sullivan, K.R., Datta, A.N., Kellinghaus, C., Althaus, J., Wiemer-Kruel, A., Baalen, A. van, Pampel, A., Alber, M., Braakman, H.M.H., Debus, O.M., Denecke, J., Hobbiebrunken, E., Breitweg, I., Diehl, D., Eitel, H., Gburek-Augustat, J., Preisel, M., Schlump, J.U., Laufs, M., Mammadova, D., Wurst, C., Prager, C., Löhr-Nilles, C., Martin, P., Garbade, S.F., Platzer, K., Benkel-Herrenbrueck, I., Egler, K., Fazeli, W., Lemke, J.R., Runkel, E., Klein, B., Linden, T., Schröter, J., Steffeck, H., Thies, B., Deimling, F. von, Illsinger, S., Borggraefe, I., Classen, G., Wieczorek, D., Ramantani, G., Koelker, S., Hoffmann, G.F., Ries, M., Helbig, I., and Syrbe, S.

Abstract

Contains fulltext : 296182.pdf (Publisher’s version ) (Open Access), BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with ep

Published
2023

4. Glutarazidurie Typ I

Author

Kölker, S., vom Dahl, Stephan, editor, Lammert, Frank, editor, Ullrich, Kurt, editor, and Wendel, Udo, editor

Published
2014
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6. EPG5-related Vici syndrome defines a new group of multisystem disorders due to defects in membrane trafficking and autophagy

Author

BYRNE, S, U-KING-IM, J M, BODI, I, DIONISI-VICI, C, AL-GAZALI, L, AL-OWAIN, M, BROWN, N J, EL-GARHI, R, GERSHONI-BARUCH, R, FILLOUX, F, KAMATH, A, KOELKER, S, MANCHESTER, D, MANZUR, A, MANDEL, H, MEIN, R, MIYATA, R, PILZ, D, ROGERS, C C, RYAN, M, SAID, E, SCHARA, U, STEIN, A, SEWRY, C A, TRAVAN, L, WIJBURG, F A, YAU, S, FANTO, M, GAUTEL, M, and JUNGBLUTH, H

Published
2015

9. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Author

Byrne, S, Jansen, L, U-King-Im, J-M, Siddiqui, A, Lidov, HGW, Bodi, I, Smith, L, Mein, R, Cullup, T, Dionisi-Vici, C, Al-Gazali, L, Al-Owain, M, Bruwer, Z, Al Thihli, K, El-Garhy, R, Flanigan, KM, Manickam, K, Zmuda, E, Banks, W, Gershoni-Baruch, R, Mandel, H, Dagan, E, Raas-Rothschild, A, Barash, H, Filloux, F, Creel, D, Harris, M, Hamosh, A, Koelker, S, Ebrahimi-Fakhari, D, Hoffmann, GF, Manchester, D, Boyer, PJ, Manzur, AY, Lourenco, CM, Pilz, DT, Kamath, A, Prabhakar, P, Rao, VK, Rogers, RC, Ryan, MM, Brown, NJ, McLean, CA, Said, E, Schara, U, Stein, A, Sewry, C, Travan, L, Wijburg, FA, Zenker, M, Mohammed, S, Fanto, M, Gautel, M, Jungbluth, H, Byrne, S, Jansen, L, U-King-Im, J-M, Siddiqui, A, Lidov, HGW, Bodi, I, Smith, L, Mein, R, Cullup, T, Dionisi-Vici, C, Al-Gazali, L, Al-Owain, M, Bruwer, Z, Al Thihli, K, El-Garhy, R, Flanigan, KM, Manickam, K, Zmuda, E, Banks, W, Gershoni-Baruch, R, Mandel, H, Dagan, E, Raas-Rothschild, A, Barash, H, Filloux, F, Creel, D, Harris, M, Hamosh, A, Koelker, S, Ebrahimi-Fakhari, D, Hoffmann, GF, Manchester, D, Boyer, PJ, Manzur, AY, Lourenco, CM, Pilz, DT, Kamath, A, Prabhakar, P, Rao, VK, Rogers, RC, Ryan, MM, Brown, NJ, McLean, CA, Said, E, Schara, U, Stein, A, Sewry, C, Travan, L, Wijburg, FA, Zenker, M, Mohammed, S, Fanto, M, Gautel, M, and Jungbluth, H

