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2. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author

Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., Senderek, J., Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., and Senderek, J.

Abstract

Item does not contain fulltext, Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Published
2021

3. Mutations in the Golgi protein GBF1 as a novel cause of distal hereditary motor neuropathy

Author

Ferreira, N. Mendoza, Karakaya, M., Cengiz, N., Beijer, D., Fuhrmann, N., Hoelker, I., Schrank, B., Brigatti, K., Gonzaga-Jauregui, C., Puffenberger, E., Wunderlich, G., De Jonghe, P., Deconinck, T., Strauss, K., Baets, J., Wirth, B., Ferreira, N. Mendoza, Karakaya, M., Cengiz, N., Beijer, D., Fuhrmann, N., Hoelker, I., Schrank, B., Brigatti, K., Gonzaga-Jauregui, C., Puffenberger, E., Wunderlich, G., De Jonghe, P., Deconinck, T., Strauss, K., Baets, J., and Wirth, B.

Published
2020

4. DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM

Author

Beijer, D, primary, Kim, HJ, additional, Guo, L, additional, O’Donovan, K, additional, Mademan, I, additional, Deconinck, T, additional, Van Schil, K, additional, Fare, CM, additional, Drake, LE, additional, Ford, AF, additional, Kochański, A, additional, Kabzińska, D, additional, Dubuisson, N, additional, Van den Bergh, P, additional, Voermans, NC, additional, Lemmers, RJLF, additional, van der Maarel, SM, additional, Bonner, D, additional, Sampson, JB, additional, Wheeler, MT, additional, Mehrabyan, A, additional, Palmer, S, additional, De Jonghe, P, additional, Shorter, J, additional, Taylor, JP, additional, and Baets, J, additional

Published
2021
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5. Diagnostic implications of genetic copy number variation in epilepsy plus

Author

Coppola, A., Cellini, E., Stamberger, H., Saarentaus, E., Cetica, V., Lal, D., Djemie, T., Bartnik-Glaska, M., Ceulemans, B., Helen Cross, J., Deconinck, T., Masi, S. D., Dorn, T., Guerrini, R., Hoffman-Zacharska, D., Kooy, F., Lagae, L., Lench, N., Lemke, J. R., Lucenteforte, E., Madia, F., Mefford, H. C., Morrogh, D., Nuernberg, P., Palotie, A., Schoonjans, A. -S., Striano, P., Szczepanik, E., Tostevin, A., Vermeesch, J. R., Van Esch, H., Van Paesschen, W., Waters, J. J., Weckhuysen, S., Zara, F., Jonghe, P. D., Sisodiya, S. M., Marini, C., Lehesjioki, A. -E., Craiu, D., Talvik, T., Caglayan, H., Serratosa, J., Sterbova, K., Moller, R. S., Hjalgrim, H., Lerche, H., Weber, Y., Helbig, I., von Spiczak, S., Barba, C., Bogaerts, A., Boni, A., Galizia, E. C., Chiari, S., Di Gacomo, G., Ferrari, A., Guarducci, S., Giglio, S., Holmgren, P., Leu, C., Melani, F., Novara, F., Pantaleo, M., Peeters, E., Pisano, T., Rosati, A., Sander, J., Schoeler, N., Stankiewicz, P., Striano, S., Suls, A., Traverso, M., Vandeweyer, G., Van Dijck, A., Zuffardi, O., Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Denni, Djémié, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Helen Cross, J., Deconinck, Tine, Masi, Salvatore De, Dorn, Thoma, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nichola, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J, Weckhuysen, Sarah, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Møller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina, Holmgren, Philip, Leu, Costin, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana, Rosati, Anna, Sander, Josemir, Schoeler, Natasha, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke, and Zuffardi, Orsetta

Subjects
epilepsy gene, Epilepsy, DNA Copy Number Variations, Genotype, Comorbidity, array CGH, copy number variants, epilepsy genes, SNP array, Phenotype, Neurology, mental disorders, Full‐length Original Research, Humans, copy number variant, Genetic Predisposition to Disease, Neurology (clinical)
Abstract

