Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies

Balestrini, Simona; Chiarello, Daniela; Γώγου, Μαρία; Silvennoinen, Katri; Puvirajasinghe, Clinda; Jones, Wendy D.; Reif, Philipp S.; Klein, Karl Martin; Rosenow, Felix; Weber, Yvonne G.; Lerche, Holger; Schubert‐Bast, Susanne; Borggraefe, Ingo; Coppola, Antonietta; Troisi, Serena; Møller, Rikke S.; Riva, Antonella; Striano, Pasquale; Zara, Federico; Hemingway, Cheryl; Marini, Carla; Rosati, Anna; Mei, Davide; Montomoli, Martino; Guerrini, Renzo; Cross, J. Helen; Sisodiya, Sanjay M.

doi:10.1136/jnnp-2020-325932

Cited by 34 publications

(34 citation statements)

References 37 publications

(40 reference statements)

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“…Different forms of intervention may be embraced, from choosing the most suitable drug according to the type of epilepsy or expected adverse effects to gene therapy. An “ideal” epilepsy therapy would stop seizures and undo the changes caused by specific genetic mutations ( 137 , 138 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

2022

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To accelerate the process of licensing antiseizure medication (ASM) in children, extrapolation of efficacy data for focal-onset seizures from adults to children ≥2 or ≥4 years of age is now accepted. We summarized the efficacy evidence from randomized, controlled trials that was used to grant approval for the pediatric indication of focal-onset seizures for the different ASMs available in Europe. Data from high-quality randomized, controlled trials in young children are limited, especially on the use of ASMs in monotherapy. Licensure trials are typically focused on seizure type irrespective of etiology or epilepsy syndrome. We elaborate on the importance of etiology- or syndrome-driven research and treatment, illustrating this with examples of childhood epilepsy syndromes characterized by predominantly focal-onset seizures. Some of these syndromes respond well to standard ASMs used for focal-onset seizures, but others would benefit from a more etiology- or syndrome-driven approach. Advances in molecular genetics and neuroimaging have made it possible to reveal the underlying cause of a child's epilepsy and tailor research and treatment. More high-quality randomized, controlled trials based on etiology or syndrome type are needed, including those assessing effects on cognition and behavior. In addition, study designs such as “N-of-1 trials” could elucidate possible new treatment options in rare epilepsies. Broadening incentives currently in place to stimulate the development and marketing of drugs for rare diseases (applicable to some epilepsy syndromes) to more common pediatric epilepsy types and syndromes might be a means to enable high-quality trials, and ultimately allow more evidence-based treatment in children.

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Section: Discussionmentioning

confidence: 99%

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

2022

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“…During the last decades, technological advances have driven genetic discovery in epilepsy and increased the understanding of the molecular mechanisms of many epileptic disorders, in some cases providing targets for precision medicine (19,56). Nevertheless, phenotyping and neurophysiological characterization are still critical for the diagnosis and better management of neurological symptoms.…”

Section: Differential Diagnosismentioning

confidence: 99%

Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

et al. 2022

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Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative diseases, characterized by progressive cerebral atrophy due to lysosomal storage disorder. Common clinical features include epileptic seizures, progressive cognitive and motor decline, and visual failure, which occur over different time courses according to subtypes. During the latest years, many advances have been done in the field of targeted treatments, and in the next future, gene therapies and enzyme replacement treatments may be available for several NCL variants. Considering that there is rapid disease progression in NCLs, an early diagnosis is crucial, and neurophysiological features might have a key role for this purpose. Across the different subtypes of NCLs, electroencephalogram (EEG) is characterized by a progressive deterioration of cerebral activity with slowing of background activity and disappearance of spindles during sleep. Some types of heterogeneous abnormalities, diffuse or focal, prevalent over temporal and occipital regions, are described in many NCL variants. Photoparoxysmal response to low-frequency intermittent photic stimulation (IPS) is a typical EEG finding, mostly described in CLN2, CLN5, and CLN6 diseases. Visual evoked potentials (VEPs) allow to monitor the visual functions, and the lack of response at electroretinogram (ERG) reflects retinal neurodegeneration. Taken together, EEG, VEPs, and ERG may represent essential tools toward an early diagnosis of NCLs.

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“…The varied regulatory interaction with a number of proteins means that, besides affecting channel biophysical properties, KCNA2 variants could also impact the physiological modulation and distribution of Kv1.2 channel. In addition, other genetic variants, epigenetics and environmental factors may affect the clinical outcome [36]. Therefore, the outcome of a pathogenic variant as well as patient's response to drugs may be far more complex than expected by in vitro functional studies.…”

Section: Genotype-phenotype Correlation and Mechanistic Hypothesesmentioning

confidence: 99%

“…Due to the high variability of clinical outcome following the identification of a genetic variant, the application of precision medicine in ataxia and epilepsy is still difficult [36]. Patients affected by KCNA2 diseases are treated with a combination of AEDs sometimes with limited benefit [11,12].…”

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

Conte

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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Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies

Cited by 34 publications

References 37 publications

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

Treatment of Focal-Onset Seizures in Children: Should This Be More Etiology-Driven?

Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses

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

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