The return of the h-current: HCN1 mutations in atypical Dravet Syndrome

Hyperpolarization. More than a quarter of a century ago, physiologists identified an electrical current in neurons and cardiac myocytes that behaved so strangely that it was called the “queer” or “funny” current: it paradoxically caused depolarization upon hyperpolarization. This current was finally named h-current and is mediated by HCN channels. The h-current has been associated with epilepsy through functional studies, but a genetic link has been elusive so far. In a recent publication in Nature Genetics, de novo mutations in HCN1 are identified in patients with early-onset epileptic encephalopathies resembling Dravet Syndrome. Continue reading

Treatable causes of intellectual disability and epilepsy that you don’t want to miss

Think metabolic. We have discussed de novo mutations as a cause of epileptic encephalopathies repeatedly on our blog. While there is emerging evidence that de novo mutations in established genes such as SCN1A or CDKL5 or novel genes including GNAO1 or CHD2 are a major cause of genetic morbidity in patients with epileptic encephalopathies, investigations for de novo mutations are not the immediate knee-jerk reaction in clinical practice. In fact, if a child presents with an epileptic encephalopathy, excluding inborn errors of metabolism (IEM) takes priority. While metabolic causes of epileptic encephalopathies are rare, they need to be excluded as some of these conditions are treatable. In a recent review in Molecular Genetics and Metabolism, van Karnebeek and colleagues review the 89 causes of intellectual disability that are potentially treatable. Many of these conditions also present with epilepsy. They present an updated diagnostic algorithm and provide an online resource for these conditions – in a nutshell, there is an app for that.  Continue reading

TBC1D24, DOORS Syndrome, and the unexpected heterogeneity of recessive epilepsies

The return of TBC1D24. In 2010, the TBC1D24 gene was the first gene for human epilepsies to be discovered through next generation sequencing techniques. Ever since, this gene has been a mystery, as the phenotypes of the families with recessive mutations in this gene varied widely. Now, a recent paper in Lancet Neurology finds recessive TBC1D24 mutations in a large proportion of patients with DOORS syndrome, a rare distinct autosomal recessive syndrome with deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures. This finding demonstrates that we have only just scratched the surface of the complicated genetic architecture of human epilepsies. Continue reading

Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy

The other sodium channel gene. The week before Christmas, the Kiel group identified its first patient with SCN2A encephalopathy. At the same time, a questionably benign SNP in the same gene is haunting our Israel Epilepsy Family Project. Time to review the mysterious SCN2A gene that initially entered the scene as a candidate for a rare, benign familial epilepsy syndrome – only to return as one of the most prominent genes for autism, intellectual disability, and epileptic encephalopathies to date. Continue reading

2B or not 2B – mutations in GRIN2B and Infantile Spasms

Year of the glutamate receptor. A few months ago we wrote a post about the triplet of Nature Genetics publications that established GRIN2A mutations as a cause of disorders within the epilepsy aphasia spectrum. GRIN2A codes for the NR2A subunit of the NMDA receptor, one of the most prominent neurotransmitter receptors in the Central Nervous System. Now, a recent paper in the Annals of Neurology reports mutations in the GRIN2B subunit as a cause of Infantile Spasms. Interestingly, the functional consequences of these mutations are completely different from GRIN2A-related epilepsies. Continue reading

Identifying core phenotypes – epilepsy, ID and recurrent microdeletions

Triad. There are three microdeletions in particular that increase the risk for the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE). This triad includes microdeletions at 15q13.3, 16p13.11 and 15q11.2, which are hotspot deletions arising from the particular architecture of the human genome. While the association of these microdeletions with epilepsy and other neurodevelopmental disorders including autism, intellectual disability and schizophrenia is well established, the core phenotype of these variants remains elusive, including the question whether such a core phenotype actually exists. In a recent paper in Neurology, Mullen and collaborators zoom in on a possible core phenotype of these microdeletions. The authors investigate a phenotype in which these microdeletions are particularly enriched: generalized epilepsy with intellectual disability. Continue reading

Dravet Syndrome and rare variants in SCN9A

How monogenic is monogenic? Dravet Syndrome is a severe epileptic encephalopathy starting in the first year of life. More than 80% of patients have mutations or deletions in SCN1A, which makes Dravet Syndrome a relatively homogeneous genetic epilepsy. In addition to SCN1A, other genetic risk factors for Dravet Syndrome have been suggested, and current, large-scale studies including EuroEPINOMICS-RES are studying the genetic basis of the minority of Dravet patients negative for SCN1A. A recent paper in Epilepsia now suggests that a significant fraction of patients with Dravet Syndrome also carry rare variants in SCN9A in addition to the mutations in SCN1A. Is a mutation in SCN1A not sufficient to result in Dravet Syndrome, but needs additional genetic modifiers? Continue reading

Epileptic encephalopathies: de novo mutations take center stage

The de novo paradigm. De novo mutations play a significant role in many neurodevelopmental disorders including autism, intellectual disability and schizophrenia. In addition, several smaller studies have indicated a role for de novo mutations in severe epilepsies. However, unless known genes for human epilepsies are involved, findings from large-scale genetic studies are difficult to interpret. De novo mutations are also seen in unaffected individuals and only very few genes are observed more than once. Now, a publication in Nature by the Epi4K and EPGP collaborators uses a novel framework to tell pathogenic mutations from genomic noise. Their study provides very strong evidence for a predominant role of de novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome. Continue reading

Exome sequencing in epileptic encephalopathies – a classification of de novo mutations

Trio-sequencing your clinic. From the perspective of a child neurology clinic, I often wonder how much information we would gain if we performed trio exome sequencing for de novo mutations systematically in all our patients with difficult-to-treat epilepsies. Many of these patients have epilepsies that are difficult to classify and they have not been included in our existing EuroEPINOMICS working groups on defined syndromes. Now, a recent publication in Epilepsia gives us an idea what we will find if we perform family-based exome sequencing in patients with unclassified epileptic encephalopathies. Basically, you will find SCN1A and CDKL5 plus mutations in several genes that are likely pathogenic. But there is much more to this issue, which motivated me to come up with a classification scheme for epilepsy-related de novo events.  Continue reading

PGAP2 mutations and intellectual disability with elevated alkaline phosphatase

Red flags. Despite the availability of a large panel of metabolic and genetic tests as well as high-resolution neuroimaging, the cause of disease in the vast majority of patients remains unknown. This situation also applies for intellectual disability, where there is little to offer in terms of diagnostic procedures once patients are negative for array comparative genomic hybridization (array CGH). In clinical practice, we often hope that some minor clinical or biochemical features may lead us to the correct diagnosis, but in the majority of cases, these investigations lead nowhere. Now, in two back-to-back publications in the American Journal of Human Genetics, two papers describe PGAP2 mutations in patients with non-syndromal intellectual disability with elevated alkaline phosphatase.  Continue reading