Summary Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Published
2019

7. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Author

Coarelli, G., Schule, R., Warrenburg, B.P.C. van de, Jonghe, P. De, Ewenczyk, C., Martinuzzi, A., Synofzik, M., Hamer, E.G., Baets, J., Anheim, M., Schols, L., Deconinck, T., Masrori, P., Fontaine, B., Klockgether, T., D'Angelo, M.G., Monin, M.L., Bleecker, J. De, Migeotte, I., Charles, P., Bassi, M.T., Klopstock, T., Mochel, F., Ollagnon-Roman, E., D'Hooghe, M., Kamm, C., Kurzwelly, D., Papin, M., Davoine, C.S., Banneau, G., Montcel, S. Tezenas du, Seilhean, D., Brice, A., Duyckaerts, C., Stevanin, G., Durr, A., Coarelli, G., Schule, R., Warrenburg, B.P.C. van de, Jonghe, P. De, Ewenczyk, C., Martinuzzi, A., Synofzik, M., Hamer, E.G., Baets, J., Anheim, M., Schols, L., Deconinck, T., Masrori, P., Fontaine, B., Klockgether, T., D'Angelo, M.G., Monin, M.L., Bleecker, J. De, Migeotte, I., Charles, P., Bassi, M.T., Klopstock, T., Mochel, F., Ollagnon-Roman, E., D'Hooghe, M., Kamm, C., Kurzwelly, D., Papin, M., Davoine, C.S., Banneau, G., Montcel, S. Tezenas du, Seilhean, D., Brice, A., Duyckaerts, C., Stevanin, G., and Durr, A.

Abstract

Item does not contain fulltext, OBJECTIVE: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 (SPG7). METHODS: We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. RESULTS: Patients with SPG7 had a mean age of 35.5 +/- 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 +/- 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 +/- 13.7 vs 32.8 +/- 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. CONCLUSIONS: This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.

Published
2019

8. GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia

Author

Eidhof, I.J.M., Baets, J., Kamsteeg, E.J., Deconinck, T., Ninhuijs, L. van, Martin, J.J., Schule, R., Zuchner, S., Jonghe, P. De, Schenck, A., Warrenburg, B.P.C. van de, Eidhof, I.J.M., Baets, J., Kamsteeg, E.J., Deconinck, T., Ninhuijs, L. van, Martin, J.J., Schule, R., Zuchner, S., Jonghe, P. De, Schenck, A., and Warrenburg, B.P.C. van de

Abstract

Contains fulltext : 196387.pdf (Publisher’s version ) (Open Access), Autosomal recessive cerebellar ataxias are a group of rare disorders that share progressive degeneration of the cerebellum and associated tracts as the main hallmark. Here, we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia. Neuropathological examination showed degenerative changes in the cerebellum, olive inferior, thalamus, substantia nigra, and pyramidal tracts, as well as tau pathology in the hippocampus and amygdala. To provide further evidence for a causative role of GDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit fly Drosophila melanogaster. Ubiquitous knockdown of Drosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight. Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation. Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress.

Published
2018

9. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013
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10. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline

Author

Hardies, K, Cai, Y, Jardel, C, Jansen, Ac, Cao, M, May, P, Djémié, T, Hachon Le Camus, C, Keymolen, K, Deconinck, T, Bhambhani, V, Long, C, Sajan, Sa, Helbig, Kl, Suls, A, Balling, R, Helbig, I, De Jonghe, P, Depienne, C, De Camilli, P, Weckhuysen, S, Afawi, Z, Baulac, S, Barisic, N, Caglayan, H, Craiu, D, De Kovel CG, Lopez, Rg, Guerrini, R, Hjalgrim, H, Lerche, H, Jahn, J, Klein, Km, Koeleman, Bc, Leguern, E, Lemke, J, Marini, C, Muhle, H, Rosenow, F, Serratosa, Jm, Štěrbová, Ks, Møller, Rs, Palotie, A, Striano, P, Weber, Y, Zara, F., Mental Health and Wellbeing research group, Public Health Sciences, Neurogenetics, Clinical sciences, AR Working Grp, and EuroEPINOMICS RES Consortium

Subjects
Male, 0301 basic medicine, Drug Resistant Epilepsy, medicine.medical_specialty, Phosphatase, Nerve Tissue Proteins, Biology, Compound heterozygosity, SYNJ1, Cohort Studies, Consanguinity, 03 medical and health sciences, Epilepsy, Arts and Humanities (miscellaneous), SYNJ1 dual phosphatase activity, Polyphosphoinositide Phosphatase, Internal medicine, early onset epilepsy, medicine, Journal Article, Humans, Missense mutation, Exome, Age of Onset, Child, neurodegenerative disorder, recessive disorder, Medicine (all), Neurology (clinical), Exome sequencing, Synaptic vesicle endocytosis, Genetics, Neurodegenerative Diseases, Heterozygote advantage, Original Articles, Neurodegenerative disorder, medicine.disease, Phosphoric Monoester Hydrolases, Pedigree, Phenotype, 030104 developmental biology, Endocrinology, Child, Preschool, Female, Human medicine
Abstract

SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs*6/p.Ser1122Thrfs*3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.

