Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Abstract

This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

Effect of fenfluramine on seizures and comorbidities in SCN8A‐developmental and epileptic encephalopathy: A case series

“…3 Seizures and comorbidities are persistent and mostly treatment-resistant, despite polypharmacy. [3][4][5][6][7] Studies with the repurposed drug and antiseizure medication (ASM) fenfluramine-a potent serotonin releaser with positive modulatory activity at Sigma-1 receptors and agonist activity at 5-HT receptors (5-HT 2 , with additional evidence for 5-HT 1D and 5-HT 4 ) 8,9 -have demonstrated decreased seizure frequency in patients with DEEs, including Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), Sunflower syndrome, and CDKL deficiency disease (CDD). 8,[10][11][12] In randomized clinical trials (RCT) and open-label extension studies (OLEs), fenfluramine was effective and well-tolerated, with no observations of pulmonary arterial hypertension or valvular heart disease.…”

“…Patients with SCN8A epilepsies are at an elevated risk of sudden unexpected death in epilepsy (SUDEP); SUDEP was reported in ~10% of patients with SCN8A‐ related disorders in a recent systematic review of 56 studies (N = 235 patients) 3 . Seizures and comorbidities are persistent and mostly treatment‐resistant, despite polypharmacy 3–7 …”

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases

“…Large prospective studies are now needed to evaluate the clinical utility and cost effectiveness of NBS-rWGS, particularly for disorders in which treatment would not be instituted until symptom onset and loci with considerable phenotypic 607745], respectively). While positive results would increase scrutiny for seizures, enable prompt, targeted, antiseizure medicine therapy, and reduce iatrogenesis, 70,71 prospective studies are needed to evaluate the positive predictive value of NBS for channelopathies. It is important to note that the panel of disorders presented herein is the initial version intended to be suitable for evaluation in prospective clinical studies.…”

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

“…In general, with the growing potential of precision medicine, it is essential to define the full range of the phenotypes that characterizes the natural history and evolution of DEEs and to identify appropriate clinical assessment tools [ 26 ]. There is also a rush to pursue the benefits of molecular diagnosis in older patients and in adults [ 27 , 28 , 29 ].…”