Torsional stress. The DNA double helix has one major problem that we know from telephone cords: it is difficult to untangle. However, our DNA is constantly twisted and untangled for gene transcription. This constant twisting and untwisting produces torsional stress that is relieved by topoisomerases. A recent publication in Nature Genetics now identified a human neurological phenotype that is caused by faulty activity of this mechanism: neurodegeneration with epileptic encephalopathy. However, there are some features of the phenotype that are not easily explained by erroneous DNA twisting. Continue reading
Category Archives: Papers
Three things about 16p11.2 duplications in Rolandic Epilepsy that surprised us
In depth. Last week, we briefly mentioned the publication by Reinthalter and collaborators on 16p11.2 duplications in Benign Rolandic Epilepsy. At first glance, you might think that Eva’s publication may just be another description of a microdeletion in another type of epilepsy. However, nothing could be further from the truth. It’s a game changer. Here are three reasons why. Continue reading
Switching inhibition on – SLC12A5/KCC2 variants in human epilepsy
Inhibition. We usually like to think of GABA as an inhibitory neurotransmitter, which counteracts the excitatory and potentially epileptogenic effects of glutamate. However, this is not always true during brain development. Initially, GABA is a powerful excitatory neurotransmitter. The excitatory effect of GABA has been shown to be important for brain development and the formation of dendritic spines – and the switch from excitation to inhibition is due to a single ion channel: KCC2, encoded by SLC12A5. Two recent publications in EMBO Reports now implicate genetic variation in SLC12A5 in human epilepsy. Continue reading
What neuronal membranes are made of – CERS1 in progressive myoclonus epilepsy
Ceramide. Sphingolipids are a major component of neuronal membranes and help neurons in intracellular signaling and trafficking. Ceramide is one of the basic building blocks of sphingolipids. In a recent publication in Annals of Neurology, mutations in CERS1, coding for ceramide synthetase, are identified in a family with progressive myoclonus epilepsy – and provides an unexpected linked between a group of storage disorders such as Niemann-Pick disease and Tay-Sachs disease and progressive myoclonus epilepsies. Continue reading
SLC25A22, migrating seizures and mitochrondial glutamate deficiency
MPSI. Migrating partial seizures of infancy (MPSI) are a catastrophic form of infantile epilepsy that was entirely unexplained until de novo mutations in KCNT1 were identified in a subset of sporadic cases in 2012. For familial MPSI, however, the genetic basis remained unknown. In a recent publication in Annals of Neurology, Poduri and collaborators identify mutations in SCL25A22 in a family with recessive MPSI. Their study sheds light on the genetic basis of catastrophic epilepsies and the phenotypic range of mitochondrial glutamate starvation. Continue reading
The many faces of PIGA – from paroxysmal nocturnal hemoglobinuria to epileptic encephalopathy
PNH. PIGA codes for a protein involved in the early steps of GPI anchor synthesis, hydrophobic anchors that are attached to a range of proteins, which allows them to be attached to the membrane. This mechanism is important for protein sorting in the endoplasmatic reticulum and the Golgi apparatus. Acquired mutations in PIGA are known to cause paroxysmal nocturnal hemoglobinuria (PNH), an anemia due to destruction of red blood cells. In a recent paper in Neurology, de novo mutations in PIGA are now identified in a complex genetic syndrome, which has early-onset intractable epilepsy as the most prominent feature. 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
Imbalance of a rare second messenger – FIG4 mutations in polymicrogyria
Brain malformations. Various brain malformations are thought to have a genetic basis, and several genes have already been identified. Polymicrogyria is a particular form of congenital brain malformation due to an excessive number of small and sometimes malformed gyri. In a recent publication in Neurology, mutations in FIG4 are described in a familial form of polymicrogyria. However, the FIG4 gene is no stranger in the field of neurogenetics. Continue reading
DUF1220, autism, and highly dosage-variable genes
Copy numbers. When we discuss structural genomic variants in the human genome on the Channelopathist blog, we usually refer to regions where simple deletions or duplications exert a pathogenic effect. However, there are also genes that are highly copy number variable, sometimes present at 80 copies or more. Copy numbers of a few of these genes have expanded during human evolution recently, turning these genes into potential candidate genes for human disease. A recent paper in PLOS Genetics now examines the role of DUF1220, which encodes a protein domain of the NBPF genes. This domain shows an unusually broad range of copy number variation in the human genome. Interestingly, this gene resides right next to the 1q21.1 region that is implicated in various neurodevelopmental disorders. Continue reading
Hidden neurometabolic disorders – the expanding spectrum of PNPO deficiency
Pyridoxal 5’-phosphate (PLP). PNPO deficiency is a rare neurometabolic disease that presents with severe neonatal epilepsy responsive to pyridoxal phosphate. While the classical clinical presentation is well described, there might be milder versions of this potentially treatable neurometabolic disease that have not been recognized so far. In a recent publication in Brain, the phenotypic spectrum of PNPO deficiency is revisited. In addition to the classical neonatal phenotype, the authors identify patients with later onset and atypical response to pyridoxal phosphate. In addition, they identify a rare, potentially causative PNPO variant that probably gets stuck in most exome filtering pipelines. Continue reading