Published
2016
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11. Detection of TRIM32 variants associated with LGMD2H in a large cohort of patients with unexplained limb-girdle weakness

Author

Johnson, K., primary, Töpf, A., additional, Bertoli, M., additional, Phillips, L., additional, De Ridder, W., additional, Baets, J., additional, De Jonghe, P., additional, Deconinck, T., additional, Rakocevic Stojanovic, V., additional, Perić, S., additional, Durmus, H., additional, Jamal-Omidi, S., additional, Nafissi, S., additional, Łusakowska, A., additional, Mongini, T., additional, Lek, M., additional, Valkanas, E., additional, Mullen, T., additional, Xu, L., additional, MacArthur, D., additional, and Straub, V., additional

Published
2017
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12. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Author

Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nurnberg, P., Balling, R., Timmerman, V., Lerche, H., Maudsley, S., Helbig, I., Suls, A., Koeleman, B. P. C., De Jonghe, P., Afawi, Z., Baulac, S., Caglayan, H., Lopez, R. G., Guerrini, R., Hjalgrim, H., Jahn, J., Klein, K. M., Leguern, E., Lemke, J., Marini, C., Muhle, H., Rosenow, F., Serratosa, J., Sterbova, K., Moller, R. S., Striano, P., Zara, F., and EuroEPINOMICS RES Consortium

Subjects
Male, medicine.medical_specialty, Adolescent, anaplerosis, epileptic encephalopathy, NaCT, recessive disorder, SLC13A5, teeth hypoplasia, medicine.medical_treatment, Developmental Disabilities, Mutant, Genes, Recessive, Biology, medicine.disease_cause, Citric Acid, Epilepsy, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Child, Gene, Anodontia, Genetics, Mutation, Brain Diseases, Symporters, Citrate transport, medicine.disease, Hypoplasia, Pedigree, Endocrinology, HEK293 Cells, Epilepsy syndromes, Female, Neurology (clinical), Human medicine, Ketogenic diet
Abstract

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.

Published
2015
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13. Erratum: Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy (Epilepsia (2013) 54 (256-264) DOI:10.1111/epi.12517)

Author

Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., and Agan, K.

Published
2013

14. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

Author

Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., Warrenburg, B.P.C. van de, Zuchner, S., Gonzalez, M.A., Schule, R., Synofzik, M., Aa, N. van der, Jonghe, P. De, Verbeek, D.S., Baets, J., Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., Warrenburg, B.P.C. van de, Zuchner, S., Gonzalez, M.A., Schule, R., Synofzik, M., Aa, N. van der, Jonghe, P. De, Verbeek, D.S., and Baets, J.

Abstract

Contains fulltext : 155287.pdf (publisher's version ) (Open Access), BACKGROUND: Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum. METHODS: Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed. RESULTS: A de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. CONCLUSIONS: We identified a de novo KCND3 mutation causing the most marked change in Kv4.3's channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.

Published
2015

15. De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy

Author

Mademan, I. Deconinck, T. Dinopoulos, A. Voit, T. Schara, U. Devriendt, K. Meijers, B. Lerut, E. Jonghe, P.D. Baets, J.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Objective: Identification of mutations in the inverted formin-2 (INF2) gene in patients with Charcot-Marie-Tooth (CMT) disease combined with focal segmental glomerulosclerosis (FSGS) in order to expand the genetic and phenotypic spectrum. Methods: We sequenced INF2 in 5 patients with CMT disease and FSGS. Mutations were subsequently screened in family members of the index patient and 264 control individuals. Results: In 3 patients, we detected 2 novel de novo INF2mutations (p.Leu77Arg and p.Leu69-Ser72-del) and a third, most likely de novo mutation (p.Gly114Asp). One of our patients displayed intellectual disability, a phenotypic characteristic not previously associated with INF2. The same patient also showed a more pronounced sensorineural hearing loss than described before. Conclusions: In exon 2 of INF2, we identified 3 novel mutations that likely affect the protein structure and function. Our findings expand the genetic spectrum of INF2-associated disorders and broaden the associated phenotype with the co-occurrence of intellectual disability and more severe hearing loss than previously reported. De novo INF2 mutations may be more common in patients with CMT disease and FSGS in comparison to FSGS alone. Furthermore, renal dysfunction is more severe and starts earlier in life when associated with CMT disease. Our study confirms that INF2 mutations are a major cause of disease in patients with CMT disease and early signs of nephropathy. Diagnostic screening of INF2 is strongly recommended in isolated patients presenting with CMT disease and FSGS. © 2013 American Academy of Neurology.

Published
2013

16. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012
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17. Reticulon mutations in hereditary spastic paraplegia

Author

Rebelo, Ap, Montenegro, G, Connell, J, Allison, R, Schüle, R, Deconinck, T, Huang, J, Pericak Vance, M, Jonghe, P, Schöls, L, Orlacchio, Antonio, Reid, E, Züchner, S, Babalini, C, and Bernardi, G.

