Three things I learned about focal epilepsies on the Faroe Islands

Focal to genetic. While there was little interest in the genetics of focal epilepsies only five years ago, the field has gained significant momentum since the discovery of DEPDC5 and the subsequent new appreciation of the mTOR pathway. This finding resulted in several gene discoveries and linked traditional genetic epilepsies with the emerging field of somatic mutations. In May 2017, the European epilepsy genetics community met on the Faroe Islands for the international conference on focal epilepsy. Here are the three things that I learned about focal epilepsies on the Faroe Islands. Continue reading

Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing

Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading

A question of conformation – chemical correction of LGI1 dysfunction

ADTLE. Autosomal Lateral Temporal Lobe Epilepsy is a rare monogenic epilepsy that has epileptic seizures with auditory auras as the most impressive feature. This condition is caused in LGI1. In contrast to most other autosomal dominant epilepsies, LGI1 is not an ion channel, but a secreted protein that binds to synaptic cell adhesion proteins. Therefore, the function of LGI1 has always remained slightly mysterious. In a recent publication in Nature Medicine, the functional properties of two LGI1 mutations are modelled in mice. Allowing neurons to secrete altered LGI1 protein otherwise targeted for degradation helped recover some of LGI1’s function. Continue reading

DEPDC5, meet the mTOR pathway – a novel mechanism in genetic focal epilepsies

Variable foci. A few weeks ago, we discussed the recent gene finding in Familial Partial Epilepsy with Variable Foci, a rare but puzzling familial epilepsy syndrome. DEPDC5 was identified as the culprit gene. However, the potential function of the gene product left researcher scratching their heads. Now, a recent paper in Science suggests that DEPDC5 might interact with the mTOR pathway, the master regulator of growth. Should we reconsider the role of the mTOR pathway in genetic focal epilepsies? Continue reading

Sturge-Weber syndrome explained – somatic mutations in GNAQ

Phakomatoses. There are a group of disorders that affect both the skin and the central nervous system. These disorders, called neurocutaneous disorders or phakomatoses, may result in epilepsy or intellectual disability, depending on the extent to which the brain is affected. While a genetic basis for some neurocutaneous disorders including Tuberous Sclerosis Complex (TSC) and neurofibromatosis is known, the etiology of other neurocutaneous diseases remains unknown. Now, a recent paper in the New England Journal of Medicine reports on the genetic alterations underlying one of the most common neurocutaneous disorders, Sturge-Weber syndrome. Continue reading

STRADA mutations, mTOR activation and personalized medicine using rapamycin

Rapamycin. The mTOR pathway, known through its role in Tuberous Sclerosis Complex (TSC), becomes increasingly important in epilepsy. A wide range of epilepsies caused by brain malformations are due to mutations in genes involved in this pathway, and several neurodevelopmental disorders associated with macrocephaly, intellectual disability and epilepsy are known, where components of this pathway are altered due to germline mutations. For one of these disorders named PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy), a recent paper in Science Translational Medicine reports the effects of treatment with rapamycin, an mTOR inhibitor. The results demonstrate that personalized medicine might in part be promising, asexisting drugs can be used in rare genetic diseases. Continue reading

Jumping genes in the brain – single neuron sequencing of L1 retrotransposons

The not so static genome. We usually think that our genome is static and that differences between cell types usually arise through mechanisms that do not necessarily involve alterations of the DNA structure. This suggestion has been challenged by initial data suggesting that retrotransposons may be particulary active in neurones. Now, a recent study in Cell investigates the role of jumping genes using single-cell sequencing of neurons.

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Somatic mutations affecting the mTOR pathway in hemimegalencephaly

Mutations, but not germline. Many of the genetic alterations that we aim to investigate within the EuroEPINOMICS projects are so-called germline mutations. In the case of de novo events, these mutations have occurred in the germ cells themselves or in very early development. In the case of autosomal dominant or recessive inheritance, the mutations have been transmitted from parents. In either case, the mutation can be found in every cell of the body. Cancer research is mainly focussed on somatic mutations, which give rise to malignant transformation in already differentiated tissues. In fact, many of the techniques that we currently use in neurogenetics were developed to study somatic genetic aberrations. Array comparative genomic hybridization for example, had initially been established for these purposes before expanding the focus to germline microdeletions and microduplications. While the role of somatic mutations in cancer research is well established, the role somatic rather than germline genetic alterations play in other disorders is mainly speculative. Some initial evidence for somatic point mutations has recently been found in Proteus syndrome, a rare overgrowth syndrome. Activating somatic mutations in AKT1 have recently been identified in this disorder. A recent paper by Lee and colleagues now identifies mutations in several genes in the mTOR pathway in patients with hemimegalencephaly, a severe form of brain malformation. Continue reading