Introduction
Seizures are often the presenting and distressing symptom of epilepsies
and syndromes including the fearsome developmental epileptic
encephalopathies (DEE) (Scheffer et al 2017). Seizures are frequently
the clinical sign that brings children to medical attention thus, the
whole community of parents, professionals and scientists has always
focused on how to stop seizures. Accordingly, studies on outcomes have
also paid much attention on the treatment of seizures. Evidences from
clinical practice and from animal models certainly vouch for a better
developmental outcome when seizures are short, infrequent and possibly
completely under control (Ragona et al 2011; Caraballo et al 2014;
Meldrum, Horton 1973; Trinka et al 2015). Yet, epilepsy represents only
a clinical manifestation that is often observed as part of complex
neurodevelopmental disorders, including intellectual disability and
autism. Thus, seizures are not the end of the story and comorbidities
including motor, cognitive and behavioural impairments are equally
relevant persisting beside and beyond seizures. In the ideal situation,
a treating physician should aim to cure the whole diseases rather than
some of the symptoms. Side effects produced by available antiseizure
medications (ASM) add to the complexity of epilepsies and syndromes. In
this complex scenario, the underlying aetiology certainly plays a
leading role. The application of new methodologies including next
generation sequencing (NGS), whole exome and genome sequencing (WES/WGS)
has deeply transformed our understanding of the basis and
pathophysiology of some epilepsies (Mei et al 2017, Dunn et al. 2018;
Nabbout, Kuchenbuch 2020). We now know that the majority of epilepsies,
especially those with infantile onset, have a genetic origin and
hundreds of monogenic forms have been identified and dissected (Parrini
et al 2017; Hebbar, Mefford 2020; Stödberg et al 2020; Symonds, McTague
2020). Ion channel gene including sodium, potassium and calcium
represent the gene family most frequently associated to epilepsy
(Parrini et al 2017; Stödberg et al 2020). Other genes have gradually
emerged and have been associated with complex developmental disorders
featuring seizures and revealing the pathogenic role of mutations
affecting diverse pathways contributing to membrane excitability,
synaptic plasticity, presynaptic neurotransmitter release, postsynaptic
receptors, transporters, cell metabolism. Additional genes have relevant
roles in many formative steps in early brain development, such as the
proliferation and migration of neuronal precursors, dendritogenesis,
synaptogenesis, cell and glial biology (Guerrini R, Noebels 2014;
Szepetowski P. 2018)
Such impressive advances in knowledge has paved the way for a shift in
the therapeutic management of patients from a population approach, based
on epilepsy types and syndromes to, an individualized approach, where
treatments could be targeted to genetically defined subgroups of
individuals. The ideal individualized approach, in addition to the
epilepsy type or syndrome, should take into consideration a combination
of characteristics specific to the individual patient including age,
race, sex and physiological parameters. This shift towards precision, or
personalized, medicine will improve outcome and enable physicians to
treat patients in a more targeted manner.
In the last few years, the scientific community, possibly sensitized by
familial associations of rare disorders, realized that is was time to
move beyond gene hunting and step into the individualized and
aetiology-based cure (Josephson, Wiebe 2021; Nabbout, Kuchenbuch 2020;
Thakran et al 2020). Thus, the gap between gene hunting and
etiology-based personalized treatment is diminishing by the hour and the
examples of applied precision medicine is growing. Identification of a
precise genetic etiology can already direct physicians to prescribe
treatments correcting specific metabolic defects avoid ASM drugs that
can aggravate the pathogenic defect or select ASM that counteract the
functional disturbance caused by the gene mutation.
In the rush for development of therapeutics for rare diseases, the Food
and Drug Administration (FDA) issued some guidance to industry
(references 17 to 19). Such guidelines emphasise the importance of
having a well-delineated natural history, identifying relevant clinical
outcomes, and identifying or developing appropriate outcome assessments.
Translation of genetic causes into new or more targeted treatments
depends on effective model systems that illuminate the underlying
biology and contribute to the development of new drug-screening
protocols.
The present review, focuses mainly on paediatric-onset epilepsies, where
the identification of multiple aetiologies and the potential for early
intervention provides the ideal environment for the implementation of a
preventive precision medicine approach. We will discuss the therapeutic
implications following a specific genetic diagnosis and the correlation
between genetic findings, pathophysiological mechanism and tailored
seizure treatment.