Published
2011

18. KCNQ2 MUTATIONS ARE A CAUSE OF NEONATAL EPILEPTIC ENCEPHALOPATHIES WITH A RECOGNIZABLE CLINICAL AND RADIOLOGICAL PHENOTYPE

Author

Weckhuysen, S., Mandelstam, S., Suls, A., Audenaert, D., Deconinck, T., Claes, L., Deprez, L., Smets, K., Hristova, D., Yordanova, I., Jordanova, A., Ceulemans, B., Anna Jansen, Hasaerts, D., Roelens, F., Lagae, L., Yendle, S., Stanley, T., Heron, S., Mulley, J., Berkovic, S., Scheffer, I., Jonghe, P., Philip A. Schwartzkroin, Phd, Simon D. Shorvon, Ma, Md, Frcp, Public Health Care, and Neurogenetics

Subjects
KCNQ2 mutations, Screening, Neonatal epileptic encephalopaties
Abstract

Purpose: KCNQ2 and KCNQ3 mutations are known to be responsible for Benign Familial Neonatal Seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether patients present with a particular phenotype. Method: We analyzed 80 patients with unexplained neonatal or earlyinfantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. Results: We found seven different heterozygous KCNQ2 mutations in eight patients (8/80; 10%); six mutations were proven de novo. One parent with a milder phenotype was mosaic for the mutation. The eight patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had severe-profound intellectual disability with motor impairment. EEG at onset showed a burst suppression pattern or multifocal epileptic activity. Early MRI of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. Conclusion: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a very distinct electro-clinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.

Published
2011

19. Genetic spectrum of hereditary neuropathies with onset in the first year of life

Author

Baets, J. Deconinck, T. De Vriendt, E. Zimoń, M. Yperzeele, L. Van Hoorenbeeck, K. Peeters, K. Spiegel, R. Parman, Y. Ceulemans, B. Van Bogaert, P. Pou-Serradell, A. Bernert, G. Dinopoulos, A. Auer-Grumbach, M. Sallinen, S.-L. Fabrizi, G.M. Pauly, F. Van Den Bergh, P. Bilir, B. Battaloglu, E. Madrid, R.E. Kabzińska, D. Kochanski, A. Topaloglu, H. Miller, G. Jordanova, A. Timmerman, V. De Jonghe, P.

Abstract

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. © 2011 The Author.

Published
2011

21. Epilepsy and part of the phenotype associated with ATP1A2 mutations

Author

Deprez L., Weckhuysen S., Peeters K., Deconinck T., Claeys KG., Claes LR., Suls A., Van Dyck T., André Luis Fernandes Palmini, Matthijs G., Van Paesschen W., and De Jonghe P.

Abstract

Submitted by Biblioteca Suporte PUCRS (biblioteca.suporte@pucrs.br) on 2022-05-18T20:20:57Z No. of bitstreams: 2 Epilepsy_and_part_of_the_phenotype_associated_with_ATP1A2_mutations.pdf: 240970 bytes, checksum: 3894edac0d33d36d4715d53099805a12 (MD5) Epilepsy_and_part_of_the_phenotype_associated_with_ATP1A2_mutations.pdf: 240970 bytes, checksum: 3894edac0d33d36d4715d53099805a12 (MD5) Made available in DSpace on 2022-05-18T20:20:57Z (GMT). No. of bitstreams: 2 Epilepsy_and_part_of_the_phenotype_associated_with_ATP1A2_mutations.pdf: 240970 bytes, checksum: 3894edac0d33d36d4715d53099805a12 (MD5) Epilepsy_and_part_of_the_phenotype_associated_with_ATP1A2_mutations.pdf: 240970 bytes, checksum: 3894edac0d33d36d4715d53099805a12 (MD5) Previous issue date: 2008

Published
2008

24. Mutations in SACS cause atypical and late-onset forms of ARSACS

Author

UCL - Cliniques universitaires Saint-Luc, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baets, J., Van den Bergh, Peter, Deconinck, T., Smets, K., Goossens, D., Dahan, Karin, Schmedding, E., Santens, P., Rasic, V. Milic, Van Damme, Patricia, Robberecht, Wim, De Meirleir, L., Michielsens, B., Del-Favero, J., Jordanova, A., De Jonghe, P., UCL - Cliniques universitaires Saint-Luc, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baets, J., Van den Bergh, Peter, Deconinck, T., Smets, K., Goossens, D., Dahan, Karin, Schmedding, E., Santens, P., Rasic, V. Milic, Van Damme, Patricia, Robberecht, Wim, De Meirleir, L., Michielsens, B., Del-Favero, J., Jordanova, A., and De Jonghe, P.