Abstract

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myeli

Published
2016

10. Diagnosis and management of glutaric aciduria type I - revised recommendations

Author

Koelker, S, Christensen, E, Leonard, JV, Greenberg, CR, Boneh, A, Burlina, AB, Burlina, AP, Dixon, M, Duran, M, Garcia Cazorla, A, Goodman, SI, Koeller, DM, Kyllerman, M, Muehlhausen, C, Mueler, E, Okun, JG, Wilcken, B, Hoffmann, GF, Burgard, P, Koelker, S, Christensen, E, Leonard, JV, Greenberg, CR, Boneh, A, Burlina, AB, Burlina, AP, Dixon, M, Duran, M, Garcia Cazorla, A, Goodman, SI, Koeller, DM, Kyllerman, M, Muehlhausen, C, Mueler, E, Okun, JG, Wilcken, B, Hoffmann, GF, and Burgard, P

Abstract

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.

Published
2011

13. Autorenverzeichnis

Author

Graul-Neumann, L., Horn, D., Hübner, C., Huppke, P., König, R., Majewski, F., Meinecke, P., Pankau, R., Rosenbaum, T., Schnabel, D., Schuelke, M., Spranger, J., Theile, U., Tinschert, S., Wilichowski, E., Wollmann, H.A., Zenker, M., Bartmann, P., Bassler, D., Bührer, C., Flemmer, A.W., Forster, J., Franz, A., Gonser, M., Gortner, L., Groneck, P., Hentschel, R., Herting, E., Hoyme, U.B., Hummler, H., Jandeck, C., Jorch, G., Korinthenberg, R., Liese, J., Maier, R.F., Martius, J., Merkenschlager, A., Poets, C.F., Pohlandt, F., Roll, C., Roos, R., Roth, B., Schneider, K.T.M., Speer, Ch., Stopfkuchen, H., Teichmann, A., Thomas, W., Vetter, K., von der Wense, A., Zielen, S., Assmann, B., Hoffmann, G.F., Kölker, S., Lindner, M., Mönch, E., Santer, R., Spiekerkötter, U., Zschocke, J., Bauer, K., Böhles, H.-J., Sinclair, Jack, Jauch, K.W., Jochum, F., Kauth, Thomas, Koletzko, B., Krawinkel, M., Krohn, K., Mihatsch, Walter, Moß, A., Mühlebach, S., Verwied-Jorky, S., Wabitsch, M., Zimmer, K.-P., Albers, N., L'Allemand, D., Binder, G., Brämswig, J.H., Dörr, H.G., Grüters-Kieslich, A., Hauffa, B.P., Heger, S., Hiort, O., Holl, R., Holterhus, P.M., Köhler, B., Korsch, Eckhard, Kratzsch, J., Krude, H., Mohnike, K., Neu, A., Pfäffle, R., Richter-Unruh, A., Riepe, F.G., Simic-Schleicher, G., Schönau, E., Sinnecker, G., Sippell, W., Willgerodt, H., Wölfle, J., Wudy, S.A., Aygören-Pürsün, E., Bas, M., Baumann, U., Biedermann, T., Blume, J., Buchholz, B., Dückers, G., Dunsch, D., Edelhäuser, M., Ehl, S., Feiterna-Sperling, C., Funk, M., Hartmann, K., Königs, C., Kreuz, W., Krudewig, J., Laws, H.-J., Linde, R., Martinez-Saguer, I., Maurer, M., Nadal, David, Niehues, T., Notheis, G., Ott, H., Schulze, I., Wedi, B., Wintergerst, U., Bürk, G., Foeldvari, I., Frosch, M., Girschick, H., Gerhold, K., Guellac, N., Haas, J.P., Häfner, R., Häuser, W., Heiligenhaus, A., Hospach, T., Horneff, G., Huppertz, H.