7 results on '"Prehl I"'
Search Results
2. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia
- Author
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University of Helsinki, Clinicum, University of Helsinki, Research Programs Unit, University of Helsinki, Neuroscience Center, Schwarz, N., Hahn, A., Bast, T., Mueller, S., Loeffler, H., Maljevic, S., Gaily, E., Prehl, I., Biskup, S., Joensuu, T., Lehesjoki, A. -E., Neubauer, B. A., Lerche, H., Hedrich, U. B. S., University of Helsinki, Clinicum, University of Helsinki, Research Programs Unit, University of Helsinki, Neuroscience Center, Schwarz, N., Hahn, A., Bast, T., Mueller, S., Loeffler, H., Maljevic, S., Gaily, E., Prehl, I., Biskup, S., Joensuu, T., Lehesjoki, A. -E., Neubauer, B. A., Lerche, H., and Hedrich, U. B. S.
- Abstract
Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
- Published
- 2016
3. Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia
- Author
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Schwarz, N., primary, Hahn, A., additional, Bast, T., additional, Müller, S., additional, Löffler, H., additional, Maljevic, S., additional, Gaily, E., additional, Prehl, I., additional, Biskup, S., additional, Joensuu, T., additional, Lehesjoki, A.-E., additional, Neubauer, B. A., additional, Lerche, H., additional, and Hedrich, U. B. S., additional
- Published
- 2015
- Full Text
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4. Comprehensive NGS-Based Diagnostics in over 800 Patients with Epileptic Encephalopathy
- Author
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Prehl, I., primary, Reicherter, K., additional, Jüngling, J., additional, Hoffmann, J., additional, Döcker, M., additional, Riesch, E., additional, Puk, O., additional, Russ, A., additional, Fehr, S., additional, Stöbe, P., additional, Grau, T., additional, Singh, Y., additional, Battke, F., additional, Lemke, J., additional, Lerche, H., additional, Biskup, S., additional, and Hörtnagel, K., additional
- Published
- 2015
- Full Text
- View/download PDF
5. Comprehensive NGS-Based Diagnostics in More Than 1,000 Patients with Epileptic Disorders
- Author
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Jüngling, J., primary, Prehl, I, additional, Döcker, M., additional, Reicherter, K., additional, Hoffmann, J., additional, Grau, T., additional, Russ, A., additional, Fehr, S., additional, Singh, Y., additional, Stöbe, P., additional, Battke, F., additional, Lemke, J., additional, Lerche, H., additional, Biskup, S., additional, and Hörtnagel, K., additional
- Published
- 2014
- Full Text
- View/download PDF
6. KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect.
- Author
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Metz KA, Teng X, Coppens I, Lamb HM, Wagner BE, Rosenfeld JA, Chen X, Zhang Y, Kim HJ, Meadow ME, Wang TS, Haberlandt ED, Anderson GW, Leshinsky-Silver E, Bi W, Markello TC, Pratt M, Makhseed N, Garnica A, Danylchuk NR, Burrow TA, Jayakar P, McKnight D, Agadi S, Gbedawo H, Stanley C, Alber M, Prehl I, Peariso K, Ong MT, Mordekar SR, Parker MJ, Crooks D, Agrawal PB, Berry GT, Loddenkemper T, Yang Y, Maegawa GHB, Aouacheria A, Markle JG, Wohlschlegel JA, Hartman AL, and Hardwick JM
- Subjects
- Age of Onset, Child, Preschool, Female, Humans, Infant, Lysosomes pathology, Male, Mutation, Pedigree, Potassium Channels genetics, Saccharomyces cerevisiae Proteins genetics, Autophagy genetics, Lysosomes genetics, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Potassium Channels deficiency
- Abstract
Objective: Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function., Methods: Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples., Results: Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology., Interpretation: Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774-788., (© 2018 American Neurological Association.)
- Published
- 2018
- Full Text
- View/download PDF
7. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.
- Author
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Mitter D, Pringsheim M, Kaulisch M, Plümacher KS, Schröder S, Warthemann R, Abou Jamra R, Baethmann M, Bast T, Büttel HM, Cohen JS, Conover E, Courage C, Eger A, Fatemi A, Grebe TA, Hauser NS, Heinritz W, Helbig KL, Heruth M, Huhle D, Höft K, Karch S, Kluger G, Korenke GC, Lemke JR, Lutz RE, Patzer S, Prehl I, Hoertnagel K, Ramsey K, Rating T, Rieß A, Rohena L, Schimmel M, Westman R, Zech FM, Zoll B, Malzahn D, Zirn B, and Brockmann K
- Subjects
- Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Phenotype, Polymorphism, Single Nucleotide, Forkhead Transcription Factors genetics, Genetic Association Studies, Genetic Variation, Nerve Tissue Proteins genetics, Rett Syndrome diagnosis, Rett Syndrome genetics
- Abstract
PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.
- Published
- 2018
- Full Text
- View/download PDF
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