PRICKLE. There are some genes implicated in human epilepsies that we have a hard time making sense of. PRICKLE1, implicated in a recessive progressive myoclonus epilepsy, is one of these genes. In a recent publication in PLoS Genetics, the interactome of the enigmatic PRICKLE proteins is explored. The authors rediscover an almost forgotten gene implicated in intellectual disability. Continue reading
The two faces of KCNA2 – a novel epileptic encephalopathy
Delayed rectifier. The discovery of de novo mutations in ion channel genes as a cause for genetic epilepsies continues. In a recent publication in Nature Genetics, we have identified de novo mutations in KCNA2 as a novel cause of epileptic encephalopathies associated with ataxia. Interestingly, even within a single gene, two different phenotypes seem to be emerging. Continue reading
Publications of the week – GABRG2, CACNA1A, and ALG13
Issue 5/2015. Each of these three genes may ring a bell, but the context in which they were described this week is new. Here is our overview of some of the most relevant publications this week. Continue reading
Galanin mutations in Temporal Lobe Epilepsy
Transmitted. When we think about epilepsy-related neurotransmitters, we often limit ourselves to the most prominent transmitters in the Central Nervous System, namely glutamate, GABA and to some extent acetylcholine. However, besides these classical transmitters, there are more than 100 small peptides released in the mammalian brain, which are referred to neuropeptides. Here is the story of galanin, the first neuropeptide in epilepsy genetics. Continue reading
Beyond SCN1A – Copy Number Variations in fever-associated epilepsies
Fever and epilepsy. When it comes to epilepsy and fever, either Febrile Seizures or Dravet Syndrome are usually the most prominent topics on our blog. However, in addition to these syndromes, there various other epilepsies that have fever-related seizures as a prominent feature. In a recent publication in Epilepsia, we investigated the role of microdeletions in a group of patients with prominent fever-associated epilepsies. Our findings suggest that fever-associated epilepsy syndromes may be a presentation of known microdeletion syndromes. Continue reading
TLR3 and the genetic predisposition to herpes encephalitis
Seizures with fever. Most times when we discussed seizures in the setting of fever on our blog, we either referred to simple Febrile Seizures or genetic syndromes such as Dravet Syndrome, which characteristically present with fever-associated seizures. However, if a child or an adult presents with a first seizure in the setting of a febrile illness and shows recurrent seizures or does not get back to baseline quickly, we are usually concerned about infections of the brain. Herpes simplex virus (HSV) encephalitis is one of the more common infections, which may result in significant impairment if not treated rapidly. A recent publication in Neurology reminds us of the genetic susceptibility of HSV encephalitis and suggests that predisposing genetic alterations can be found in an appreciable number of patients. Continue reading
CHD2 myoclonic encephalopathy – delineating a novel disease
CHD2. In 2013, mutations in CHD2 were reported in various publications including two major studies on epileptic encephalopathies, reinforcing the notion that de novo mutations in this gene are a recurrent cause of epileptic encephalopathies. However, large-scale studies often cannot fully appreciate the complete phenotype of the patient behind the gene finding. Therefore, it is difficult to appreciate similarities between patients and assess whether phenotypes constitute a recognizable entity. In a recent publication in Neurology, the phenotype of CHD2 encephalopathy is explored in detail – it represents a distinct, recognizable disease entity. Continue reading
EFHC1 – retiring an epilepsy gene
The era of gene retirement. As of 2015, the list of epilepsy genes has shrunk by one. EFHC1, a gene initially proposed to be a monogenic cause of Juvenile Myoclonic Epilepsy, is no longer an epilepsy gene. A recent study in Epilepsia finds that EFHC1 variants initially thought to be pathogenic are found in unaffected controls of the same ancestry. Follow us on one of the most perplexing journeys that modern day neurogenetics has to offer, and the retirement of the first epilepsy gene. Continue reading
Speech dyspraxia and dysarthria – the other side of GRIN2A
GRIN2A. Mutations in several genes coding for NMDA receptor subunits have recently been found in various neurodevelopmental disorders. Amongst the different genes, GRIN2A is one of the most prominent ones and mutations in this gene are found in patients with epilepsy-aphasia syndromes. So far, we have mainly looked at GRIN2A from the epilepsy side. In a recent publication in Neurology, Turner and collaborators now examine the speech phenotype in GRIN2A families. They examine two families where speech issues are a prominent phenotypic feature. It turns out that GRIN2A mutations may predispose to a distinct speech phenotype. Continue reading
A genetic counselor’s wish list for epilepsy genetics in 2015
Mt. Rainier. After our recent posts about the 2014 AES in Seattle, we received an email from Beth in Boston, highlighting some of the issues that genetic counselor face in epilepsy genetics when dealing with next gen sequencing data. Beth drew up a wish list for 2015 and asked us for comments. Here is a brief discussion between Beth and me on how high throughput epilepsy genetics sometimes comes to grinding halt in clinical practice. Continue reading