-I., Illhardt, A., Jansson, A.F., Kallinich, T., Michels, H., Mönkemöller, K., Neudorf, U., Richter, M., Schnöbel-Müller, E., Thon, A., Zernikow, B., Behnisch, W., Cario, H., Dickerhoff, R., Eber, S., Führer, M., Kohne, E., Kulozik, A.E., Kunz, J., Muckenthaler, M., Eberl, W., Gaedicke, G., Muntean, W., Streif, W., Beck, J.D., Berthold, F., Bielack, S., Calaminus, G., Claviez, A., Creutzig, U., Dirksen, U., Dworzak, M., Göbel, U., Graf, N., Grießmeier, B., Henze, G., Hero, B., Jürgens, H., Kaiser, U., Klingebiel, T., Koscielniak, E., Kramm, C., Langer, T., Lawrenz, B., Lehrnbecher, T., Leiss, U., Mentzel, H.-J., Minkov, M., Peitz, J., Placzek, R., Reinhardt, D., Reiter, A., Rutkowski, S., Schmittenbecher, P., Schneider, D.T., Schreiber-Gollwitzer, B.M., Schrappe, M., Schroten, H., Schröder, H.M., Schuster, V., von Schweinitz, D., Sörensen, N., Tallen, G., Timmermann, B., Warmuth-Metz, M., Weckesser, M., Wessel, L., Wirth, T., Wolff, J.E.A., Wößmann, W., Zehnhoff-Dinnesen, A. am, Apitz, C., Arnold, R., Baumgartner, H., Bennink, G., Bertram, H., Blankenburg, M., Bönner, G., von der Breek, J., Breuer, J., Buchhorn, R., Bürsch, J., Cesnjevar, R., Dähnert, I., Deisenhofer, I., Diller, G.-P., Doenst, T., Dubowy, K.-O., Eicken, A., Ewert, P., Fink, C., Franke, J., Gebauer, R., Gorenflo, M., Grabitz, Haas, N.A., Häusler, H.-J., Hager, A., Hebebrand, J., Henschel, W., Hirt, M., Hoeper, M.M., Hörer, J., Hofbeck, M., Horke, A., Hraska, V., Hulpke-Wette, M., šek, J. Janou, Jux, C., Kändler, L., Kandolf, R., Kaulitz, R., Kienast, W., Klaassen, S., Knirsch, W., Kramer, H.H., Kreuder, J.G., Kriebel, T., Läer, S., Laser, K.T., Lê, T.-P., Lewin, M.A.G., Lindinger, A., Mackenzie, C.R., Mebus, S., van der Mei, S.H., Miera, O., Ovroutski, S., Paul, T., Photiadis, J., Pozza, R. Dalla, Rickers, C., Rosendahl, W., Ruschewski, W., Sachweh, J.S., Schäfers, H.-J., Scheewe, J., Schirmer, K.-R., Schlensak, C., Schlez, M., Schmaltz, A.A., Schmitt, K., Schneider, H., Schneider, M.B., Schranz, D., Schreiber, C., Schulze-Neick, I., Sieverding, L.F.J., Singer, H., Stieh, J., Sreeram, N., Thies, W.-R., Thul, J., Trauzeddel, R., Tschöpe, C., Uebing, A., Ulmer, H.E., Vogel, M., Vogt, M., Weil, J., Wessel, A., Will, J.C., Wühl, E., Ballmann, M., Barben, J., Bauer, C.P., Bend, J., Berdel, D., Blankenstein, O., Bremer, W., Brunsmann, F., Buchholz, T., Bufe, A., Derichs, N., Eber, E., Friedrichs, F., Frischer, T., Gembruch, U., Gieler, U., Götz, M., Haas, W.H., Hamelmann, E., Hammer, J., Hellermann, M., Jacobeit, J., Jung, A., Keim, V., Kitz, R., Kleinheinz, A., Koletzko, S., Kopp, I., Kopp, M., Lau, S., Lauener, R., Loff, Magdorf, K., Muche-Borowski, C., Müller, F.