2. Precision medicine: novel treatment strategies developed from
pathophysiological knowledge
Advances in the identification of the underlying causes of epilepsies
led to a novel therapeutic approach which targets the underlying
pathophysiology causing seizures and other comorbidities (EpiPM
consortium 2015). Several conditions can now benefit from a more
tailored treatment using novel compounds or drugs aiming to counteract
or resolve the pathological mechanism and restore the disrupted brain
function (Mei et al 2017; Perucca P, Perucca E 2020; Nabbout, Kuchenbuch
2020). We can distinguish three different categories of therapy which
are used in these individual treatment strategies:
- Substitutive therapies
- Therapies that modify cell-signalling pathways
- Function-based therapies
Substitutive therapies
Substitutive therapies are currently used to treat disorders that are
related to inherited metabolic diseases including epilepsies caused by
glucose transporter type 1 deficiency (GLUT1) or by vitamin
deficiencies. The GLUT1 deficiency syndrome is caused by
haploinsufficiency of the SLC2A gene (solute carrier family 2,
facilitated glucose transporter member 1) (De Vivo et al 1991; Klepper
et al 2020). Low level of cerebral glucose, due to the impaired
transport, are associated to a spectrum of symptoms from paroxysmal,
often exercise induced, movement disorders to epilepsy often combined
and with variable degree of intellectual disability (De Vivo et al 1991;
Weber et al 2008; Suls et al 2009; Mullen et al 2010). For this
hereditary neurometabolic disorder, early diagnosis and treatment with
ketogenic diets (KD) is an important and individualizing treatment. The
KD, a high-fat, low protein, and low-carbohydrate diet provides ketone
bodies and also have a mechanism of action through GABA synthesis,
resulting in a neuroprotective effect and protecting from
epileptogenesis (Klepper et al 2020). Keton bodies transported through
the blood-brain barrier and used as an alternative energetic substrate.
Although inborn errors of metabolism do not represent the most common
cause of seizures, their early identification is of utmost importance,
since for some the substitutive therapeutic measures beyond common
anti-epileptic drugs, is essential either to control seizures, or to
decrease the risk of neurodegeneration (van Karnebeek et al 2018)
Amongst the vitamin responsive epilepsies pyridoxine and pyridoxal
phosphate (PLP) deficiencies caused by homozygous or compound
heterozygous mutations of the ALDH7A1 (antiquitin) and PNPO genes are
relatively frequent (Plecko B 2013, Wilson et al 2019). Administration
of either pyridoxine and/or PLP determine seizures resolution and
improvement of the overall general condition with a lifelong dependency
on vitamin B6 supply (Coughlin et al 2021).
Cerebral folate deficiency is characterized by low levels of
5-methyltetrahydrofolate (the active metabolite of folate) in the
nervous system but normal folate metabolism in the rest of the body. It
may be associated mutations in the FOLR1 gene encoding the folate
receptor α. The intracerebral deficiency leads to severe developmental
delay, movement disorder, white matter changes, bilateral basal ganglia
calcification, and drug-refractory epilepsy. Treatment includes
initiation of folinic acid to correct 5- methyltetrahydrofolate CSF
levels (Pope et al 2019).
Biotinidase enzyme deficiency is a rare, autosomal recessive
neurometabolic disorder, classical clinical presentation includes
recurrent seizures in the first few months of life. Testing for
biotinidase enzyme activity in the peripheral blood is readily available
and is part of neonatal screening at birth in developed countries.
Genetic testing is confirmatory. Treatment is life-long biotin
supplementation at 5–20 mg/d regardless of weight or age for both these
disorders (Wolf 2012)
Early diagnosis is also important for the treatment of epilepsy caused
by neurodegenerative diseases such as neuronal ceroid lipofuscinosis
type 2 (CLN2). In 2017, enzyme replacement therapy with cerliponase alfa
(recombinant human TPP1) has been approved for the treatment of CLN2
disease, a rare neurodegenerative paediatric disorder caused by
autosomal recessive mutations in the TPP1 gene resulting in a
deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1)
(Markham 2017). CLN2 is characterized by seizures between the age of 2
and 4 years, language delay, motor dysfunction and behavioural problems.
Long-term outcome of patients with CLN2 has dramatically improved since
the introduction of targeted therapy with recombinant human tripeptidyl
peptidase (Schultz et al 2018, Specchio et al 2020). This treatment has
been associated with a slowing or even stabilization of the
deterioration in gait and language ability. Participants receiving this
treatment have been followed-up for 3 years and this effect seems to be
maintained over time (Schultz et al 2019).