5 results on '"Hedrich, Ulrike B. S."'
Search Results
2. KCNC2 variants of uncertain significance are also associated to various forms of epilepsy.
- Author
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Seiffert, Simone, Pendziwiat, Manuela, Hedrich, Ulrike B. S., Helbig, Ingo, Weber, Yvonne, and Schwarz, Niklas
- Subjects
EPILEPSY ,POTASSIUM channels ,XENOPUS laevis ,VALPROIC acid ,CHANNEL coding - Abstract
Recently, de novo variants in KCNC2, coding for the potassium channel subunit KV3.2, have been described as causative for various forms of epilepsy including genetic generalized epilepsy (GGE) and developmental and epileptic encephalopathy (DEE). Here, we report the functional characteristics of three additional KCNC2 variants of uncertain significance and one variant classified as pathogenic. Electrophysiological studies were performed in Xenopus laevis oocytes. The data presented here support that KCNC2 variants with uncertain significance may also be causative for various forms of epilepsy, as they show changes in the current amplitude and activation and deactivation kinetics of the channel, depending on the variant. In addition, we investigated the effect of valproic acid on KV3.2, as several patients carrying pathogenic variants in the KCNC2 gene achieved significant seizure reduction or seizure freedom with this drug. However, in our electrophysiological investigations, no change on the behavior of KV3.2 channels could be observed, suggesting that the therapeutic effect of VPA may be explained by other mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.
- Author
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Hedrich, Ulrike B. S., Lauxmann, Stephan, Wolff, Markus, Synofzik, Matthis, Bast, Thomas, Binelli, Adrian, Serratosa, José M., Martínez-Ulloa, Pedro, Allen, Nicholas M., King, Mary D., Gorman, Kathleen M., Zeev, Bruria Ben, Tzadok, Michal, Wong-Kisiel, Lily, Marjanovic, Dragan, Rubboli, Guido, Sisodiya, Sanjay M., Lutz, Florian, Ashraf, Harshad Pannikkaveettil, and Torge, Kirsten
- Subjects
POTASSIUM channels ,POTASSIUM antagonists ,PHYSICIANS ,SEIZURES (Medicine) ,GAIN-of-function mutations ,CEREBELLAR ataxia ,VAGUS nerve - Abstract
Targeting the K
+ ey current: Gain-of-function (GOF) mutations in the potassium channel Kv1.2 cause a subtype of developmental KCNA2-encephalopathy, characterized by the occurrence of seizures, cerebellar ataxia, and intellectual disabilities. The available treatments are mostly ineffective. Here, Hedrich et al. showed that the potassium channel blocker 4-aminopyridine (4-AP) corrected electrophysiological abnormalities in neurons in vitro. 4-AP was effective in reducing symptoms in 9 of 11 patients carrying GOF Kv1.2 mutations. Seizure reduction and improvements in movements and cognition were reported for the majority of the treated patients, without causing severe side effects. The results suggest that blocking potassium channels could be an effective approach for treating patients with GOF in Kv1.2. Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV 1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment. [ABSTRACT FROM AUTHOR]- Published
- 2021
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4. KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum.
- Author
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Park, Joohyun, Koko, Mahmoud, Hedrich, Ulrike B. S., Hermann, Andreas, Cremer, Kirsten, Haberlandt, Edda, Grimmel, Mona, Alhaddad, Bader, Beck‐Woedl, Stefanie, Harrer, Merle, Karall, Daniela, Kingelhoefer, Lisa, Tzschach, Andreas, Matthies, Lars C., Strom, Tim M., Ringelstein, Erich Bernd, Sturm, Marc, Engels, Hartmut, Wolff, Markus, and Lerche, Holger
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POTASSIUM channels ,INTELLECTUAL disabilities ,DISEASES ,DEVELOPMENTAL delay ,FUNCTIONAL analysis - Abstract
A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism. [ABSTRACT FROM AUTHOR]
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- 2019
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5. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.
- Author
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Syrbe, Steffen, Bertsche, Astrid, Bernhard, Matthias K, Merkenschlager, Andreas, Kiess, Wieland, Serratosa, José M, Nothnagel, Michael, May, Patrick, Krause, Roland, Dorn, Thomas, Vogt, Heinrich, Krämer, Günter, Mullis, Primus E, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Sterbova, Katalin, Craiu, Dana C, Hoffman-Zacharska, Dorota, Hedrich, Ulrike B S, and Müller, Stephan
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NEURONS ,EPILEPSY ,SPASMS ,PHENOTYPES ,POTASSIUM channels - Abstract
Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel K
V 1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV 1.2-expressing neurons. [ABSTRACT FROM AUTHOR]- Published
- 2015
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