The top three publications in epilepsy genetics 25 years ago

Looking back. In this week’s ILAE Genetics Commission post, we would like to look 25 years back and examine the most important publication in the field in 1989, the year the Berlin wall fell. What concepts did we have back then and how did our understanding of epilepsy and genes change? Here are the top three publications of 1989. 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

How genome sequencing in intellectual disability breaks the 50% boundary

Exome failures. Trio exome sequencing has the huge potential to discover the genetic basis of neurodevelopmental disorders. However, the results are negative for the majority of patients. In a recent study published in Nature, genome sequencing was applied to exome-negative patients with intellectual disability, identifying mutations in coding regions that were previously missed. But are the authors correct in stating that they can explain more than 60% of cases in an unselected cohort? 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 – 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