Phase IIB Randomized Trial on the Use of 4-Aminopyridine in Guillain-Barré Syndrome

Meythaler, Jay M.; Brunner, Robert; Péduzzi, J.

doi:10.1016/j.arrct.2021.100123

Cited by 1 publication

(1 citation statement)

References 47 publications

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“…Interestingly, fampridine (Fampyra ® ), a modified release form of the Kv channel blocker 4-AP, is being offered, as a more specific therapy, to patients carrying KCNA2 GoF variants with seizure reduction and improvements in movements and cognition [14,25,29]. As mentioned above, this drug already represents an approved symptomatic treatment to improve motor function in those suffering from multiple sclerosis and other demyelinated disorders and has been trialed in some gait disorders of cerebellar origin [15,16,30,39,40]. Off-label treatment with 4-AP also improved the clinical outcome of one patient affected by vesicle-associated membrane protein 2 (VAMP2)-related epilepsy through increased exocytosis and improved GABAergic tone [41].…”

Section: Towards Precision Medicine For Kcna2-disordersmentioning

confidence: 99%

A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine

Imbrici

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Blunck

et al. 2021

IJMS

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Kv1.2 channels, encoded by the KCNA2 gene, are localized in the central and peripheral nervous system, where they regulate neuronal excitability. Recently, heterozygous mutations in KCNA2 have been associated with a spectrum of symptoms extending from epileptic encephalopathy, intellectual disability, and cerebellar ataxia. Patients are treated with a combination of antiepileptic drugs and 4-aminopyridine (4-AP) has been recently trialed in specific cases. We identified a novel variant in KCNA2, E236K, in a Serbian proband with non-progressive congenital ataxia and early onset epilepsy, treated with sodium valproate. To ascertain the pathogenicity of E236K mutation and to verify its sensitivity to 4-AP, we transfected HEK 293 cells with Kv1.2 WT or E236K cDNAs and recorded potassium currents through the whole-cell patch-clamp. In silico analysis supported the electrophysiological data. E236K channels showed voltage-dependent activation shifted towards negative potentials and slower kinetics of deactivation and activation compared with Kv1.2 WT. Heteromeric Kv1.2 WT+E236K channels, resembling the condition of the heterozygous patient, confirmed a mixed gain- and loss-of-function (GoF/LoF) biophysical phenotype. 4-AP inhibited both Kv1.2 and E236K channels with similar potency. Homology modeling studies of mutant channels suggested a reduced interaction between the residue K236 in the S2 segment and the gating charges at S4. Overall, the biophysical phenotype of E236K channels correlates with the mild end of the clinical spectrum reported in patients with GoF/LoF defects. The response to 4-AP corroborates existing evidence that KCNA2-disorders could benefit from variant-tailored therapeutic approaches, based on functional studies.

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