Epilepsy genes: The link between molecular dysfunction and pathophysiology

Abstract

Our understanding of the genetic basis of epilepsy is progressing at a rapid pace. Gene mutations causing several of the inherited epilepsies have been mapped, and several more are likely to be added in coming years. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate with the pathophysiological mechanisms of brain hyperexcitability. Mutations leading to epilepsy have been identified in genes encoding voltage‐ and ligand‐gated ion channels (benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, generalized epilepsy with febrile seizures “plus”), neurotransmitter receptors (Angelman syndrome), the molecular cascade of cellular energy production (myoclonic epilepsy with ragged red fibers), and proteins without a known role in neuronal excitability (Unverricht‐Lundborg disease). Gene defects can lead to epilepsy by altering multiple and diverse aspects of neuronal function. MRDD Research Reviews 2000;6:281–292. © 2000 Wiley‐Liss, Inc.

Epilepsy in four genetically determined syndromes of intellectual disability

“…Levels of expression of these subunits are indeed altered in AS subjects (Roden et al . 2010), which could result in a modification of the original AS phenotype (Stafstrom & Tempel 2000). In such individuals, GABA‐related neural synchrony of the primary sensory cortex is disturbed (Egawa et al .…”

“…The severity of the microdeletion genotype may stem from hemizygosity of the non-imprinted GABRB3, GABRG3 and GABRA5 genes, which code for subunits of the GABA A receptor and normally reside in this region (Saitoh et al 1994). Levels of expression of these subunits are indeed altered in AS subjects (Roden et al 2010), which could result in a modification of the original AS phenotype (Stafstrom & Tempel 2000). In such individuals, GABA-related neural synchrony of the primary sensory cortex is disturbed (Egawa et al 2008), which could contribute to the aetiology of ID; the representation of information is dependent on the generation of complex spontaneous activity, which may be precluded in the presence of overwhelming neuronal network synchrony (Dan & Boyd 2003).…”

Epilepsy

“…30 generalized epilepsies associated with ion-channel mutations inheritance pattern and are associated with singlegene mutations (Table 1). [42][43][44] Almost all these mutations have been found in genes encoding ionchannel proteins (Fig. 2).…”

Myoclonic Epilepsy in Gaucher Disease: Genotype-Phenotype Insights from a Rare Patient Subgroup

“…In the past few years, our understanding of the genetic basis of myoclonic epilepsy has progressed rapidly and many different defects and specific genes and mutations have been identified (33)(34)(35). Genetic lesions have been elucidated in recessive disorders with a myoclonic component, such as Unverricht-Lundberg disease, Lafora disease, five forms of ceroid lipofuscinosis, GM 2 gangliosidosis, and sialidosis; in dominant disorders like dentatorubropallidoluysian atrophy (DRPLA); and in a mitochondrial disorder, MERRF (mitochondrial encephalomyopathy and ragged red fibers).…”