Unravelling the BAFME mystery. The mystery surrounding Benign Adult Familial Myoclonic Epilepsy (BAFME) – also known as Familial Adult Myoclonic Epilepsy (FAME) or Familial Cortical Myoclonic Tremor and Epilepsy (FCMTE) – has persisted for years. BAFME is an autosomal dominant neurological disorder characterized by adult onset of myoclonic/cortical tremor and infrequent seizures. The clinical course is typically considered to be benign. Linkage studies have shown linkage to several regions including 8q24, 2p11.1-q12.2, 3q26.32-q28, and 5p15. A recent publication identified a variant in CTNND2 segregating with disease in a Dutch family with BAFME3, although it remains to be determined how broadly applicable CTNND2 variants are in other individuals with BAFME. Now in an elegant set of experiments by Ishiura and colleagues, a significant proportion of BAFME appears to be solved and is due to expansions of pentanucleotide intronic sequences in SAMD12.
Category Archives: Familial epilepsies
Zeroing in on FAME – the dilemma of familial epilepsies
FAME. Some familial epilepsy syndromes are notoriously resistant to gene discovery. Familial Adult Myoclonus Epilepsy (FAME), a rare but distinct familial epilepsy, has been one of the familial epilepsy syndromes that has been around for more than a decade. Despite the power of modern massive parallel sequencing technologies, this syndrome has been hard to tackle. In a recent publication, we take a small step in narrowing down the region for the FAME gene. Let’s use this opportunity for a reality check of the somewhat disappointing state of gene discovery in familial epilepsies in 2016 and what we can do about this. Continue reading
Familial epilepsies revisited – the big picture
Family genetics. The analysis of epilepsy families helped jumpstart the field of epilepsy genetics by identifying SCN1A and several other epilepsy genes in the late 1990s. However, more recently, gene discovery in familial epilepsies has been overshadowed by the explosion of gene identifications in sporadic epileptic encephalopathies. A recent publication in Neurology now reviews the results of a decade-long endeavor to characterize familial epilepsies in Israel and Palestine. Find out why we are far from understanding the majority of familial epilepsies, why GGE/IGE families are the main problem, and what the “familial four” are.
Mysteries of a neuronal pathfinder – this is what you should know about PCDH19 in 2015
Protocadherin. There are some genes that we have mentioned less frequently on our blog than we should have. PCDH19 and CDKL5 are two examples of this. With this post, we try to catch up by reviewing some of the new findings related to PCDH19 Female Epilepsy including the role of neurosteroids, anti-NMDA receptor antibodies, stiripentol and the mechanism behind this epilepsy. Continue reading
This is what you should know about KCNT1 – a 2015 update
Dual phenotypes. When KCNT1 was first described as a gene for Migrating Partial Seizures of Infancy in 2012, it wasn’t just a novel gene for epileptic encephalopathies. In parallel, the same gene was found to underlie a novel subtype of autosomal dominant nocturnal frontal lobe epilepsies (ADNFLE). At the time, this left us scratching our heads how a gene could cause such distinct, but entirely separate phenotypes. In a recent publication in Epilepsia, Møller and collaborators revisit the phenotypic spectrum of KCNT1. They find that both phenotypes can occur within a single family and that KCNT1 mutations can result in other phenotypes, adding to the mystery of KCNT1. Continue reading
Reelin, migration and an unexpected gene for lateral temporal lobe epilepsy
Reeler. In 1951, the geneticist D.S. Falconer identified a spontaneous mouse mutant with an abnormal, “reeling” gait. This mouse, aptly called reeler, was later found to have developmental abnormalities of the cerebellum and, most prominently, an inversion of the layers of the cortex. At this point, interest was piqued to identify the underlying gene, which was eventually pinpointed in 1995. Reelin, the culprit gene, was found to be a secreted protein of cortical support cells and was subsequently found to be the cause of human lissencephaly with cerebellar hypoplasia (LCH). In a recent study in the American Journal of Human Genetics, reelin takes on a new role as a novel gene for a familial form of lateral temporal lobe epilepsy. Continue reading
SCN1A – this is what you should know in 2015
2015 update. Our updates on SCN1A mutations and Dravet Syndrome are amongst our most frequently read posts. Therefore, following the tradition of annual reviews that we started last year, we thought that a quick update on SCN1A would be timely again, building on our previous 2014 update. These are the five things about SCN1A that you should know in 2015. Continue reading
The microdeletion landscape of Genetic Generalized Epilepsy
CNV. Structural genomic variations or Copy Number Variations (CNVs) significantly contribute to the genetic architecture of many neurodevelopmental disorders. However, given the enormous variation in the human genome in healthy individuals, the precise contribution of CNVs remains poorly understood. In a recent publication in PLOS Genetics, we were able to assess the microdeletion architecture in more than 1,000 patients with Genetic Generalized Epilepsy (GGE) compared to more than 5,000 controls. We found that microdeletions occur almost twice as often in GGE patients compared to controls, an analysis that revealed both known suspects and interesting candidates. Continue reading
Epi25 – breaking the genetic sound barrier
25,000 genomes. The epilepsy community is currently preparing for the largest sequencing project in the epilepsies so far, responding to a call by the National Human Genome Research Institute (NHGRI). If funded, the Epi25 project will allow us to begin sequencing 25,000 individuals with epilepsy, helping us to achieve the next, necessary level for gene discovery in human epilepsies. Here are some of the reasons why we need Epi25 and why you should be part of it. Continue reading
Cause or coincidence – recessive SCN1A variants in Dravet Syndrome
Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading
