The Atlas of Monogenic Epilepsies

Epilepsy may be the consequence of several causes, including genetic anomalies, structural brain malformations, hypoxic-ischemic encephalopathy, brain tumors, and drugs, all contributing to the imbalance between excitatory and inhibitory neurons and modulatory interneurons, which in turn provoke abnormal, simultaneous electric discharge(s) involving part or all the brain.[1] [2] [3] In the pregenetic, pregenomic era, in most cases, the exact cause of such neuronal/interneuronal disequilibrium remained unknown and the term idiopathic epilepsy was used to define all the epilepsies without cause. At the same time, some specific epileptic syndromes were indicated by the eponym of the first physician who originally described the condition (e.g., West syndrome, Dravet syndrome, Ohtahara syndrome, Lennox–Gastaut syndrome) or by some characteristic clinical features (e.g., nocturnal frontal lobe epilepsy, absence epilepsy, epilepsy and mental retardation limited to females). In many of these occurrences, the distinct epileptic syndrome was defined mainly by its most relevant clinical feature (e.g., seizure semiology), associated comorbidities, and electroencephalographic patterns.[3] [4]

In the last 20 years, the field of epilepsy gene discoveries has gone through at least three different stages: (1) an early stage of relentless gene discovery in monogenic familial epilepsy syndromes; (2) a relatively quiescent and disappointing period characterized by largely negative genome-wide association candidate gene studies; and (3) a genome-wide era in which large-scale molecular genetic studies have led to the identification of several novel epilepsy genes, especially in sporadic forms of epilepsy.[1] [2] [3]

In this monographic issue (subdivided in part 1 and part 2), entitled The Atlas of Monogenic Epilepsies, Pediatric Neurologists and Medical Geneticists and Scientists from different Italian universities contributed to 25 in-depth reviews covering many genes related to monogenic epilepsies. All the reviews encompass a molecular analysis of the genes and their related protein, as well as a clinical description of the associated phenotypes and the possibilities of gene-specific treatment.

These reviews may be subdivided, according to proteins functions, to:

• Channelopathies: SCN1A, SCN1B, SCN2A, SCN8A, KCNT1, KCNQ2 and KCNQ3, GABA receptors genes, GRIN2A and GRIN2B, calcium channels genes.

• Synaptopathies: STXBP1, PRRT2, DNM1, SYNGAP1.

• mTORpathies: TSC1 and TSC2, DEPDC5.

• Otheropathies:

• - Rett syndrome and beyond: MECP2, FOXG1, CDKL5.

• - Solute carriers and pyridoxine-dependent epilepsies: SLC2A1, SLC25A22, ALDH7A1.

• - Neuronal migration and other functions: PCDH19, ARX, TBC1D24, WDR45.

Publication History

Received: 22 March 2023

Accepted: 23 March 2023

Article published online:
27 April 2023

• References

• 1 Fisher RS, Acevedo C, Arzimanoglou A. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55 (04) 475-482
• 2 Falco-Walter JJ, Scheffer IE, Fisher RS. The new definition and classification of seizures and epilepsy. Epilepsy Res 2018; 139: 73-79
• 3 Staley K. Molecular mechanisms of epilepsy. Nat Neurosci 2015; 18 (03) 367-372
• 4 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113