-M., Müsken, H., Naehrlich, L., Nicolai, T., Nüßlein, Th., Paditz, E., Palm, Frau B., Paul, K., Pfeiffer-Auler, S., Pfeiffer-Kascha, Frau D., Posselt, H.-G., Przybilla, B., Räwer, H.-C., Ratjen, F., Reese, I., Riedler, J., Rietschel, E., Rose, M., Rossi, R., Ruëff, F., Schäfer, T., Schmidt, S., Schmitt-Grohé, S., Schulze, J., Schuster, A., Seidenberg, J., Sitter, H., Smaczny, C., Spindler, T., Staab, D., Stern, M., Strassburg, C.P., Strömer, K., Stuhrmann-Spangenberg, M., Szczepanski, R., Tacke, A., Tiedgen, M., Urschitz, M.S., Vagts, J., Vogelberg, C., Wahn, U., Walker, A., Werfel, T., Wildhaber, J.H., Zach, M., Zimmermann, Th., Ballauff, A., Bannert, N., Böhn, I., Buderus, S., Bufler, P., Burdelski, M., Gerner, P., Grosse, K.-P., Henker, J., Henneke, P., Huber, W., Lang, T., Lentze, M.J., Melter, M., Müller, T., Pfister, E.-D., Rodeck, B., Schmidt-Choudhury, A., Skopnik, H., Wirth, S., Witt, H., Bachmann, H., Dötsch, J., Ehrich, J.H., Fuchshuber, Arno, Hoppe, B., Hoyer, P.F., Kemper, M.J., Michalk, D., Müller, D., Müller-Wiefel, D.E., Pohl, M., Tönshoff, B., Zerres, K., Bast, T., Baumeister, F.A.M., Berner, R., Bode, H., Christen, H.J., Collmann, H., Ebinger, F., Eiffert, H., Evers, S., Gold, R., Groß, S., Hanefeld, F., Heinen, F., Holthausen, H., Hübner, A., Jacobi, G., Karch, D., Kauschke, C., Kerkhoff, G., Kiese-Himmel, C., Klepper, J., Kohlschütter, A., Korn-Merker, E., Krägeloh-Mann, I., Kropp, P., Kurlemann, G., de Langen-Müller, U., Lenard, H.G., Michael, Th., von Moers, A., Felderhoff-Müser, U., Nau, R., Neubauer, B.A., Neuhäuser, G., Neumann, K., Noterdaeme, M., Pothmann, R., Rating, D., Reitter, B., Rickels, E., Ritz, A.M., Rosenkötter, H., Schmitt, B., Stephani, U., Stöver, B., Tibussek, D., Trollmann, R., Trommer, G., Tuxhorn, I., Wohlrab, G., Boergen, K.P., Brosch, S., Delb, W., Frank, R., Herrmann, B., von Hofacker, N., de Camargo, O. Kraus, Kries, R.v., Michaelis, R., Papousek, M., Schlack, H.G., Schriever, J., Skrodzki, K., Straßburg, H.-M., Thyen, U., Becker, K., Fels, T., Fitze, G., Grasshoff-Derr, S., Göbel, P., Illing, P., Lieber, J., Schmidt, A., Wessel, L.M., Berthold, L.D., Hahn, G., Hirsch, W., Moritz, J.D., Schröder, C., Schumacher, R., Stegmann, J., Steinborn, M., Tietze, R., Wunsch, R., Deppe, W., Hermann, T., Kiosz, D., Leidig, E., Mayer, H., Oepen, J., Stachow, R., Ahrens, F., Frey, G., Huttegger, I., Preil, M.-L., Schmittenbecher, P.P., Traupe, H., Eberhardt, O., Hasler, C., Krauspe, R., Meenen, N.M., Meurer, A., Rödl, R., Stücker, R., and Zilkens, C.

