Mark Gardiner

Summary:  The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non‐mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3, generalized epilepsy with febrile seizures plus due to mutations in SCN1A, SCN2A, SCN1B, and GABRG2, autosomal‐dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub‐types. There has also been progress in understanding the non‐mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2, increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.

A genetic contribution to aetiology is estimated to be present in up to 40% of patients with epilepsy. It is useful to categorise genetic epilepsies according to the mechanisms of inheritance into Mendelian disorders, non-mendelian or ‘complex’ disorders, and chromosomal disorders. Over 200 Mendelian diseases include epilepsy as part of the phenotype, and the genes for a number of these have been identified recently. These include autosomal recessive progressive myoclonic epilepsies such as Unverricht-Lundborg disease, Lafora disease and the neuronal ceroid lipofuscinoses, and three autosomal dominant idiopathic epilepsies. The last named have been shown to arise from mutations in ion channel genes. Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in CHRNA4, benign familial neonatal convulsions by mutations in KCNQ2 and KCNQ3, and generalised epilepsy with febrile seizures plus by mutations in SCN1B. ‘Complex’, familial epilepsies are more difficult to analyse, but evidence has been obtained for loci predisposing to juvenile myoclonic epilepsy on chromosome 6p and 15q. Lastly, the genes underlying several spike-wave epilepsies in mice have been cloned, and three of these encode sub-units of voltage-gated calcium channels.

Molecular genetic analysis of mendelian epilepsies in humans and mice has revealed a diversity of underlying genes in symptomatic epilepsies associated with disordered brain development and neuronal survival. In contrast, the idiopathic mendelian epilepsies have emerged as a new category of channelopathies. New epilepsy loci have been mapped and one new epilepsy gene isolated. Functional analysis of epilepsy genes is providing new insights into the pathways that lead from mutant gene to hyperexcitable neurones. The major challenge for the future is the analysis of genetic epilepsies with complex inheritance.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterised by the accumulation of autofluorescent storage material in neurons and other cell types. The clinical features include visual impairment, progressive myoclonic epilepsy, and cognitive decline reflecting progressive neurodegeneration. The NCLs are subdivided into several subtypes according to age of onset, clinical course, and ultrastructure of the storage material. The molecular genetic basis of this group of disorders has recently been clarified. Mutations in the gene encoding a lysosomal enzyme, palmitoyl protein thioesterase (PPT), cause infantile NCL (locus CLN1 on chromosome 1p32) or Haltia‐Santavuori disease. This Finnish disease is characterised ultrastructurally by granular osmiophilic deposits (GRODs). Juvenile‐onset NCL with GRODs also is caused by mutations in PPT. Classic late‐infantile NCL (Jansky‐Bielschowsky disease) is caused by mutations in a gene encoding a pepstatin‐insensitive lysosomal peptidase (CLN2 on chromosome 11p15), and juvenile‐onset NCL (Batten disease) is caused by mutations in a gene encoding a 438‐amino‐acid membrane protein (CLN3 on chromosome 16p12) of unknown function. A locus for Finnish variant late‐infantile NCL, CLN5, has been mapped to chromosome 13q22 and a locus for variant late‐infantile NCL, CLN6, to chromosome 15q21–23. These and further advances will allow the molecular basis of the NCLs to be elucidated and may lead to new strategies for diagnosis and treatment.