Publications of the week – DOCK7, DEPDC5 and the yield of diagnostic gene panels

This week in epilepsy genetics. The following publications are a selection of what was published in the last week. These studies might be relevant for you because they both extend the phenotype of recent gene findings and describe novel genes that you should be aware of. 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 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

GABRA1 and STXBP1 as novel genes for Dravet Syndrome

Beyond SCN1A. Dravet Syndrome is a severe fever-associated epileptic encephalopathy. While the large majority of patients with Dravet Syndrome carry mutations in the SCN1A gene, the genetic basis is unknown in up to 20% of patients. Some female patients with Dravet-like epilepsies have mutations in PCDH19, but other than this, no additional major gene for typical Dravet Syndrome is known. In a recent paper in Neurology, de novo mutations in GABRA1 and STXBP1 are identified as novel causes for Dravet Syndrome. In addition, several SCN1A-negative patients were shown to have mutations in SCN1A that were initially missed. Continue reading

Papers of the week – DEPDC5, a “female protective model” and rescued KCNT1 mutations

In final week before our EuroEPINOMICS Bild1bioinformatics workshop in Leuven people get a little busy and start reading up on all sorts of things. Accordingly, this week’s papers come from all areas of genetics and life science, including three studies in Annals of Neurology on epilepsy genetics.

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Papers of the week – 15q11 duplications, Olig1 & Automated decision-making

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A productive week in epilepsy genetics.  Scientists and editors were certainly busy this week reporting novel variants and deletions as well the experimental and statistical advances for their interpretation.

A de novo GRIN2A missensmutation in early-onset epileptic encephalopathy. We and others have associated variants affecting the GRIN2A gene with a range of childhood focal epilepsy syndromes. Continue reading

How to become a pediatric neurologist

Milestones. Today I passed my board exam for pediatric neurology or neuropediatrics, as we call it in Germany. Even though I am usually not big on celebrating occasions like this, I wanted to use this blog post to reflect upon a journey that led me to three different continents and started eleven years ago in the foothills of AppalachiaContinue 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

CACNA2D2, the ducky mouse, and what it takes to be an epilepsy gene

Subunit. Spontaneous mouse mutants help to identify candidate genes for disease mechanisms and have hinted at an important role for ion channels in epilepsy long before the first human channelopathies were identified. The ducky mouse has absence seizures and suffers from ataxia. A truncation mutation in CACNA2D2 could be identified in this phenotype, encoding for an auxiliary calcium channel subunit. This finding emphasizes the role of calcium channels in absence seizures and begs the question whether genetic variation in CACNA2D2 is also involved in human epilepsy. A recent publication in PLOS One now identifies the second recessive CACNA2D2 mutation in a patient with epileptic encephalopathy. But are two independent cases sufficient anymore to claim causality? Continue reading