Published
2015
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16. Dynamic changes of striatal and extrastriatal MR abnormalities in glutaric aciduria type I

Author

Harting, I., Neumaier-Probst, E., Seitz, A., Maier, E. M., Assmann, B., Baric, I., Troncoso, M., Muehlhausen, C., Zschocke, J., Boy, N., Hoffmann, G. F., Sven F Garbade, Koelker, S., Zschocke, Johannes, and Hoffmann, Georg F.

Subjects
glutaric aciduria type I, MR changes
Abstract

Our results highlight that MR abnormalities of glutaric aciduria type I are more complex and dynamic than previously described. Some MR abnormalities are related to age and appear to manifest following a distinct time pattern. Pathophysiological and therapeutic concepts should not only focus on acute striatal injury and its prevention but should also integrate extrastriatal abnormalities.

17. Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1 .

Author

Thalwitzer KM, Driedger JH, Xian J, Saffari A, Zacher P, Bölsterli BK, Ruggiero SM, Sullivan KR, Datta AN, Kellinghaus C, Althaus J, Wiemer-Kruel A, van Baalen A, Pampel A, Alber M, Braakman HMH, Debus OM, Denecke J, Hobbiebrunken E, Breitweg I, Diehl D, Eitel H, Gburek-Augustat J, Preisel M, Schlump JU, Laufs M, Mammadova D, Wurst C, Prager C, Löhr-Nilles C, Martin P, Garbade SF, Platzer K, Benkel-Herrenbrueck I, Egler K, Fazeli W, Lemke JR, Runkel E, Klein B, Linden T, Schröter J, Steffeck H, Thies B, von Deimling F, Illsinger S, Borggraefe I, Classen G, Wieczorek D, Ramantani G, Koelker S, Hoffmann GF, Ries M, Helbig I, and Syrbe S

Subjects
Child, Child, Preschool, Humans, Cross-Sectional Studies, Munc18 Proteins genetics, Mutation, Retrospective Studies, Seizures, Spasm, Speech Disorders, Adult, Epilepsy, Spasms, Infantile genetics
Abstract

Background and Objectives: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control., Methods: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1 -related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups., Results: We collected data of 71 individuals with STXBP1 -related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores ( p = 0.02) than individuals with later epilepsy onset., Discussion: We expand the spectrum of STXBP1 -related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1 -related disorders., (© 2023 American Academy of Neurology.)

Published
2023
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18. The incidence of urea cycle disorders.

Author

Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, and Kirmse B

Subjects
Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors epidemiology, Argininosuccinate Synthase deficiency, Argininosuccinic Aciduria, Europe epidemiology, Female, Humans, Infant, Newborn, Male, United States epidemiology, Urea Cycle Disorders, Inborn epidemiology, Urea Cycle Disorders, Inborn pathology, Argininosuccinate Lyase genetics, Argininosuccinate Synthase genetics, Neonatal Screening, Urea Cycle Disorders, Inborn genetics
Abstract

A key question for urea cycle disorders is their incidence. In the United States two UCDs, argininosuccinic synthetase and lyase deficiency, are currently detected by newborn screening. We used newborn screening data on over 6million births and data from the large US and European longitudinal registries to determine how common these conditions are. The incidence for the United States is predicted to be 1 urea cycle disorder patient for every 35,000 births presenting about 113 new patients per year across all age groups., (© 2013.)

Published
2013
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19. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.