Abstract

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a complex neurodegenerative disorder caused by mutations in SACS. The phenotype consists of a childhood-onset triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs. Objective: To provide more insight into the prevalence of SACS mutations and the variability of the associated phenotype. Methods: Mutation screening of SACS by direct sequencing and multiplex amplicon quantification for detection of intragenic copy number variations in a cohort of 85 index patients with phenotypes suggestive for ARSACS. Additional short tandem repeat (STR) marker analysis was performed for haplotype sharing. Results: In 11 families, 18 new SACS mutations were found (12.9% of total cohort). Five patients displayed onset ages in adulthood, a feature not known to be associated with ARSACS. The remaining index patients displayed a classic early onset phenotype. Initial phenotypic presentation was atypical in several patients, obscuring the clinical diagnosis. A founder mutation in SACS was identified in 3 Belgian families. In one isolated patient, an intragenic SACS deletion of exons 3-5 was detected. Partial SACS deletions were not previously described. Conclusions: In this study, we enlarge the ARSACS phenotype and the underlying genetic spectrum of SACS mutations. Patients with ARSACS are more common than previously known and risk underdiagnosis due to late onset age and unusual presentation. Neurology (R) 2010; 75: 1181-1188

Published
2010

25. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.

Author

Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.N., Zhu, H., Kremer, H.P.H., Frints, S.G., Zelst-Stams, W.A.G. van, Byrne, P., Otto, S., Nygren, A.O., Baets, J., Smets, K., Ceulemans, B., Dan, B., Nagan, N., Kassubek, J., Klimpe, S., Klopstock, T., Stolze, H., Smeets, H.J.M., Schrander-Stumpel, C.T.R.M., Hutchinson, M., Warrenburg, B.P.C. van de, Braastad, C., Deufel, T., Pericak-Vance, M., Schols, L., Jonghe, P. de, Zuchner, S., Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.N., Zhu, H., Kremer, H.P.H., Frints, S.G., Zelst-Stams, W.A.G. van, Byrne, P., Otto, S., Nygren, A.O., Baets, J., Smets, K., Ceulemans, B., Dan, B., Nagan, N., Kassubek, J., Klimpe, S., Klopstock, T., Stolze, H., Smeets, H.J.M., Schrander-Stumpel, C.T.R.M., Hutchinson, M., Warrenburg, B.P.C. van de, Braastad, C., Deufel, T., Pericak-Vance, M., Schols, L., Jonghe, P. de, and Zuchner, S.

Abstract

Contains fulltext : 71291.pdf (publisher's version ) (Closed access), Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

Published
2008

26. P25 – 2072 Diagnostic clues and difficulties in Dravet syndrome starting from 34 Dravet patients analysis within Romanian Research Group for Rare Genetic Epilepsies

Author

Craiu, D, primary, Barca, D, additional, Burloiu, C, additional, Butoianu, N, additional, Deconinck, T, additional, Gos, M, additional, Hoffman-Zacharska, D, additional, Iancu, D, additional, Minciu, I, additional, Motoescu, C, additional, Sandu, C, additional, Tarta-Arsene, O, additional, Weckhuysen, S, additional, and Iliescu, C, additional

Published
2013
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28. Gene Identification in Axonopathies by Applying Massive Whole Exome Sequencing (S27.005)

Author

Zuchner, S., primary, Gonzalez, M., additional, Schuele, R., additional, Siskind, C., additional, Powell, E., additional, Montenegro, G., additional, Shengru, G., additional, Blanton, S., additional, Beecham, G., additional, Speziani, F., additional, Deconinck, T., additional, Young, P., additional, Kennerson, M., additional, Nicholson, G., additional, De Jonghe, P., additional, Vance, J., additional, Schoels, L., additional, Menezes, M., additional, Herrmann, D., additional, Scherer, S., additional, Reilly, M., additional, Shy, M., additional, and Zuchner, S., additional

Published
2012
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29. Genetic spectrum of hereditary neuropathies with onset in the first year of life

Author

Baets, J., primary, Deconinck, T., additional, De Vriendt, E., additional, Zimon, M., additional, Yperzeele, L., additional, Van Hoorenbeeck, K., additional, Peeters, K., additional, Spiegel, R., additional, Parman, Y., additional, Ceulemans, B., additional, Van Bogaert, P., additional, Pou-Serradell, A., additional, Bernert, G., additional, Dinopoulos, A., additional, Auer-Grumbach, M., additional, Sallinen, S.-L., additional, Fabrizi, G. M., additional, Pauly, F., additional, Van den Bergh, P., additional, Bilir, B., additional, Battaloglu, E., additional, Madrid, R. E., additional, Kabzinska, D., additional, Kochanski, A., additional, Topaloglu, H., additional, Miller, G., additional, Jordanova, A., additional, Timmerman, V., additional, and De Jonghe, P., additional

