Epilepsies Gene Panel
Dr. med. Imma Rost, Dr. rer. nat. Karin Mayer
Epilepsies occur with a frequency of 0,5% to 1%. Almost half of all cases have their onset in childhood and of these 50% have a genetic background, however, the causes are mainly multifactorial or polygenic. Only 1-2% of the idiopathic epilepsies follow a monogenic pattern of inheritance. The ILAE (International League Against Epilepsy) recommends the idiopathic epilepsies to be termed genetic epilepsies.
Besides idiopathic (genetic) epilepsies there are symptomatic epilepsies which for instance can arise secondarily from inherited cerebral malformations (e.g. migration defects), be a part of a genetic syndrome (e.g. Angelman syndrome, Rett syndrome, tuberous sclerosis) or occur in context with chromosomal imbalances (e.g. ring chromosome 20 or 14, microdeletion 15q13.3, 15q11.2, 16p13.11, supernumerary marker chromosome 15 including the region 15q11.2 and others). According to the revised terminology of the ILAE those epilepsies would be classified as nonsyndromic epilepsies.
The early infantile epileptic encephalopathies (EIEEs) constitute a special group since they have an early onset, show a severe course, are usually difficult to treat and, besides the almost always existing disorder of cognitive development, exhibit other comorbidities. Examples are the Ohtahara syndrome, the West syndrome and the Dravet syndrome. The causes are varied: structural, metabolic, genetic. In the monogenic forms genetic diagnostics is increasingly important for the clarification of the underlying cause.
Genetic diagnostics in epilepsies can confirm a diagnosis and therefore avoid further diagnostics, facilitate an estimation of prognosis, and provide information on recurrence risks. Especially in the case of idiopathic generalized epilepsies, genes currently known to be causative should be considered only as susceptibility factors since further causative factors are suspected. Therapeutic consequences of genetic testing are still low. In epilepsies caused by mutations in ion channel genes, adapted medication can be used or also be avoided, for example, sodium channel blockers in GRFS+ or Dravet syndrome, use of stiripentol in Dravet syndrome, or future use of retigabine, which has an activating effect on the potassium channel that in BFNS is inactivated by mutations in KCNQ2. When a mutation in the SLC2A1 gene is detected, which causes a glucose transporter deficiency, a ketogenic diet is the treatment of choice. Mutations in the ALGH7A1 gene lead to a vitamin B6 dependent epilepsy and are treated by administration of vitamin B6. In the presence of a mutation in the PNPO gene the treatment consists of administration of pyridoxal-5'-phosphate.
Due to the clinical and genetic heterogeneity of the EIEEs, next generation sequencing (NGS) is especially useful, allowing all potential causative genes involved being analyzed simultaneously. NGS can also be useful in the testing of the parents of a patient with a dominant new mutation in order to clarify the inheritance and thus the risk of recurrence, since in some families the causative mutation was detected in one parent in mosaic form and NGS is more sensitive in detecting mosaics than the classical Sanger sequencing.
A chromosome analysis is indicated, for example, in frontal lobe epilepsy and suspected ring chromosome 20 (mosaic). As several studies (Mefford et al, Ann Neurol 70 (6), 974-985, 2011; Striano et al, Arch Neurol 69 (3): 322-30, 2012) have shown that epilepsies may also occur in the context of microdeletions and -duplications, array CGH may be indicated as well, especially when there are further major symptoms present such as developmental delay or other neuropsychiatric symptoms.
The following panels can be requested:
- Epilepsies master panel
- Early infantile epileptic encephalopathy (EIEE)
- Focal epilepsies
- Idiopathic generalized epilepsies (IGEs)
- Familial hemiplegic migraine (FHM)
All coding exons and their flanking intronic sequences from the genes in the epilepsies gene panel are analyzed either by Sanger sequencing or by next generation sequencing (NGS).
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