Recessive mutations in autism – the return of hidden metabolic disorders

My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading

NRXN1 deletions and the double hit hypothesis of idiopathic epilepsy

Old friends. Structural genomic variants or Copy Number Variations (CNVs) play an important role in many neurodevelopmental disorders including epilepsy, autism, schizophrenia and intellectual disability. Many of the CNVs representing genetic risk factors overlap between these diseases. Now, a recent study in Epilepsia reports on the exon-disrupting deletions in NRXN1 as genetic risk factors for Idiopathic Generalised Epilepsy. NRNX1 deletions were previously reported in several other neurodevelopmental disorders. However, there is an interesting and unanticipated twist to the story. Continue reading

Eyelid myoclonia with absences meets GEFS+

Running in the family. Eyelid myoclonia with absences (EMA) is a rare generalized epilepsy syndrome characterized by brief episodes of myoclonic jerks that are often accompanied by an upward deviation of the eyeballs and an extension of the head. The EEG shows generalized spike-wave discharges during these episodes, and most patients are highly photosensitive. Therefore, it would be natural to think of EMA as related to other classical generalized epilepsies including Childhood Absence Epilepsy or Juvenile Myoclonic Epilepsy. Now, a recent paper in Epilepsia shows that the families of patients with EMA tell a slightly different story. Continue reading

Traveling with Lennox – the petit mal triad

Lights on and lights out. Staring spells, petits mals, pyknolepsy and absence seizures. The brief spells that occur in patients with epilepsy have riddled neurologists for centuries. This became clear to me when Zaid Afawi and myself saw an epilepsy family in the West Bank on Sunday. When are staring spells epileptic and what kind of seizures are they? For me, this was a good opportunity to read Lennox’s thoughts on this. Eventually, after a long day under the Middle Eastern sun, I fell asleep over the chapter on absence status. Continue reading

Close encounters of the third kind – rare genetic variants in families

A new beast. Rare genetic variants probably account for a significant fraction of the genetic liability to many common and rare disorders. Rare variants occupy the liability space between monogenic variants and common genetic variants. Their existence has often been postulated, and genetic investigations looking at copy number variants have elucidated some examples of rare variants. These rare variants appear to carry particular properties that are quite unexpected including the way that these variants run in families. Now, in a recent paper in the European Journal of Human Genetics, we have developed a model of the way rare variants behave in families. And there is a lot of misbehaving. Continue reading

15q11.2 – the microdeletion spectre

Genetic mirage. We look at genetic variants all the time. There are few genetic variants that stare back at us. 15q11.2 is one these variants, facing us with the constant question how we define and perceive genetic risk. Not because of its pathogenicity, but because of the confusion that it causes. Continue reading

Genetic Generalized Epilepsy might be less genetic than you think

Ceci n’est pas une pipe. The painter René Magritte was known for his series of paintings that he called The Treachery of Images. He basically painted objects such as pipes, but then felt compelled to point out that the image actually betrays you. It’s not a real pipe, but only an image of it. For some reason, Magritte’s pipe comes to my mind when I read or hear the term Genetic Generalized Epilepsy. Again, the treachery of images. Ceci n’est pas une épilepsie génétique. Continue reading

Double Impact

Second hits. Genomic disorders are genetic disorders due to recurrent microdeletions or microduplications, i.e. small losses or gains of genomic material that happen again and again due to existing breakpoints in the human genome. Intriguingly, additional large microdeletions or microduplications can be identified in some patients with genomic disorders. A recent study in the New England Journal of Medicine tries to explain why. Continue reading

Standing on the shoulders of giants: the EPICURE GWAS on Idiopathic Generalized Epilepsy

Pushing the reset button. The history of epilepsy genetics can broadly be distinguished into two major eras: the time before September 4th, 2012 and everything after this. September 4th, 2012 was the date that the first large genome-wide association study in IGE/GGE was published online in Human Molecular Genetics. Each of the >100 association studies in IGE listed in PubMed is now dated and needs to measure up against the current study, which will likely be remembered as the “EPICURE study”. The results of the EPICURE study are surprising and upset our conventional wisdom of what causes one of the most common forms of epilepsy. Continue reading

A microscopic look at the 16p13.11 microdeletion

The patchwork chromosome. The human genome is a puzzle of duplications, duplications-within-duplications and more complex rearrangements.. Some of these duplications can misalign at meiosis and generate microdeletions and microduplications. The duplication architecture of the human genome is more pronounced in some chromosomes than in others. Chromosomes 15 and 16 are particularly rich in duplications, which is the reason several syndrome-associated microdeletions and microduplications are found there. One of these microdeletions is the 16p13.11 microdeletion. As a recent paper has looked as histological findings in brain tissue of patients with these deletions, it is time to review the only established genetic risk factor that contributes to wide range of epilepsy syndromes. Continue reading