Published
2011
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31. Mutations in SACS cause atypical and late-onset forms of ARSACS

Author

Baets, J., primary, Deconinck, T., additional, Smets, K., additional, Goossens, D., additional, Van den Bergh, P., additional, Dahan, K., additional, Schmedding, E., additional, Santens, P., additional, Rasic, V. Milic, additional, Van Damme, P., additional, Robberecht, W., additional, De Meirleir, L., additional, Michielsens, B., additional, Del-Favero, J., additional, Jordanova, A., additional, and De Jonghe, P., additional

Published
2010
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33. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Author

Dierick, I., primary, Baets, J., additional, Irobi, J., additional, Jacobs, A., additional, De Vriendt, E., additional, Deconinck, T., additional, Merlini, L., additional, Van den Bergh, P., additional, Rasic, V. M., additional, Robberecht, W., additional, Fischer, D., additional, Morales, R. J., additional, Mitrovic, Z., additional, Seeman, P., additional, Mazanec, R., additional, Kochanski, A., additional, Jordanova, A., additional, Auer-Grumbach, M., additional, Helderman-van den Enden, A. T. J. M., additional, Wokke, J. H. J., additional, Nelis, E., additional, De Jonghe, P., additional, and Timmerman, V., additional

Published
2007
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34. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.

Author

Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, Merlini L, Van den Bergh P, Rasic VM, Robberecht W, Fischer D, Morales RJ, Mitrovic Z, Seeman P, Mazanec R, Kochanski A, Jordanova A, Auer-Grumbach M, Helderman-van den Enden AT, and Wokke JH

Abstract

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders. [ABSTRACT FROM AUTHOR]

Published
2008
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35. Mutations in SACScause atypical and late-onset forms of ARSACS

Author

Baets, J., Deconinck, T., Smets, K., Goossens, D., Van den Bergh, P., Dahan, K., Schmedding, E., Santens, P., Rasic, V. Milic, Van Damme, P., Robberecht, W., De Meirleir, L., Michielsens, B., Del-Favero, J., Jordanova, A., and De Jonghe, P.

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a complex neurodegenerative disorder caused by mutations in SACS. The phenotype consists of a childhood-onset triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs.

Published
2010
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36. Further evidence that mutations in FGD4/frabincause Charcot-Marie-Tooth disease type 4H

Author

Fabrizi, G M., Taioli, F, Cavallaro, T, Ferrari, S, Bertolasi, L, Casarotto, M, Rizzuto, N, Deconinck, T, Timmerman, V, and De Jonghe, P

Abstract

Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were reported in five families.

Published
2009
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38. Loss of paraplegin drives spasticity rather than ataxia in SPG7: A European cohort analysis of 238 patients

Author

Coarelli, G., Schule, R., Vande Warrenburg, B., Jonghe, P., Ewenczyk, C., Martinuzzi, A., Synofzik, M., Hamer, E., Baets, J., Anheim, M., Schols, L., Deconinck, T., Fontaine, B., Klockgether, T., D Angelo, M. G., Monin, M. L., Charles, P., Bassi, M. T., Klopstock, T., Ollagnon-Roman, E., Kamm, C., Papin, M., Davoine, C. S., Banneau, G., Montcel, S. Tezenasdu, Seilhean, D., Alexis Brice, Duyckaerts, C., Stevanin, G., and Durr, A.

41. Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation

Author

Cyril Goizet, Dagmar Nolte, Jonathan Baets, Tine Deconinck, Camilo Toro, Susanna Tulli, Valentina Baderna, Davide Mazza, Franca Codazzi, Peter DeJonghe, Alessandro Ambrosi, Giorgio Casari, Francesca Maltecca, Andrea Del Bondio, Tyler Mark Pierson, Paola Mandich, Tulli, S., Del Bondio, A., Baderna, V., Mazza, D., Codazzi, F., Pierson, T. M., Ambrosi, A., Nolte, D., Goizet, C., Toro, C., Baets, J., Deconinck, T., Dejonghe, P., Mandich, P., Casari, G., and Maltecca, F.