Author

Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F, Urry Z, Simpson MA, Yau S, Bertini E, McClelland V, Al-Owain M, Koelker S, Koerner C, Hoffmann GF, Wijburg FA, ten Hoedt AE, Rogers RC, Manchester D, Miyata R, Hayashi M, Said E, Soler D, Kroisel PM, Windpassinger C, Filloux FM, Al-Kaabi S, Hertecant J, Del Campo M, Buk S, Bodi I, Goebel HH, Sewry CA, Abbs S, Mohammed S, Josifova D, Gautel M, and Jungbluth H

Subjects
Autophagy-Related Proteins, Biopsy, Consanguinity, Exome, Family, Humans, Intracellular Signaling Peptides and Proteins, Lysosomal Membrane Proteins, Lysosomes metabolism, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Proteins metabolism, Vesicular Transport Proteins, Agenesis of Corpus Callosum genetics, Antigens, Neoplasm genetics, Autophagy genetics, Cataract genetics, Genes, Recessive, Mutation
Abstract

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.

Published
2013
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20. Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism.

Author

Sauer SW, Okun JG, Hoffmann GF, Koelker S, and Morath MA

Subjects
Animals, Carnitine chemistry, Carnitine metabolism, Cattle, Electron Transport Complex III antagonists & inhibitors, Electron Transport Complex III metabolism, Humans, Reye Syndrome metabolism, Acids chemistry, Acids metabolism, Acyl Coenzyme A chemistry, Acyl Coenzyme A metabolism, Carnitine analogs & derivatives, Energy Metabolism, Mitochondria metabolism
Abstract

Accumulation of organic acids as well as their CoA and carnitine esters in tissues and body fluids is a common finding in organic acidurias, beta-oxidation defects, Reye syndrome, and Jamaican vomiting sickness. Pathomechanistic approaches for these disorders have been often focused on the effect of accumulating organic acids on mitochondrial energy metabolism, whereas little is known about the pathophysiologic role of short- and medium-chain acyl-CoAs and acylcarnitines. Therefore, we investigated the impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on central components of mitochondrial energy metabolism, namely alpha-ketoglutarate dehydrogenase complex, pyruvate dehydrogenase complex, and single enzyme complexes I-V of respiratory chain. Although at varying degree, all acyl-CoAs had an inhibitory effect on pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity. Effect sizes were critically dependent on chain length and number of functional groups. Unexpectedly, octanoyl-CoA was shown to inhibit complex III. The inhibition was noncompetitive regarding reduced ubiquinone and uncompetitive regarding cytochrome c. In addition, octanoyl-CoA caused a blue shift in the gamma band of the absorption spectrum of reduced complex III. This effect may play a role in the pathogenesis of medium-chain and multiple acyl-CoA dehydrogenase deficiency, Reye syndrome, and Jamaican vomiting sickness which are inherited and acquired conditions of intracellular accumulation of octanoyl-CoA.

Published
2008
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21. Acrodermatitis acidemica secondary to malnutrition in glutaric aciduria type I.

Author

Niiyama S, Koelker S, Degen I, Hoffmann GF, Happle R, and Hoffmann R

Subjects
Acrodermatitis diet therapy, Amino Acid Metabolism, Inborn Errors diagnosis, Child Nutrition Disorders diet therapy, Child, Preschool, Dietary Proteins administration & dosage, Female, Humans, Selenium therapeutic use, Vitamins therapeutic use, Zinc therapeutic use, Acrodermatitis etiology, Amino Acid Metabolism, Inborn Errors complications, Child Nutrition Disorders etiology, Glutarates urine, Hydroxylysine metabolism, Lysine metabolism, Tryptophan metabolism
Abstract

We encountered a patient with glutaric aciduria type I (GA-I) associated with skin lesions resembling acrodermatitis enteropathica (AE). This child was being fed with a low-protein diet when the skin disorder developed. A deficiency in plasma levels of essential amino acids, particularly isoleucine, and zinc was confirmed. Supplementation of a high-caloric, protein-rich diet together with zinc, selenium and vitamins led to a prompt improvement of the skin lesions. We assume that in our patient the skin lesions were the result of malnutrition, rather than being primarily associated with the underlying metabolic disease. To our knowledge, no other report is so far available concerning GA-I complicated by skin eruptions.

Published
2001

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