For academic purposes, current evidences have been divided into four
subtypes according to the impact of such knowledge on real patient’s
treatment:
- Clinical-based evidence of known ASM affecting seizure
frequency either worsening or improving seizure frequency
- Precision medicine: novel treatment strategies developed from
pathophysiological knowledge
- Precision medicine: aetiology-based preventive treatments and
in progress treatments
Clinical-based evidence of known ASM modifying - either
worsening or improving - seizure frequency
One of the first and best example of how the identification of the
underling genetic aetiology guides treatment is that of Dravet Syndrome
(DS) the most renowned and studied developmental and epileptic
encephalopathy (DEE) (Mei et al 2019). Well before the genetic cause was
identified, some clinical reports indicated that sodium channel blockers
including lamotrigine (LTG) and carbamazepine (CBZ) should be avoided in
patients with DS since they have the potential to determine an increase
in seizure frequency evolving to status epilepticus in some patients
(Guerrini et al, 1998; de Lange et al 2018). Following the discovery
that DS is associated to mutations of the alpha1 subunit of the sodium
channel (SCN1A) possibly causing loss of channel function, the clinical
evidence that the administration of sodium channel blockers made seizure
worse was partly explained (Claes et al 2001; Mantegazza, Marini 2010;
Mei et al 2019). Although complete seizure control is rarely attainable,
clinical studies have shown that the combination of valproic acid (VPA),
clobazam (CLB) and stiripentol (STP) is the most effective in preventing
seizures especially avoiding the evolution into status epilepticus,
frequently observed in infants with DS (Ceulemans et al 2004; Wirrel et
al 2018, Wirrel and Nabbout 2019). STP was associated with a greater
than 50% reduction in convulsive seizure frequency in 71% of cases,
when added to VPA and CLB and markedly reduced status epilepticus
(Chiron et al 2000). STP has multiple mechanisms of action including
increasing peak concentration and duration of action of CLB and a direct
anti-convulsing activity likely due to enhancement of inhibitory,
GABAergic neurotransmission (Fisher 2011).These agents are generally
well tolerated, with few patients discontinuing for adverse effects.
A second straightforward example of seizures aggravation by sodium
channel blockers is observed in the DEE related to HCN1 gene
Gly39Asp mutation (Marini et al 2018). Two patients with complete
genotype-phenotype correlation also shared the response to ASM
especially worsening of seizures frequency when treated with phenytoin
(PHT) and lacosamide (LCS). Consistent with this clinical report from
HCN1 patients the administration of LTG in the genetic knock-in mouse
model resulted in a paradoxical induction of seizures and spiking
induction in mutant animals (Bleakley et al 2021).
On the contrary, in some well-defined DEE including those associated toSCN2A and SCN8A gene mutations, seizures are fully
controlled by CBZ and PHT (Numis et al 2014; Pisano et al 2015; Ohba et
al 2014; Larsen et al 2015; Wolff et al 2017; Dilena et al 2017;
Gardella, Moeller 2019). SCN2A mutations response to sodium
channel blockers is related to missense mutations leading to a gain of
channel function and seizure onset before age 3 months, severe
phenotypes yet seizures are stopped with PHT and CBZ (Wolff et al 2017).
The story of SCN2A adds another level of complexity to take into
account when treating a patient with a genetic epilepsy. In some
patients, the choice of the best ASM medication is guided not only by
knowledge of the mutated gene but also by its functional consequences.
Carbamazepine and PHT are also recommended as first-line drugs for the
treatment of seizures in patients with KCNQ2-encephalopathy, including
those presenting with status epilepticus (Numis et al 2014; Pisano et al
2015). Most patients achieve seizure freedom on these ASM and it has
been suggested that early seizure control may also improve
neurodevelopmental outcome (Pisano et al 2015).
The proline-rich transmembrane protein 2 (PRRT2) is a presynaptic
transmembrane protein interacting with members of the SNARE complex,
which enables synaptic vesicle fusion. Disease-causing variants in PRRT2
gene result in haploinsufficiency and are clinically expressed with
infantile onset focal seizures that have a very benign outcome and
disappear by age 2 years in otherwise normal infants. During childhood
or adolescence, some patients may develop paroxysmal kinesigenic
choreoathetosis (Chen et al 2011; Marini et al 2012). Additional rare
manifestations include hemiplegic migraine and absence seizures (Marini
et al 2012). Small doses of CBZ are very effective to suppress seizures
and the movement disorder episodes (De Gusmao, Silveira-Moriyama 2019).
Tuberous sclerosis complex (TSC) is a multisystem disease caused by
inactivating mutations in either TSC1 or TSC2 genes that are important
components of the mTOR (mammalian target of rapamycin) pathway which
regulates a variety of neuronal functions, including cell proliferation,
survival, growth, and plasticity. TSC is a major cause of severe and
drug-resistant epilepsy, with focal seizures and infantile spasms
occurring in about 80% of TSC infants (Curatolo et al 2018). Vigabatrin
(GVG), a conventional GABAergic ASM is the first line drug for infantile
spasms of patients with TSC, is very effective and spasms disappear
completely in most patients (see below in the section of preventive
treatment).
Precision medicine in the epilepsies also has an equally important role
in facilitating avoidance of adverse reactions as in maximising
efficacy, as illustrated by a number of recent example including POLG1
mutations who might develop fatal hepatic failure when treated with
valproate (Hynynen et al 2014). An additional example is that of the
HLA-B*15:02 allele which is highly predictive of carbamazepine-induced
Stevens-Johnson syndrome, a severe hypersensitivity reaction, in
patients of Asian origin (Chung et al 2004). These examples clearly show
how much clinicians and families have gained from the knowledge of the
underling gene mutations in the therapeutically management of some
epilepsies and syndromes. Most epilepsies for which we obtained greater
pathophysiological insights are related to ion channel gene mutations
and available drugs targeting ion channels are our initial treating
choice.
Table 1, here below, summarizes the above reported examples