Subjects
0301 basic medicine, Haploinsufficiency, Mitochondrion, Medical and Health Sciences, Mice, 0302 clinical medicine, ATP-Dependent Proteases, Models, cell biology, molecular genetic, 2.1 Biological and endogenous factors, Missense mutation, genetics, Mitochondrial calcium uptake, Neurogenetics, Genetics (clinical), Genetics & Heredity, Mice, Knockout, Metalloendopeptidases, Biological Sciences, Mitochondria, Cell biology, mitochondria, mitochondrial fusion, Spinocerebellar ataxia, movement disorders (other than parkinsons), Protein Binding, Transcriptional Activation, Knockout, Physiological, Biology, Stress, Models, Biological, Frameshift mutation, molecular genetics, 03 medical and health sciences, Rare Diseases, Protein Domains, Stress, Physiological, Genetics, medicine, Animals, Humans, Genetic Variation, Fibroblasts, Biological, medicine.disease, HEK293 Cells, 030104 developmental biology, Proteostasis, Proteolysis, movement disorders, ATPases Associated with Diverse Cellular Activities, Calcium, Human medicine, Protein Multimerization, genetic, 030217 neurology & neurosurgery
Abstract

BackgroundSpinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.MethodsWe derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/− HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2−/− murine fibroblasts.ResultsWe found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.ConclusionOur data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/− cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.

Published
2019

42. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, 610 Medicine & health, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Temporal lobe, Epilepsy, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Copy-number variation, Child, Molecular Biology, Genetics (clinical), Chromosomes, Human, Pair 15, Infant, General Medicine, Odds ratio, medicine.disease, Epilepsy, Rolandic, Rolandic epilepsy, Exact test, Chromosomes, Human, Pair 1, Child, Preschool, Female, Chromosomes, Human, Pair 16
Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Published
2014
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43. Vitamin D 3 deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis.

Author

Ehnert S, Hauser S, Hengel H, Höflinger P, Schüle R, Lindig T, Baets J, Deconinck T, de Jonghe P, Histing T, Nüssler AK, Schöls L, and Rattay TW

Subjects
Humans, Mutation, Paraplegia, Homeostasis, Vitamin D therapeutic use, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary metabolism, Oxysterols
Abstract

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D 3 metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D 3 substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5., (© 2024. The Author(s).)

Published
2024
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44. Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1 -associated diseases.

Author

Beijer D, Marte S, Li JC, De Ridder W, Chen JZ, Tadenev ALD, Miers KE, Deconinck T, Macdonell R, Marques W Jr, De Jonghe P, Pratt SL, Meyer-Schuman R, Züchner S, Antonellis A, Burgess RW, and Baets J

Abstract

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase ( NARS1 ) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease., Competing Interests: The authors report no competing interests., (© Crown copyright 2024.)

Published
2024
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45. A homozygous loss of function variant in POPDC3: From invalidating exercise intolerance to a limb-girdle muscular dystrophy phenotype.

Author

De Ridder W, de Vries G, Van Schil K, Deconinck T, Mouly V, Straub V, and Baets J

Subjects
Humans, Myalgia pathology, Muscle, Skeletal pathology, Phenotype, Mutation, Muscle Proteins genetics, Cell Adhesion Molecules genetics, Muscular Dystrophies, Limb-Girdle pathology, Muscular Diseases pathology
Abstract

Recessive pathogenic variants in POPDC3 have recently been associated with the rare limb-girdle muscular dystrophy (LGMD) subtype LGMDR26. We studied three siblings and a distantly related individual with a skeletal muscle disorder, harboring the c.486-6T>A splice site variant in POPDC3 in homozygosity. Immunohistochemistry, western blot, and mRNA experiments on patients' skeletal muscle tissue as well as on patients' myoblasts were performed to study the pathogenicity of the predicted loss of function mechanism of the variant. Patients mainly presented with invalidating myalgia and exercise intolerance and limited to no segmentary muscle weakness. CK levels were markedly elevated in all patients. A loss of function mechanism at the RNA level was shown (r.485&#95;486insauag, p.Ile163*). Muscle biopsies performed in three out of four patients showed non-specific myopathic features with a marked type 2 fiber predominance and the presence of a large number of severely atrophic fibers with pyknotic nuclear clumps. We show that skeletal muscle symptoms in LGMDR26 may range from an overt late juvenile to young adult-onset limb-girdle muscular dystrophy phenotype to severe exercise intolerance and myalgia, with consistently highly elevated CK levels. We further prove a clear LOF mechanism of POPDC3 in this rare disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Published
2023
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46. Distinct features in adult polyglucosan body disease: a case series.

