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

The ARX problem – how an epilepsy gene escapes exome sequencing

Silence. You might wonder why you hear very little about ARX in exome studies these days. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Mutations in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, it’s on the differential list for patients with Infantile Spasms without a known cause. Let me tell you about the problems that the ARX gene poses for exome sequencing. Continue reading

SCN1A – This is what you need to know in 2014

Update. As information on the epilepsies caused by SCN1A mutations are amongst our most frequently read posts, we thought that a quick update on the state-of-the art regarding SCN1A would be timely. These are the ten things about SCN1A that you should known in 2014. Continue reading

The OMIM epileptic encephalopathy genes – a 2014 review

EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading

The final EuroEPINOMICS General Assembly – Impressions from Helsinki

Time flies by. Last week, we have had the final General Assembly of the EuroEPINOMICS project in Tuusula, Finland. All four projects of the EuroEPINOMICS consortium presented the current, ongoing projects and it’s good to hear that there are multiple publications in various stages coming up. Over the three years of the consortium, the diverse groups grew closer together. During this meeting many unpublished results were shown, including extension of studies on genes such as HCN1, CHD2GRIN2A, GRIN2B or RBFOX1 as well as more data on epigenetics in acquired epilepsy.

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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

QARS mutations, tRNA, and neurodegeneration with migrating seizures

Q for glutamine. Transfer RNAs (tRNAs) are small adaptor molecules that match a nucleotide sequence to a given amino acid during protein translation. After unloading their amino acid payload, tRNAs are recharged with new amino acids through specific tRNA synthetases. Q is the official letter for the amino acid glutamine, and its respective tRNA synthetase is glutaminyl-tRNA synthetase (QARS). In a recent publication in the American Journal of Human Genetics, Zhang and colleagues identify compound heterozygous mutations in the QARS gene in two families with progressive microcephaly, neurodegeneration, and intractable, early-onset epilepsy. Interestingly, in at least two probands, the seizures are described as migrating partial seizures reminiscent of Malignant Migrating Partial Seizures of Infancy (MMPSI) due to mutations in KCNT1. The disease mechanism, however, appears to be entirely different. Continue reading