Page 102 - Read Online

Mohammadi et al. J Transl Genet Genom 2020;4:238-50 I https://doi.org/10.20517/jtgg.2020.29 Page 239

INTRODUCTION
[1]
Epilepsy is one of the most common neurological disorders , with a prevalence of 4-8 per 1000 and a
[2]
lifetime risk of 3% . Epilepsy is not a single disease entity, but rather a generic name used for diseases and
[3,4]
syndromes, where abnormal brain activity causes seizures . The underlying pathomechanisms of epilepsies
[5]
are largely unknown ; however, genetic factors play a major role, either as variants in single genes causing
monogenic epilepsies or as polygenic risk factors in common epilepsies. Like all other diseases, epilepsy
has benefited from the genomic sequencing revolution in medicine. Next-generation sequencing-based
methods such as targeted gene panels and exome sequencing are now routine analyses in many countries.
It is estimated that these tests can provide a genetic diagnosis in up to 30% of patients with early-onset
[6-9]
epilepsies . Parallel to the increasing number of patients with genetically verified diagnosis, the demand
for more accurate and targeted drug treatment also increases. The increasing number of patients with a
precise genetic diagnosis enables researchers and clinicians to compare cohorts of patients with the same
genetic defect and evaluate their treatment response to antiepileptic drugs (AEDs). These efforts along with
functional studies have led to more precise treatment strategies in a subset of monogenic epilepsies, mainly
ion channel disorders (channelopathies) [7,8,10] . The first-line treatment for most epilepsies is medication, and
the choice of AED is primarily based on the epilepsy syndrome/seizure type and the age of the patient, while
the underlying etiology plays only a minor role. However, more than 30 AEDs are available, and a therapy
targeting the functional consequence of a given genetic variant without going through the odyssey of trial-
error drug applications is crucial. In channelopathies, the drug of choice depends on whether a given genetic
defect is a gain-of-function (GoF) or loss-of-function (LoF) variant, (activating vs. inactivating variant)
leading to an imbalance in the function of inhibitory (e.g., GABAergic) or excitatory (e.g., glutamatergic)
neurons. Patient-specific in vitro models, such as neurons differentiated from human-induced pluripotent
stem cells (hiPSCs) with a given pathogenic variant can provide a tool for understanding the function of the
gene variant and serve as drug screening platforms for targeted therapy of the patients. In this study, we focus
on the application of iPSC-based functional studies and drug screening possibilities in monogenic epilepsies.

EPILEPTIC CHANNELOPATHIES
Ion channels can broadly be classified as either voltage-gated or ligand-gated, depending on whether the
stimulus for their activation is a change in the membrane potential or a chemical messenger such as a
neurotransmitter, respectively. The role of ion channels in neuronal excitability is well established, and
channelopathies include diseases of the central nervous system (CNS), and cardiovascular, respiratory,
urinary, endocrine and immune systems. CNS-related channelopathies include familial hemiplegic migraine,
[11]
episodic ataxia and various types of epilepsies .

Channelopathies account for a substantial fraction of epilepsy syndromes ranging from severe infantile
developmental and epileptic encephalopathies to relatively benign focal epilepsies. More than 20 ion channel
genes have so far been associated with epilepsy, and the majority of the most common epilepsy genes encode
either voltage-gated sodium (SCN1A, SCN2A, SCN8A), potassium (KCNQ2, KCNQ3, KCNT1, KCNB1,
[12]
KCNA2) or calcium channels (CACNA1A) . Recent molecular genetic advances have contributed to our
understanding of the pathophysiological mechanisms underlying these epilepsies. Careful clinical assessment
and appropriate genetic tests and functional studies enable an accurate diagnosis, which is consequential
for genetic counseling and guiding treatment options. Recently, some evidence emerged that dysfunctional
channels can be specifically targeted by drugs acting on them [7,8,13] . However, different variants in the same
gene can lead to either LoF or GoF, and it is challenging to predict the functional outcome of a given variant,
which hampers choosing the right AED [7,8,14-16] . The combination of phenotypic, genetic and functional
studies has resulted in remarkable advances in understanding the molecular and cellular disease mechanisms,
and to find a steadily increasing number of tailored treatments. This translational road, from bed to bench