Author

De Winter J, Cypers G, Jacobs E, Bossche SV, Deconinck T, De Ridder W, Dekeyzer S, and Baets J

Subjects
Middle Aged, Adult, Humans, Central Nervous System, Muscle, Skeletal pathology, Glycogen Storage Disease diagnosis, Glycogen Storage Disease genetics, Glycogen Storage Disease pathology, Nervous System Diseases diagnostic imaging, Nervous System Diseases genetics
Abstract

Adult polyglucosan body disease (APBD) is caused by bi-allelic pathogenic variants in GBE1 and typically shows middle age onset urinary symptoms followed by progressive gait disturbances and possibly cognitive decline. Here we present a Belgian cohort of four patients from three families showing both classical and atypical signs of APBD. By clinical phenotyping, detailed neuroimaging of both central nervous system and skeletal muscle, genetic and biochemical testing, we confront our findings with the classical presentation of adult polyglucosan body disease and emphasize the importance of a multidisciplinary approach when diagnosing these patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Published
2023
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47. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

Author

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S, Schüle R, Stevanin G, Synofzik M, Basak AN, and Baets J

Subjects
Humans, Mutation genetics, Paraplegia genetics, Pedigree, Phenotype, Spectrin genetics, Carrier Proteins genetics, Cerebellar Ataxia genetics, Intellectual Disability genetics, Microfilament Proteins genetics, Spastic Paraplegia, Hereditary genetics
Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy., Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia., Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants., Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat., Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Published
2022
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48. Erratum to: Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Author

Wiessner M, Maroofian R, Ni MY, Pedroni A, Müller JS, Stucka R, Beetz C, Efthymiou S, Santorelli FM, Alfares AA, Zhu C, Uhrova Meszarosova A, Alehabib E, Bakhtiari S, Janecke AR, Otero MG, Chen JYH, Peterson JT, Strom TM, De Jonghe P, Deconinck T, De Ridder W, De Winter J, Pasquariello R, Ricca I, Alfadhel M, van de Warrenburg BP, Portier R, Bergmann C, Ghasemi Firouzabadi S, Jin SC, Bilguvar K, Hamed S, Abdelhameed M, Haridy NA, Maqbool S, Rahman F, Anwar N, Carmichael J, Pagnamenta AT, Wood NW, Tran Mau-Them F, Haack T, Di Rocco M, Ceccherini I, Iacomino M, Zara F, Salpietro V, Scala M, Rusmini M, Xu Y, Wang Y, Suzuki Y, Koh K, Nan H, Ishiura H, Tsuji S, Lambert L, Schmitt E, Lacaze E, Küpper H, Dredge D, Skraban C, Goldstein A, Willis MJH, Grand K, Graham JM, Lewis RA, Millan F, Duman Ö, Olgac Dundar N, Uyanik G, Schöls L, Nürnberg P, Nürnberg G, Català-Bordes A, Seeman P, Kuchar M, Darvish H, Rebelo A, Bouçanova F, Medard JJ, Chrast R, Auer-Grumbach M, Alkuraya FS, Shamseldin H, Al Tala S, Rezazadeh Varaghchi J, Najafi M, Deschner S, Gläser D, Hüttel W, Kruer MC, Kamsteeg EJ, Takiyama Y, Züchner S, Baets J, Synofzik M, Schüle R, Horvath R, Houlden H, Bartesaghi L, Lee HJ, Ampatzis K, Pierson TM, and Senderek J

Published
2021
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49. Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response.

Author

Beijer D, Agnew T, Rack JGM, Prokhorova E, Deconinck T, Ceulemans B, Peric S, Milic Rasic V, De Jonghe P, Ahel I, and Baets J

Subjects
ADP-Ribosylation physiology, Adolescent, Adult, Alleles, DNA Damage physiology, DNA Repair genetics, Family, Female, Glycoside Hydrolases metabolism, Humans, Male, Mutation genetics, Pedigree, Poly (ADP-Ribose) Polymerase-1, Poly Adenosine Diphosphate Ribose metabolism, ADP-Ribosylation genetics, Glycoside Hydrolases genetics, Neuralgia genetics
Abstract

ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Recessive ADPRHL2/ ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control., (© 2021 Beijer et al.)

Published
2021
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50. Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation.

Author

Beijer D, Kim HJ, Guo L, O'Donovan K, Mademan I, Deconinck T, Van Schil K, Fare CM, Drake LE, Ford AF, Kochański A, Kabzińska D, Dubuisson N, Van den Bergh P, Voermans NC, Lemmers RJ, van der Maarel SM, Bonner D, Sampson JB, Wheeler MT, Mehrabyan A, Palmer S, De Jonghe P, Shorter J, Taylor JP, and Baets J

Subjects
Adolescent, Adult, Child, DNA Mutational Analysis, Female, Genetic Association Studies, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Heterozygote, Humans, Male, Middle Aged, Mutation, Pedigree, Stress Granules metabolism, Exome Sequencing, Young Adult, Amyotrophic Lateral Sclerosis genetics, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Muscular Atrophy, Spinal genetics
Abstract

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.

Published
2021
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