Structure. Despite tremendous advances in understanding its genetic underpinnings in the last few years, electrical status epilepticus during slow-wave sleep (ESES) is a poorly understood neurodevelopmental disorder and to a certain extent the prototype of an epileptic encephalopathy. Slow-wave sleep in affected children is entirely replaced by epileptiform activity, leading to significant neurocognitive impairment with an emphasis on speech impairment. In a recent publication in Annals of Neurology, alterations in CNKSR2 are identified in families with a more severe course of ESES, highlighting the postsynapse as a possible player in ESES pathogenesis. Continue reading
Category Archives: autism
Publications of the week – SRP9, Nebulin, and Kuf’s disease
Issue 2/2015. For the second issue of our publications of the week in 2015, we have selected recent publications on the genetics of Febrile Seizures, the complexities of interpreting variants in large genes and functional studies on progressive myoclonus epilepsies due to mutations in SCARB2 and CTSF. Continue reading
SCN8A encephalopathy – and how it differs from Dravet Syndrome
Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading
What is the genomic blind spot?
Beneath the surface. Even though the comprehensiveness of next generation sequencing technologies may suggest that we can capture all the variation in the human genome, there is an entire gray zone of small rearrangements that current technologies are blind to. In a recent publication in the American Journal of Human Genetics, Brand and collaborators now use a novel technology to explore the twilight zone of genomics, the realm of small deletions, duplication, inversions and cryptic complex rearrangements. Continue reading
SETBP1, ZMYND11, and the power of joint exome and CNV analysis
Parallel worlds. There are two fields of genetics for neurodevelopmental disorders that currently produce large amounts of data – the field of copy number variation analysis and the field of exome sequencing. When assigning pathogenicity, information from both genetic technologies are rarely considered jointly. A recent study in Nature Genetics now performs a combined analysis of a large CNV and exome datasets in intellectual disability and autism. Interestingly, this method produces robust results, highlighting novel causative genes. Continue reading
The 1003 possible autism genes – a matter of constraint
Overview. There have been numerous publications on de novo mutations in autism and intellectual disability over the last three years. Many of these studies struggle to distinguish signal from noise, and the plethora of findings leaves the reader wondering which genes are bona fide autism genes and in which cases the evidence is limited. A recent paper in Nature Genetics uses a new metric to assess expected versus observed de novo mutations in more than published 1000 autism patient-parent trios – and the answers appear to be straightforward. Continue reading
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
GPHN deletions in IGE and mutation-dependent recessive inheritance
Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. 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
Papers of the week – Encephalitis-antibodies, FAN1, Art and Parent-of-Origin Effects
Biggest surprise this week: Imprinted genes interact with non-imprinted genes frequently. But first sequencing reports, statistical frameworks for rare variants analyzes and an impressive translational result.
A novel encephalitis with seizures and the analysis of the effects of antibodies. In their study published in LANCET NEUROLOGY Petit-Pedrol and coworkers characterized serum and CSF samples for antigens in 140 patients with encephalitis, seizures or status epilepticus as well as antibodies to unknown neurophil antigens. High titres of serum and CSF GABAA receptor antibodies are reported to be associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both, which could be exploited for immunotherapy with 15 patients.
